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Sample records for fetal liver induced

  1. Comparative retention of fission fragment 147Pm in regenerated and fetal liver on induction of chromosome aberrations in these cells

    International Nuclear Information System (INIS)

    Zhu Shoupeng; Zheng Siying; Wang Liuyi; Yang Shujin

    1989-01-01

    The purpose of the present study is to ascertain comparative retention of fission fragment 147 Pm in regenerated and fetal liver on induction of chromosome aberrations in these cells. The results indicated that retention of 147 Pm in regenerated liver was about 700 times than in fetal liver. The cumulative absorption dose in regenerated liver was about 2.87 Gy, while in fetal liver-only 0.004 Gy. Under the same conditions, the incidence rate of chromosome aberrations in regenerated liver cells induced by 147 Pm was 50.2%, and in fetal liver cells-about 28.3%. It should be concluded that the radiosensitivity to 147 Pm was not uniform among the regenerated and fetal liver cells. The study suggested that fetal liver cells show to be more radiosensitive to 147 Pm than regenerated liver cells. Among the type of aberrations in both cells induced by 147 Pm, chromatid breakages were predominant, accompanied with a few chromosome breakages

  2. Fetal liver T2* values: defining a standardized scale.

    Science.gov (United States)

    Goitein, Orly; Eshet, Yael; Hoffmann, Chen; Raviv-Zilka, Lisa; Salem, Yishay; Hamdan, Ashraf; Goitein, David; Kushnir, Tamar; Eshed, Iris; Di-Segni, Elio; Konen, Eli

    2013-12-01

    To define the normal T2* values of liver in the third trimester of pregnancy in normal fetuses. Multi-echo gradient echo T2* sequence was applied to the fetal abdomen in the axial plane in women undergoing a fetal MRI (1.5 Tesla [T], MRI system). A region of interest, best visualizing in the liver parenchyma was used for measurements. Studies were independently read by two experienced readers to assess intra- and interobserver variability. The study cohort included 46 pregnant women undergoing fetal MRI for any indication other than liver pathology evaluation. Three scans were excluded due to fetal motion. Average maternal and gestational age were 33 ± 4 years and 31.9 ± 3 weeks, respectively. Average T2* values were found to be 19.7 ± 7.4 ms. The intra- and interobserver agreement were very good: 0.93 and 0.8-0.084, respectively. T2* MRI allows noninvasive evaluation liver iron content in the third trimester fetus. Measured values at this stage of pregnancy are significantly lower compared with values cited in the literature for adults. This is of major importance in the correct diagnosis of fetal iron overload states. We propose this as the standard reference when evaluating fetal iron overload pathology. Copyright © 2013 Wiley Periodicals, Inc.

  3. File list: His.Liv.20.AllAg.Fetal_liver [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Liv.20.AllAg.Fetal_liver hg19 Histone Liver Fetal liver SRX860907,SRX860899,SRX...860908,SRX860905,SRX860900,SRX860906,SRX860904,SRX860903,SRX860902,SRX860901 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Liv.20.AllAg.Fetal_liver.bed ...

  4. File list: ALL.Liv.50.AllAg.Fetal_liver [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Liv.50.AllAg.Fetal_liver hg19 All antigens Liver Fetal liver SRX860899,SRX86090...7,SRX860905,SRX860900,SRX860903,SRX860906,SRX860904,SRX860908,SRX860902,SRX860901 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Liv.50.AllAg.Fetal_liver.bed ...

  5. File list: ALL.Liv.10.AllAg.Fetal_liver [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Liv.10.AllAg.Fetal_liver hg19 All antigens Liver Fetal liver SRX860905,SRX86090...7,SRX860901,SRX860899,SRX860900,SRX860904,SRX860903,SRX860908,SRX860906,SRX860902 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Liv.10.AllAg.Fetal_liver.bed ...

  6. File list: His.Liv.50.AllAg.Fetal_liver [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Liv.50.AllAg.Fetal_liver hg19 Histone Liver Fetal liver SRX860899,SRX860907,SRX...860905,SRX860900,SRX860903,SRX860906,SRX860904,SRX860908,SRX860902,SRX860901 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Liv.50.AllAg.Fetal_liver.bed ...

  7. File list: His.Liv.05.AllAg.Fetal_liver [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Liv.05.AllAg.Fetal_liver hg19 Histone Liver Fetal liver SRX860905,SRX860904,SRX...860907,SRX860901,SRX860900,SRX860908,SRX860899,SRX860906,SRX860903,SRX860902 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Liv.05.AllAg.Fetal_liver.bed ...

  8. File list: His.Liv.10.AllAg.Fetal_liver [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Liv.10.AllAg.Fetal_liver hg19 Histone Liver Fetal liver SRX860905,SRX860907,SRX...860901,SRX860899,SRX860900,SRX860904,SRX860903,SRX860908,SRX860906,SRX860902 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Liv.10.AllAg.Fetal_liver.bed ...

  9. File list: ALL.Liv.05.AllAg.Fetal_liver [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Liv.05.AllAg.Fetal_liver hg19 All antigens Liver Fetal liver SRX860905,SRX86090...4,SRX860907,SRX860901,SRX860900,SRX860908,SRX860899,SRX860906,SRX860903,SRX860902 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Liv.05.AllAg.Fetal_liver.bed ...

  10. File list: ALL.Liv.20.AllAg.Fetal_liver [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available ALL.Liv.20.AllAg.Fetal_liver hg19 All antigens Liver Fetal liver SRX860907,SRX86089...9,SRX860908,SRX860905,SRX860900,SRX860906,SRX860904,SRX860903,SRX860902,SRX860901 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/ALL.Liv.20.AllAg.Fetal_liver.bed ...

  11. Antithyroid drug-induced fetal goitrous hypothyroidism

    DEFF Research Database (Denmark)

    Bliddal, Sofie; Rasmussen, Ase Krogh; Sundberg, Karin

    2011-01-01

    Maternal overtreatment with antithyroid drugs can induce fetal goitrous hypothyroidism. This condition can have a critical effect on pregnancy outcome, as well as on fetal growth and neurological development. The purpose of this Review is to clarify if and how fetal goitrous hypothyroidism can...... be prevented, and how to react when prevention has failed. Understanding the importance of pregnancy-related changes in maternal thyroid status when treating a pregnant woman is crucial to preventing fetal goitrous hypothyroidism. Maternal levels of free T(4) are the most consistent indication of maternal...... and fetal thyroid status. In patients with fetal goitrous hypothyroidism, intra-amniotic levothyroxine injections improve fetal outcome. The best way to avoid maternal overtreatment with antithyroid drugs is to monitor closely the maternal thyroid status, especially estimates of free T(4) levels....

  12. Development of the liver during the fetal period

    International Nuclear Information System (INIS)

    Albay, S.; Malas, Mehmet A.; Cetin, E.; Cankara, N.; Karahan, N.

    2005-01-01

    To investigate the development of the liver in human fetuses aged between 9-40 weeks. We studied 121 human fetuses (62 males, 59 females) with no external anomalies aged between 9-40 postmenstrual weeks during 2003-2004 in Suleyman Demirel University, Isparta, Turkey. The fetuses were divided into four groups as 1st, 2nd and 3rd trimesters and full term fetuses. We measured fetal weight, length, width, thickness, and volume of the liver. We established localization of the liver and its relation with the neighboring structures, its ligaments, and size of itself and its lobes, shapes of the liver and the localization of the porta hepatis on the visceral surface of the liver. We found significant correlations between the size, weight, volume of the liver, sizes of its lobe and gestational age (p 0.05). However, the proportion of the distance between the porta hepatis and the upper margin to the distance between the porta hepatis and the lower margin decreased significantly with gestational age (p<0.05). Type 3 liver (square) was the most commonly observed type of fetal liver (53%). Our opinion is that the parameters obtained can be useful to diagnose pathologies of liver development and anomalies concerning several branches of medicine such as anatomy, pathologic anatomy (fetopathology), forensic medicine, medical imaging, obstetrics and pediatrics. (author)

  13. T cell progenitors in the mouse fetal liver

    International Nuclear Information System (INIS)

    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

  14. Fetal liver stromal cells promote hematopoietic cell expansion

    International Nuclear Information System (INIS)

    Zhou, Kun; Hu, Caihong; Zhou, Zhigang; Huang, Lifang; Liu, Wenli; Sun, Hanying

    2009-01-01

    Future application of hematopoietic stem and progenitor cells (HSPCs) in clinical therapies largely depends on their successful expansion in vitro. Fetal liver (FL) is a unique hematopoietic organ in which hematopoietic cells markedly expand in number, but the mechanisms involved remain unclear. Stromal cells (StroCs) have been suggested to provide a suitable cellular environment for in vitro expansion of HSPCs. In this study, murine StroCs derived from FL at E14.5, with a high level of Sonic hedgehog (Shh) and Wnt expression, were found to have an increased ability to support the proliferation of HSPCs. This effect was inhibited by blocking Shh signaling. Supplementation with soluble Shh-N promoted the proliferation of hematopoietic cells by activating Wnt signaling. Our findings suggest that FL-derived StroCs support proliferation of HSPCs via Shh inducing an autocrine Wnt signaling loop. The use of FL-derived StroCs and regulation of the Shh pathway might further enhance HPSC expansion.

  15. The effect of copper deficiency on fetal growth and liver anti-oxidant capacity in the Cohen diabetic rat model

    Energy Technology Data Exchange (ETDEWEB)

    Ergaz, Zivanit, E-mail: zivanit@hadassah.org.il [Hebrew University Hadassah Medical School, Jerusalem (Israel); Shoshani-Dror, Dana [Hebrew University Hadassah Medical School, Jerusalem (Israel); Guillemin, Claire [Department of Pharmacology and Therapeutics, McGill University, Montreal (Canada); Neeman-azulay, Meytal; Fudim, Liza [Hebrew University Hadassah Medical School, Jerusalem (Israel); Weksler-Zangen, Sarah [Diabetes Research Unit, Hebrew University Hadassah Medical School and Hospital, Jerusalem (Israel); Stodgell, Christopher J.; Miller, Richard K. [Department of Obstetrics and Gynecology, University of Rochester, Rochester, MN (United States); Ornoy, Asher [Hebrew University Hadassah Medical School, Jerusalem (Israel)

    2012-12-01

    High sucrose low copper diet induces fetal growth restriction in the three strains of the Cohen diabetic rats: an inbred copper deficient resistant (CDr), an inbred copper deficient sensitive (CDs that become diabetic on high sucrose low copper diet -HSD) and an outbred Wistar derived Sabra rats. Although those growth restricted fetuses also exhibit increased oxidative stress, antioxidants do not restore normal growth. In the present study, we evaluated the role of copper deficiency in the HSD induced fetal growth restriction by adding to the drinking water of the rats 1 ppm or 2 ppm of copper throughout their pregnancy. Fetal and placental growth in correlation with fetal liver copper content and anti-oxidant capacity was evaluated on day 21 of pregnancy. HSD compared to regular chow induced fetal growth restriction, which was most significant in the Cohen diabetic sensitive animals. The addition of 1 ppm and 2 ppm copper to the drinking water normalized fetal growth in a dose dependent manner and reduced the degree of hyperglycemia in the diabetes sensitive rats. The CDs fetuses responded to the HSD with lower catalase like activity, and less reduced superoxide dismutase levels compared to the Sabra strain, and had high malondialdehyde levels even when fed regular chow. Immunostaining was higher for nitrotyrosine among the CDr and higher for hypoxia factor 1 α among the CDs. We conclude that in our model of dietary-induced fetal growth restriction, copper deficiency plays a major etiologic role in the decrease of fetal growth and anti-oxidant capacity. -- Highlights: ► High sucrose low copper diet restricted fetal growth in the Cohen diabetic rat model ► Maternal copper blood levels directly correlated with fetal liver copper content ► Copper supplementation decreased embryonic resorption in the inbred strains ► Copper supplementation reduced hyperglycemia in the sucrose sensitive inbred strain ► Copper supplementation alleviated growth restriction and

  16. The effect of copper deficiency on fetal growth and liver anti-oxidant capacity in the Cohen diabetic rat model

    International Nuclear Information System (INIS)

    Ergaz, Zivanit; Shoshani-Dror, Dana; Guillemin, Claire; Neeman-azulay, Meytal; Fudim, Liza; Weksler-Zangen, Sarah; Stodgell, Christopher J.; Miller, Richard K.; Ornoy, Asher

    2012-01-01

    High sucrose low copper diet induces fetal growth restriction in the three strains of the Cohen diabetic rats: an inbred copper deficient resistant (CDr), an inbred copper deficient sensitive (CDs that become diabetic on high sucrose low copper diet -HSD) and an outbred Wistar derived Sabra rats. Although those growth restricted fetuses also exhibit increased oxidative stress, antioxidants do not restore normal growth. In the present study, we evaluated the role of copper deficiency in the HSD induced fetal growth restriction by adding to the drinking water of the rats 1 ppm or 2 ppm of copper throughout their pregnancy. Fetal and placental growth in correlation with fetal liver copper content and anti-oxidant capacity was evaluated on day 21 of pregnancy. HSD compared to regular chow induced fetal growth restriction, which was most significant in the Cohen diabetic sensitive animals. The addition of 1 ppm and 2 ppm copper to the drinking water normalized fetal growth in a dose dependent manner and reduced the degree of hyperglycemia in the diabetes sensitive rats. The CDs fetuses responded to the HSD with lower catalase like activity, and less reduced superoxide dismutase levels compared to the Sabra strain, and had high malondialdehyde levels even when fed regular chow. Immunostaining was higher for nitrotyrosine among the CDr and higher for hypoxia factor 1 α among the CDs. We conclude that in our model of dietary-induced fetal growth restriction, copper deficiency plays a major etiologic role in the decrease of fetal growth and anti-oxidant capacity. -- Highlights: ► High sucrose low copper diet restricted fetal growth in the Cohen diabetic rat model ► Maternal copper blood levels directly correlated with fetal liver copper content ► Copper supplementation decreased embryonic resorption in the inbred strains ► Copper supplementation reduced hyperglycemia in the sucrose sensitive inbred strain ► Copper supplementation alleviated growth restriction and

  17. Fetal liver iron overload: the role of MR imaging

    International Nuclear Information System (INIS)

    Cassart, Marie; Avni, Freddy Efraim; Guibaud, Laurent; Molho, Marc; D'Haene, Nicky; Paupe, Alain

    2011-01-01

    To assess the potential role of MR imaging in the diagnosis of fetal liver iron overload. We reviewed seven cases of abnormal liver signal in fetuses referred to MR imaging in a context of suspected congenital infection (n = 2), digestive tract anomalies (n = 3) and hydrops fetalis (n = 2). The average GA of the fetuses was 31 weeks. The antenatal diagnoses were compared with histological data (n = 6) and postnatal work-up (n = 1). Magnetic resonance imaging demonstrated unexpected abnormal fetal liver signal suggestive of iron overload in all cases. The iron overload was confirmed on postnatal biopsy (n = 2) and fetopathology (n = 4). The final diagnosis was hepatic hemosiderosis (haemolytic anaemia (n = 2) and syndromal anomalies (n = 2)) and congenital haemochromatosis (n = 3). In all cases, the liver appeared normal on US. Magnetic resonance is the only imaging technique able to demonstrate liver iron overload in utero. Yet, the study outlines the fundamental role of MR imaging in cases of congenital haemochromatosis. The antenatal diagnosis of such a condition may prompt ante - (in the case of recurrence) or neonatal treatment, which might improve the prognosis. (orig.)

  18. Fetal liver iron overload: the role of MR imaging

    Energy Technology Data Exchange (ETDEWEB)

    Cassart, Marie; Avni, Freddy Efraim [Erasme Hospital, Medical imaging, Brussels, Brabant (Belgium); Guibaud, Laurent [Hopital femme mere enfant, Imagerie Pediatrique et Foetale, Lyon-Bron (France); Molho, Marc [C.H.I Poissy/St Germain-en-Laye, Imagerie Medicale, Poissy (France); D' Haene, Nicky [Erasme Hospital, Anatomopathology Department, Brussels (Belgium); Paupe, Alain [C.H.I Poissy/St Germain-en-Laye, Pediatrie, Poissy (France)

    2011-02-15

    To assess the potential role of MR imaging in the diagnosis of fetal liver iron overload. We reviewed seven cases of abnormal liver signal in fetuses referred to MR imaging in a context of suspected congenital infection (n = 2), digestive tract anomalies (n = 3) and hydrops fetalis (n = 2). The average GA of the fetuses was 31 weeks. The antenatal diagnoses were compared with histological data (n = 6) and postnatal work-up (n = 1). Magnetic resonance imaging demonstrated unexpected abnormal fetal liver signal suggestive of iron overload in all cases. The iron overload was confirmed on postnatal biopsy (n = 2) and fetopathology (n = 4). The final diagnosis was hepatic hemosiderosis (haemolytic anaemia (n = 2) and syndromal anomalies (n = 2)) and congenital haemochromatosis (n = 3). In all cases, the liver appeared normal on US. Magnetic resonance is the only imaging technique able to demonstrate liver iron overload in utero. Yet, the study outlines the fundamental role of MR imaging in cases of congenital haemochromatosis. The antenatal diagnosis of such a condition may prompt ante - (in the case of recurrence) or neonatal treatment, which might improve the prognosis. (orig.)

  19. Fetal responses to induced maternal relaxation during pregnancy

    OpenAIRE

    DiPietro, Janet A.; Costigan, Kathleen A.; Nelson, Priscilla; Gurewitsch, Edith D.; Laudenslager, Mark L.

    2007-01-01

    Fetal responses to induced maternal relaxation during the 32nd week of pregnancy were recorded in 100 maternal-fetal pairs using a digitized data collection system. The 18-minute guided imagery relaxation manipulation generated significant changes in maternal heart rate, skin conductance, respiration period, and respiratory sinus arrhythmia. Significant alterations in fetal neurobehavior were observed, including decreased fetal heart rate (FHR), increased FHR variability, suppression of fetal...

  20. Dysregulation of the DNA Damage Response and KMT2A Rearrangement in Fetal Liver Hematopoietic Cells.

    Directory of Open Access Journals (Sweden)

    Mai Nanya

    Full Text Available Etoposide, a topoisomerase 2 (TOP2 inhibitor, is associated with the development of KMT2A (MLL-rearranged infant leukemia. An epidemiological study suggested that in utero exposure to TOP2 inhibitors may be involved in generation of KMT2A (MLL rearrangement. The present study examined the mechanism underlying the development of KMT2A (MLL-rearranged infant leukemia in response to in utero exposure to etoposide in a mouse model. Fetal liver hematopoietic stem cells were more susceptible to etoposide than maternal bone marrow mononuclear cells. Etoposide-induced Kmt2a breakage was detected in fetal liver hematopoietic stem cells using a newly developed chromatin immunoprecipitation (ChIP assay. Assessment of etoposide-induced chromosomal translocation by next-generation RNA sequencing (RNA-seq identified several chimeric fusion messenger RNAs that were generated by etoposide treatment. However, Kmt2a (Mll-rearranged fusion mRNA was detected in Atm-knockout mice, which are defective in the DNA damage response, but not in wild-type mice. The present findings suggest that in utero exposure to TOP2 inhibitors induces Kmt2a rearrangement when the DNA damage response is defective.

  1. Synthesis of erythrocyte membrane proteins in dispersed cells from fetal rat liver

    International Nuclear Information System (INIS)

    Kitagawa, Yasuo; Murakami, Akihiko; Sugimoto, Etsuro

    1984-01-01

    Protein synthesis in dispersed cells from fetal liver was studied by fluorography of SDS-polyacrylamide gel electrophoresis of a [ 35 S] methionine labeled cell lysate. Synthesis of several proteins with molecular weights ranging from 45,000 to 220,000 was observed during erythropoiesis in fetal liver. Some of these proteins were demonstrated to be erythrocyte membrane proteins because they were immunoprecipitated with antiserum against rat red blood cells and the immunoprecipitation was competitive with non-radioactive proteins solubilized from erythrocyte ghosts. The same antiserum caused agglutination of dispered cells from fetal liver. This supported the possibility that these proteins are translocated onto plasma membranes of the dispersed cells. (author)

  2. Fetal responses to induced maternal relaxation during pregnancy.

    Science.gov (United States)

    DiPietro, Janet A; Costigan, Kathleen A; Nelson, Priscilla; Gurewitsch, Edith D; Laudenslager, Mark L

    2008-01-01

    Fetal responses to induced maternal relaxation during the 32nd week of pregnancy were recorded in 100 maternal-fetal pairs using a digitized data collection system. The 18-min guided imagery relaxation manipulation generated significant changes in maternal heart rate, skin conductance, respiration period, and respiratory sinus arrhythmia. Significant alterations in fetal neurobehavior were observed, including decreased fetal heart rate (FHR), increased FHR variability, suppression of fetal motor activity (FM), and increased FM-FHR coupling. Attribution of the two fetal cardiac responses to the guided imagery procedure itself, as opposed to simple rest or recumbency, is tempered by the observed pattern of response. Evaluation of correspondence between changes within individual maternal-fetal pairs revealed significant associations between maternal autonomic measures and fetal cardiac patterns, lower umbilical and uterine artery resistance and increased FHR variability, and declining salivary cortisol and FM activity. Potential mechanisms that may mediate the observed results are discussed.

  3. Abacavir-induced liver toxicity

    Directory of Open Access Journals (Sweden)

    Maria Diletta Pezzani

    2016-09-01

    Full Text Available Abacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine.

  4. Cadmium-induced fetal toxicity in the rat

    International Nuclear Information System (INIS)

    Levin, A.A.

    1980-01-01

    Cadmium, a heavy metal environment contaminant, induces fetal death and placental necrosis in the Wistar rat. This study investigated fetal, maternal, and placental responses to cadmium intoxication. Subcutaneous injection of CdCl 2 to dams on day 18 of pregnancy produced a high incidence of fetal death (75%) and placental necrosis. Death in the fetus was produced despite limited fetal accumulations of cadmium. Distribution studies using 109 Cd-labeled CdCl 2 demonstrated that less than 0.1% of the injected dose was associated with the fetus. To determine if fetuses were sensitive to these low levels of cadmium, direct injections of CdCl 2 into fetuses were performed in utero. Direct injections produced fetal accumulations 8-fold greater than those following maternal injections. The 8-fold greater fetal accumulations following direct injection were associated with only a 12% fetal mortality compared to the 75% mortality following maternal injections. The data indicated that the fetal toxicity of cadmium following maternal injections was not the result of direct effects of cadmium on the fetus. In conclusion, cadmium-induced fetal death was not the result of direct effects of cadmium on the fetus but may have been induced by placental cellular injury resulting from high accumulations of cadmium in the placenta. A vascular response to placental injury, leading to decreased utero-placental bood flow and cadmium-induced alterations in trophoblastic function, resulted in fetal death

  5. Gestational exposure to BDE-99 produces toxicity through upregulation of CYP isoforms and ROS production in the fetal rat liver.

    Science.gov (United States)

    Blanco, Jordi; Mulero, Miquel; Domingo, José L; Sánchez, Domènec J

    2012-05-01

    On gestation day (GD) 6 to GD 19, pregnant Sprague Dawley rats were orally exposed to 0, 0.5, 1, and 2 mg/kg/day to one of the most prevalent polybrominated diphenyl ethers congeners found in humans, 2,2',4,4',5-pentaBDE (BDE-99). All dams were euthanized on GD 20, and live fetuses were evaluated for sex, body weight, and external, internal, and skeletal malformations and developmental variations. The liver from one fetus of each litter was excised for the evaluation of oxidative stress markers and the messenger RNA expression of multiple cytochrome P450 (CYP) isoforms. Exposure to BDE-99 during the gestational period produced delayed ossification, slight hypertrophy of the heart, and enlargement of the liver in fetuses. A transplacental effect of BDE-99, evidenced by the activation of nuclear hormones receptors that induce the upregulation of CYP1A1, CYP1A2, CYP2B1, and CYP3A2 isoforms, was also found in fetal liver. These isoforms are correlated with the activity level of the enzyme catalase and the levels of thiobarbituric acid reactive substances. However, teratogenic effects from BDE-99 exposure were not observed. Clear signs of embryo/fetal toxicity, due to a possible hormonal disruption, were evidenced by a large increase in the CYP system and the production of reactive oxygen species in fetal liver.

  6. Morphology and morphometry of fetal liver at 16-26 weeks of gestation by magnetic resonance imaging: Comparison with embryonic liver at Carnegie stage 23.

    Science.gov (United States)

    Hamabe, Yui; Hirose, Ayumi; Yamada, Shigehito; Uwabe, Chigako; Okada, Tomohisa; Togashi, Kaori; Kose, Katsumi; Takakuwa, Tetsuya

    2013-06-01

    Normal liver growth was described morphologically and morphometrically using magnetic resonance imaging (MRI) data of human fetuses, and compared with embryonic liver to establish a normal reference chart for clinical use. MRI images from 21 fetuses at 16-26 weeks of gestation and eight embryos at Carnegie stage (CS)23 were investigated in the present study. Using the image data, the morphology of the liver as well as its adjacent organs was extracted and reconstructed three-dimensionally. Morphometry of fetal liver growth was performed using simple regression analysis. The fundamental morphology was similar in all cases of the fetal livers examined. The liver tended to grow along the transversal axis. The four lobes were clearly recognizable in the fetal liver but not in the embryonic liver. The length of the liver along the three axes, liver volume and four lobes correlated with the bodyweight (BW). The morphogenesis of the fetal liver on the dorsal and caudal sides was affected by the growth of the abdominal organs, such as the stomach, duodenum and spleen, and retroperitoneal organs, such as the right adrenal gland and right kidney. The main blood vessels such as inferior vena cava, portal vein and umbilical vein made a groove on the surface of the liver. Morphology of the fetal liver was different from that of the embryonic liver at CS23. The present data will be useful for evaluating the development of the fetal liver and the adjacent organs that affect its morphology. © 2012 The Japan Society of Hepatology.

  7. Drug-induced liver injury

    DEFF Research Database (Denmark)

    Nielsen, Mille Bækdal; Ytting, Henriette; Skalshøi Kjær, Mette

    2017-01-01

    OBJECTIVE: The idiosyncratic subtype of drug-induced liver injury (DILI) is a rare reaction to medical treatment that in severe cases can lead to acute liver failure and death. The aim of this study was to describe the presentation and outcome of DILI and to identify potential predictive factors...... that DILI may be severe and run a fatal course, and that bilirubin and INR levels may predict poor outcome....

  8. Long-lasting inhibitory effects of fetal liver mesenchymal stem cells on T-lymphocyte proliferation.

    Directory of Open Access Journals (Sweden)

    Massimo Giuliani

    Full Text Available Human bone marrow mesenchymal stem cells (BM-MSC are multipotent progenitor cells that have transient immunomodulatory properties on Natural Killer (NK cells, Dendritic Cells (DC, and T cells. This study compared the use of MSC isolated from bone marrow and fetal liver (FL-MSC to determine which displayed the most efficient immunosuppressive effects on T cell activation. Although both types of MSC exhibit similar phenotype profile, FL-MSC displays a much more extended in vitro life-span and immunomodulatory properties. When co-cultured with CD3/CD28-stimulated T cells, both BM-MSC and FL-MSC affected T cell proliferation by inhibiting their entry into the cell cycle, by inducing the down-regulation of phospho-retinoblastoma (pRb, cyclins A and D1, as well as up-regulating p27(kip1 expression. The T cell inhibition by MSC was not due to the soluble HLA-G5 isoform, but to the surface expression of HLA-G1, as shown by the need of cell-cell contact and by the use of neutralizing anti-HLA-G antibodies. To note, in a HLA-G-mediated fashion, MSC facilitated the expansion of a CD4(low/CD8(low T subset that had decreased secretion of IFN-γ, and an induced secretion of the immunomodulatory cytokine IL-10. Because of their longer lasting in vitro immunosuppressive properties, mainly mediated by HLA-G, and their more efficient induction of IL-10 production and T cell apoptosis, fetal liver MSC could be considered a new tool for MSC therapy to prevent allograft rejection.

  9. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

    Science.gov (United States)

    Woodman, Andrew G; Mah, Richard; Keddie, Danae; Noble, Ronan M N; Panahi, Sareh; Gragasin, Ferrante S; Lemieux, Hélène; Bourque, Stephane L

    2018-06-01

    Prenatal iron deficiency alters fetal developmental trajectories, which results in persistent changes in organ function. Here, we studied the effects of prenatal iron deficiency on fetal kidney and liver mitochondrial function. Pregnant Sprague-Dawley rats were fed partially or fully iron-restricted diets to induce a state of moderate or severe iron deficiency alongside iron-replete control rats. We assessed mitochondrial function via high-resolution respirometry and reactive oxygen species generation via fluorescence microscopy on gestational d 21. Hemoglobin levels were reduced in dams in the moderate (-31%) and severe groups (-54%) compared with controls, which was accompanied by 55% reductions in fetal hemoglobin levels in both moderate and severe groups versus controls. Male iron-deficient kidneys exhibited globally reduced mitochondrial content and respiration, as well as increased cytosolic superoxide and decreased NO. Female iron-deficient kidneys exhibited complex II down-regulation and increased mitochondrial oxidative stress. Male iron-deficient livers exhibited reduced complex IV respiration and increased cytosolic superoxide, whereas female liver tissues exhibited no alteration in oxidant levels or mitochondrial function. These findings indicate that prenatal iron deficiency causes changes in mitochondrial content and function as well as oxidant status in a sex- and organ-dependent manner, which may be an important mechanism that underlies the programming of cardiovascular disease.-Woodman, A. G., Mah, R., Keddie, D., Noble, R. M. N., Panahi, S., Gragasin, F. S., Lemieux, H., Bourque, S. L. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

  10. A novel method of mouse ex utero transplantation of hepatic progenitor cells into the fetal liver

    International Nuclear Information System (INIS)

    Shikanai, Mima; Asahina, Kinji; Iseki, Sachiko; Teramoto, Kenichi; Nishida, Tomohiro; Shimizu-Saito, Keiko; Ota, Masato; Eto, Kazuhiro; Teraoka, Hirobumi

    2009-01-01

    Avoiding the limitations of the adult liver niche, transplantation of hepatic stem/progenitor cells into fetal liver is desirable to analyze immature cells in a hepatic developmental environment. Here, we established a new monitor tool for cell fate of hepatic progenitor cells transplanted into the mouse fetal liver by using ex utero surgery. When embryonic day (ED) 14.5 hepatoblasts were injected into the ED14.5 fetal liver, the transplanted cells expressed albumin abundantly or α-fetoprotein weakly, and contained glycogen in the neonatal liver, indicating that transplanted hepatoblasts can proliferate and differentiate in concord with surrounding recipient parenchymal cells. The transplanted cells became mature in the liver of 6-week-old mice. Furthermore, this method was applicable to transplantation of hepatoblast-like cells derived from mouse embryonic stem cells. These data indicate that this unique technique will provide a new in vivo experimental system for studying cell fate of hepatic stem/progenitor cells and liver organogenesis.

  11. TRANSPLANTATION OF CRYOPRESERVED FETAL LIVER CELLS SEEDED INTO MACROPOROUS ALGINATE-GELATIN SCAFFOLDS IN RATS WITH LIVER FAILURE

    Directory of Open Access Journals (Sweden)

    D. V. Grizay

    2015-01-01

    Full Text Available Aim. To study the therapeutic potential of cryopreserved fetal liver cells seeded into macroporous alginategelatin scaffolds after implantation to omentum of rats with hepatic failure.Materials and methods.Hepatic failure was simulated by administration of 2-acetyl aminofl uorene followed partial hepatectomy. Macroporous alginate-gelatin scaffolds, seeded with allogenic cryopreserved fetal liver cells (FLCs were implanted into rat omentum. To prevent from colonization of host cells scaffolds were coated with alginate gel shell. Serum transaminase activity, levels of albumin and bilirubin as markers of hepatic function were determined during 4 weeks after failure model formation and scaffold implantation. Morphology of liver and scaffolds after implantation were examined histologically. Results. Macroporous alginate-gelatin scaffolds after implantation to healthy rats were colonized by host cells. Additional formation of alginate gel shell around scaffolds prevented the colonization. Implantation of macroporous scaffolds seeded with cryopreserved rat FLCs and additionally coated with alginate gel shell into omentum of rats with hepatic failure resulted in signifi cant improvement of hepatospecifi c parameters of the blood serum and positive changes of liver morphology. The presence of cells with their extracellular matrix within the scaffolds was confi rmed after 4 weeks post implantation.Conclusion. The data above indicate that macroporous alginate-gelatin scaffolds coated with alginate gel shell are promising cell carriers for the development of bioengineered liver equivalents.

  12. Nonacetaminophen Drug-Induced Acute Liver Failure.

    Science.gov (United States)

    Thomas, Arul M; Lewis, James H

    2018-05-01

    Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non-acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Measurement of the capability of DNA synthesis of human fetal liver cells by the assay of 3H-TdR incorporation

    International Nuclear Information System (INIS)

    Wang Tao; Ma Xiangrui; Wang Hongyun; Cao Xia

    1987-01-01

    The fetal liver is one of the major sites of hematopoiesis during gestation. Under erythropoietin (EPO) stimulation, in erythroid precusor cells of fetal liver, proliferation and differentiation occurred and function of metabolism was enhanced. The technique of 3 H-TdR incorporation was used to measure the function of fetal liver cellular DNA synthesis. As EPO concentration at the range of approximately 20 ∼ 100 mU/ml, the counts of 3 H-TdR incorporation into fetal liver cells increased. As the concentration of EPO increased, however, its incorporation counts are lower than that in bone marrow of either the fetal or the adult. It suggested that precusors of erythrocyte of fetal liver has differentiated to later phases with the progressive accumulation of mature cells, therefore, both proliferation and function of metabolism are more or less decreased respectively. Under EPO stimulation, however, precusor of erythroid of fetal liver can greatly increase potential effects on DNA synthesis

  14. Montelukast induced acute hepatocellular liver injury

    Directory of Open Access Journals (Sweden)

    Harugeri A

    2009-01-01

    Full Text Available A 46-year-old male with uncontrolled asthma on inhaled albuterol and formoterol with budesonide was commenced on montelukast. He developed abdominal pain and jaundice 48 days after initiating montelukast therapy. His liver tests showed an increase in serum total bilirubin, conjugated bilirubin, aspartate aminotranferase, alanine aminotranferase, and alkaline phosphatase. The patient was evaluated for possible non-drug related liver injury. Montelukast was discontinued suspecting montelukast induced hepatocellular liver injury. Liver tests began to improve and returned to normal 55 days after drug cessation. Causality of this adverse drug reaction by the Council for International Organizations of Medical Sciences or Roussel Uclaf Causality Assessment Method (CIOMS or RUCAM and Naranjo′s algorithm was ′probable′. Liver tests should be monitored in patients receiving montelukast and any early signs of liver injury should be investigated with a high index of suspicion for drug induced liver injury.

  15. Uridine prevents fenofibrate-induced fatty liver.

    Directory of Open Access Journals (Sweden)

    Thuc T Le

    Full Text Available Uridine, a pyrimidine nucleoside, can modulate liver lipid metabolism although its specific acting targets have not been identified. Using mice with fenofibrate-induced fatty liver as a model system, the effects of uridine on liver lipid metabolism are examined. At a daily dosage of 400 mg/kg, fenofibrate treatment causes reduction of liver NAD(+/NADH ratio, induces hyper-acetylation of peroxisomal bifunctional enzyme (ECHD and acyl-CoA oxidase 1 (ACOX1, and induces excessive accumulation of long chain fatty acids (LCFA and very long chain fatty acids (VLCFA. Uridine co-administration at a daily dosage of 400 mg/kg raises NAD(+/NADH ratio, inhibits fenofibrate-induced hyper-acetylation of ECHD, ACOX1, and reduces accumulation of LCFA and VLCFA. Our data indicates a therapeutic potential for uridine co-administration to prevent fenofibrate-induced fatty liver.

  16. Hedgehog signal activation coordinates proliferation and differentiation of fetal liver progenitor cells

    International Nuclear Information System (INIS)

    Hirose, Yoshikazu; Itoh, Tohru; Miyajima, Atsushi

    2009-01-01

    Hedgehog (Hh) signaling plays crucial roles in development and homeostasis of various organs. In the adult liver, it regulates proliferation and/or viability of several types of cells, particularly under injured conditions, and is also implicated in stem/progenitor cell maintenance. However, the role of this signaling pathway during the normal developmental process of the liver remains elusive. Although Sonic hedgehog (Shh) is expressed in the ventral foregut endoderm from which the liver derives, the expression disappears at the onset of the liver bud formation, and its possible recurrence at the later stages has not been investigated. Here we analyzed the activation and functional relevance of Hh signaling during the mouse fetal liver development. At E11.5, Shh and an activation marker gene for Hh signaling, Gli1, were expressed in Dlk + hepatoblasts, the fetal liver progenitor cells, and the expression was rapidly decreased thereafter as the development proceeded. In the culture of Dlk + hepatoblasts isolated from the E11.5 liver, activation of Hh signaling stimulated their proliferation and this effect was cancelled by a chemical Hh signaling inhibitor, cyclopamine. In contrast, hepatocyte differentiation of Dlk + hepatoblasts in vitro as manifested by the marker gene expression and acquisition of ammonia clearance activity was significantly inhibited by forced activation of Hh signaling. Taken together, these results demonstrate the temporally restricted manner of Hh signal activation and its role in promoting the hepatoblast proliferation, and further suggest that the pathway needs to be shut off for the subsequent hepatic differentiation of hepatoblasts to proceed normally.

  17. Gene targeting and cloning in pigs using fetal liver derived cells.

    Science.gov (United States)

    Waghmare, Sanjeev K; Estrada, Jose; Reyes, Luz; Li, Ping; Ivary, Bess; Sidner, Richard A; Burlak, Chris; Tector, A Joseph

    2011-12-01

    Since there are no pig embryonic stem cells, pig genetic engineering is done in fetal fibroblasts that remain totipotent for only 3 to 5 wk. Nuclear donor cells that remain totipotent for longer periods of time would facilitate complicated genetic engineering in pigs. The goal of this study was to test the feasibility of using fetal liver-derived cells (FLDC) to perform gene targeting, and create a genetic knockout pig. FLDC were isolated and processed using a human liver stem cell protocol. Single copy α-1,3-galactosyl transferase knockout (GTKO) FLDCs were created using electroporation and neomycin resistant colonies were screened using PCR. Homozygous GTKO cells were created through loss of heterozygosity mutations in single GTKO FLDCs. Double GTKO FLDCs were used in somatic cell nuclear transfer (SCNT) to create GTKO pigs. FLDCs grew for more than 80 population doublings, maintaining normal karyotype. Gene targeting and loss of heterozygosity mutations produced homozygous GTKO FLDCs. FLDCs used in SCNT gave rise to homozygous GTKO pigs. FDLCs can be used in gene targeting and SCNT to produce genetically modified pigs. The increased life span in culture compared to fetal fibroblasts may facilitate genetic engineering in the pig. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Hydroxycut-induced Liver Toxicity

    African Journals Online (AJOL)

    hanumantp

    Annals of Medical and Health Sciences Research | Jan-Feb 2014 | Vol 4 ... supplements can be responsible for documented or undocumented adverse drug effects. The ... Keywords: Hydroxycut, Liver toxicity, Nutritional supplements ... Caffeine anhydrous: 200 mg* ... series and review of liver toxicity from herbal weight loss.

  19. Radiation-induced liver damage

    International Nuclear Information System (INIS)

    Marcial, V.A.; Santiago-Delpin, E.A.; Lanaro, A.E.; Castro-Vita, H.; Arroyo, G.; Moscol, J.A.; Gomez, C.; Velazquez, J.; Prado, K.

    1977-01-01

    Due to the recent increase in the use of radiation therapy in the treatment of cancer with or without chemotherapy, the risk of liver radiation damage has become a significant concern for the radiotherapist when the treated tumour is located in the upper abdomen or lower thorax. Clinically evident radiation liver damage may result in significant mortality, but at times patients recover without sequelae. The dose of 3000 rads in 3 weeks to the entire liver with 5 fractions per week of 200 rads each, seems to be tolerated well clinically by adult humans. Lower doses may lead to damage when used in children, when chemotherapy is added, as in recent hepatectomy cases, and in the presence of pre-existent liver damage. Reduced fractionation may lead to increased damage. Increased fractionation, limitation of the dose delivered to the entire liver, and restriction of the high dose irradiation volume may afford protection. With the aim of studying the problems of hepatic radiation injury in humans, a project of liver irradiation in the dog is being conducted. Mongrel dogs are being conditioned, submitted to pre-irradiation studies (haemogram, blood chemistry, liver scan and biopsy), irradiated under conditions resembling human cancer therapy, and submitted to post-irradiation evaluation of the liver. Twenty-two dogs have been entered in the study but only four qualify for the evaluation of all the study parameters. It has been found that dogs are susceptible to liver irradiation damage similar to humans. The initial mortality has been high mainly due to non-radiation factors which are being kept under control at the present phase of the study. After the initial experiences, the study will involve variations in total dose and fractionation, and the addition of anticoagulant therapy for possible prevention of radiation liver injury. (author)

  20. Selective accumulation of 147Pm in organism on induction of PCE's micronucleus and SCE of bone marrow cells as well as the chromosome aberrations on fetal liver and spleen

    International Nuclear Information System (INIS)

    Zhu Shoupeng; Zheng Siying; Wang Liuyi; Lu Zhongyan; Yang Shuqin

    1989-01-01

    Study of accumulation peculiarity of 147 Pm showed that I.V. different doses of 147 Pm were the same selectively localized in skeleton and liver. Retention of 147 Pm in skeleton and liver was elevated when the radioactive doses of 147 Pm were increased. At the same time absorption does of 147 Pm radiation was heightened. The ability of 147 Pm to induce sister chromatid exchanges (SCEs) has been investigated by IdU labelling methods. A statistically significant elevation of SCEs was observed after 147 Pm intake.In mice the number of SCEs per cell in bone marrow cells was always higher when the animals were maintained on the doses of 37 Bq/g. The injurious effects of 147 Pm, using PCE's micronucleus rates in bone marrow cells were observed. 147 Pm was dominantly deposited on maternal liver. Deposition of 147 Pm in maternal spleen was about quandrantal of the maternal liver. Studies indicated that maternal contamination of 147 Pm could induced chromosome aberrations in fetal liver and spleen cells. Among the type of aberrations induced by 147 Pm, chromatid breakage were predominant. The incidence of chromosome aberrations on fetal liver cells induced by 147 Pm was higher on fetal spleen cells

  1. Drug-induced liver injuries

    African Journals Online (AJOL)

    2011-06-02

    Jun 2, 2011 ... liver failure in the developed world and a prominent aetiological factor ... most drugs is not known and several epidemiological studies have had major ... eosinophilia, are also pointers towards the cause of the injury and are.

  2. TWEAK induces liver progenitor cell proliferation

    Science.gov (United States)

    Jakubowski, Aniela; Ambrose, Christine; Parr, Michael; Lincecum, John M.; Wang, Monica Z.; Zheng, Timothy S.; Browning, Beth; Michaelson, Jennifer S.; Baestcher, Manfred; Wang, Bruce; Bissell, D. Montgomery; Burkly, Linda C.

    2005-01-01

    Progenitor (“oval”) cell expansion accompanies many forms of liver injury, including alcohol toxicity and submassive parenchymal necrosis as well as experimental injury models featuring blocked hepatocyte replication. Oval cells can potentially become either hepatocytes or biliary epithelial cells and may be critical to liver regeneration, particularly when hepatocyte replication is impaired. The regulation of oval cell proliferation is incompletely understood. Herein we present evidence that a TNF family member called TWEAK (TNF-like weak inducer of apoptosis) stimulates oval cell proliferation in mouse liver through its receptor Fn14. TWEAK has no effect on mature hepatocytes and thus appears to be selective for oval cells. Transgenic mice overexpressing TWEAK in hepatocytes exhibit periportal oval cell hyperplasia. A similar phenotype was obtained in adult wild-type mice, but not Fn14-null mice, by administering TWEAK-expressing adenovirus. Oval cell expansion induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was significantly reduced in Fn14-null mice as well as in adult wild-type mice with a blocking anti-TWEAK mAb. Importantly, TWEAK stimulated the proliferation of an oval cell culture model. Finally, we show increased Fn14 expression in chronic hepatitis C and other human liver diseases relative to its expression in normal liver, which suggests a role for the TWEAK/Fn14 pathway in human liver injury. We conclude that TWEAK has a selective mitogenic effect for liver oval cells that distinguishes it from other previously described growth factors. PMID:16110324

  3. Radiation induced liver disease: A clinical update

    International Nuclear Information System (INIS)

    Benson, R.; Madan, R.; Chander, S.; Kilambi, R.

    2016-01-01

    Radiation-induced liver disease (RILD) or radiation hepatitis is a sub-acute form of liver injury due to radiation. It is one of the most dreaded complications of radiation which prevents radiation dose escalation and re irradiation for hepatobiliary or upper gastrointestinal malignancies. This complication should be kept in mind whenever a patient is planned for irradiation of these malignancies. Although, incidence of RILD is decreasing due to better knowledge of liver tolerance, improved investigation modalities and modern radiation delivery techniques, treatment options are still limited. In this review article, we have focussed on pathophysiology, risk factors, prevention and management of RILD

  4. Ectopic Liver Tissue Formation in Rats with Induced Liver Fibrosis

    Directory of Open Access Journals (Sweden)

    Bauyrzhan Umbayev

    2014-12-01

    Full Text Available Introduction: The possible alternative approach to whole-organ transplantation is a cell-based therapy, which can also be used as a "bridge" to liver transplantation.  However, morphological and functional changes in the liver of patients suffering from chronic liver fibrosis and cirrhosis restrict the effectiveness of direct cell transplantation. Therefore, extra hepatic sites for cell transplantation, including the spleen, pancreas, peritoneal cavity, and subrenal capsule, could be a useful therapeutic approach for compensation of liver functions. However, a method of transplantation of hepatocytes into ectopic sites is needed to improve hepatocyte engraftment. Previously published data has demonstrated that mouse lymph nodes can support the engraftment and proliferation of hepatocytes as ES and rescue Fah mice from lethal liver failure. Thus, the aim of the study was to evaluate the engraftment of i.p. injected allogeneic hepatocytes into extra hepatic sites in albino rats with chemically induced liver fibrosis (LF. Materials and methods: Albino rats were randomly divided into 4 groups: (1 intact group (n = 18; (2 rats with induced LF (n = 18; (3 rats with induced LF and transplanted with hepatocytes (n = 18; (4 as a control, rats were treated with cyclosporine A only (n = 18. In order to prevent an immune response, groups 2 and 3 were subjected to immunosuppression by cyclosporine A (25 mg/kg per day. LF was induced using N-nitrosodimethylamine (NDMA, i.p., 10 mg/kg, three times a week for 4 weeks and confirmed by histological analysis of the liver samples. Hepatocytes transplantation (HT was performed two days after NDMA exposure cessation by i.p. injection of 5×106 freshly isolated allogeneic hepatocytes. Liver function was assessed by quantifying blood biochemical parameters (ALT, AST, GGT, total protein, bilirubin, and albumin at 1 week, 1 month, and 2 months after hepatocytes transplantation (HT. To confirm a hepatocytes

  5. Fetal and adult hematopoietic stem cells require beta1 integrin function for colonizing fetal liver, spleen, and bone marrow

    DEFF Research Database (Denmark)

    Potocnik, A J; Brakebusch, C; Fässler, R

    2000-01-01

    hematolymphoid differentiation potential in vitro and in fetal organ cultures but were unable to seed fetal and adult hematopoietic tissues. Adult beta1 integrin null HSCs isolated from mice carrying loxP-tagged beta1 integrin alleles and ablated for beta1 integrin expression by retroviral cre transduction......Homing of hematopoietic stem cells (HSCs) into hematopoietic organs is a prerequisite for the establishment of hematopoiesis during embryogenesis and after bone marrow transplantation. We show that beta1 integrin-deficient HSCs from the para-aortic splanchnopleura and the fetal blood had...

  6. Highly proliferative primitive fetal liver hematopoietic stem cells are fueled by oxidative metabolic pathways

    Directory of Open Access Journals (Sweden)

    Javed K. Manesia

    2015-11-01

    Full Text Available Hematopoietic stem cells (HSCs in the fetal liver (FL unlike adult bone marrow (BM proliferate extensively, posing different metabolic demands. However, metabolic pathways responsible for the production of energy and cellular building blocks in FL HSCs have not been described. Here, we report that FL HSCs use oxygen dependent energy generating pathways significantly more than their BM counterparts. RNA-Seq analysis of E14.5 FL versus BM derived HSCs identified increased expression levels of genes involved in oxidative phosphorylation (OxPhos and the citric acid cycle (TCA. We demonstrated that FL HSCs contain more mitochondria than BM HSCs, which resulted in increased levels of oxygen consumption and reactive oxygen species (ROS production. Higher levels of DNA repair and antioxidant pathway gene expression may prevent ROS-mediated (genotoxicity in FL HSCs. Thus, we here for the first time highlight the underestimated importance of oxygen dependent pathways for generating energy and building blocks in FL HSCs.

  7. Fetal liver transplantation in 2 patients with acute leukaemia after total body irradiation

    International Nuclear Information System (INIS)

    Lucarelli, G.; Izzi, T.; Porcellini, A.; Delfini, C.; Galimberti, M.; Moretti, L.; Polchi, P.; Agostinelli, F.; Andreani, M.; Manna, M.; Dallapiccola, B.

    1982-01-01

    2 patients with acute leukaemia in relapse were transplanted with fetal liver cells following a conditioning regimen of cyclophosphamide (120 mg/kg) and total body irradiation (1000 r). Each patient achieved a remission with haematopoietic recovery that was rapid in one case and delayed in the other. In one case there was evidence of chimerism as demonstrated by the presence of the XYY karyotype of the donor fetus in 20 % of marrow metaphases, by the presence of double Y bodies in the peripheral blood, by the appearance of new HLA-antigens, and by red cell isoenzyme phenotypes of donor origin. In the second case there was prompt haemotopoietic recovery and the appearance of red cell isoenzyme phenotypes of donor origin. Survival was 153 and 30 d, respectively, and both patients died of interstitial pneumonia without evidence of graft versus host disease. (author)

  8. 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....

  9. Amiodarone-Induced Liver Injury and Cirrhosis.

    Science.gov (United States)

    Buggey, Jonathan; Kappus, Matthew; Lagoo, Anand S; Brady, Carla W

    2015-01-01

    We present a case report of an 80-year-old woman with volume overload thought initially to be secondary to heart failure, but determined to be amiodarone-induced acute and chronic liver injury leading to submassive necrosis and bridging fibrosis consistent with early cirrhosis. Her histopathology was uniquely absent of steatosis and phospholipidosis, which are commonly seen in AIC.

  10. Organ-Specific Gene Expression Changes in the Fetal Liver and Placenta in Response to Maternal Folate Depletion

    Directory of Open Access Journals (Sweden)

    Jill A. McKay

    2016-10-01

    Full Text Available Growing evidence supports the hypothesis that the in utero environment can have profound implications for fetal development and later life offspring health. Current theory suggests conditions experienced in utero prepare, or “programme”, the fetus for its anticipated post-natal environment. The mechanisms responsible for these programming events are poorly understood but are likely to involve gene expression changes. Folate is essential for normal fetal development and inadequate maternal folate supply during pregnancy has long term adverse effects for offspring. We tested the hypothesis that folate depletion during pregnancy alters offspring programming through altered gene expression. Female C57BL/6J mice were fed diets containing 2 mg or 0.4 mg folic acid/kg for 4 weeks before mating and throughout pregnancy. At 17.5 day gestation, genome-wide gene expression was measured in male fetal livers and placentas. In the fetal liver, 989 genes were expressed differentially (555 up-regulated, 434 down-regulated in response to maternal folate depletion, with 460 genes expressed differentially (250 up-regulated, 255 down-regulated in the placenta. Only 25 differentially expressed genes were common between organs. Maternal folate intake during pregnancy influences fetal gene expression in a highly organ specific manner which may reflect organ-specific functions.

  11. Organ-Specific Gene Expression Changes in the Fetal Liver and Placenta in Response to Maternal Folate Depletion.

    Science.gov (United States)

    McKay, Jill A; Xie, Long; Adriaens, Michiel; Evelo, Chris T; Ford, Dianne; Mathers, John C

    2016-10-22

    Growing evidence supports the hypothesis that the in utero environment can have profound implications for fetal development and later life offspring health. Current theory suggests conditions experienced in utero prepare, or "programme", the fetus for its anticipated post-natal environment. The mechanisms responsible for these programming events are poorly understood but are likely to involve gene expression changes. Folate is essential for normal fetal development and inadequate maternal folate supply during pregnancy has long term adverse effects for offspring. We tested the hypothesis that folate depletion during pregnancy alters offspring programming through altered gene expression. Female C57BL/6J mice were fed diets containing 2 mg or 0.4 mg folic acid/kg for 4 weeks before mating and throughout pregnancy. At 17.5 day gestation, genome-wide gene expression was measured in male fetal livers and placentas. In the fetal liver, 989 genes were expressed differentially (555 up-regulated, 434 down-regulated) in response to maternal folate depletion, with 460 genes expressed differentially (250 up-regulated, 255 down-regulated) in the placenta. Only 25 differentially expressed genes were common between organs. Maternal folate intake during pregnancy influences fetal gene expression in a highly organ specific manner which may reflect organ-specific functions.

  12. Piroxicam induced submassive necrosis of the liver.

    Science.gov (United States)

    Paterson, D; Kerlin, P; Walker, N; Lynch, S; Strong, R

    1992-01-01

    Several widely used non-steroidal anti-inflammatory drugs have been reported as causing severe hepatitis. Three cases of severe acute hepatitis have been reported in association with piroxicam. A fatal submassive necrosis that occurred in a 68 year old lady who had received piroxicam for 15 months is described. A 48 year old man who developed submassive hepatic necrosis six weeks after beginning piroxicam but was successfully treated with orthotopic liver transplantation is also reported. Piroxicam may induce submassive necrosis of the liver, probably as an idiosyncratic reaction. Images Figure 1 Figure 2 Figure 3 PMID:1446877

  13. Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells

    Science.gov (United States)

    Zalzman, Michal; Gupta, Sanjeev; Giri, Ranjit K.; Berkovich, Irina; Sappal, Baljit S.; Karnieli, Ohad; Zern, Mark A.; Fleischer, Norman; Efrat, Shimon

    2003-06-01

    Beta-cell replacement is considered to be the most promising approach for treatment of type 1 diabetes. Its application on a large scale is hindered by a shortage of cells for transplantation. Activation of insulin expression, storage, and regulated secretion in stem/progenitor cells offers novel ways to overcome this shortage. We explored whether fetal human progenitor liver cells (FH) could be induced to differentiate into insulin-producing cells after expression of the pancreatic duodenal homeobox 1 (Pdx1) gene, which is a key regulator of pancreatic development and insulin expression in beta cells. FH cells possess a considerable replication capacity, and this was further extended by introduction of the gene for the catalytic subunit of human telomerase. Immortalized FH cells expressing Pdx1 activated multiple beta-cell genes, produced and stored considerable amounts of insulin, and released insulin in a regulated manner in response to glucose. When transplanted into hyperglycemic immunodeficient mice, the cells restored and maintained euglycemia for prolonged periods. Quantitation of human C-peptide in the mouse serum confirmed that the glycemia was normalized by the transplanted human cells. This approach offers the potential of a novel source of cells for transplantation into patients with type 1 diabetes.

  14. Effects of intrauterine growth restriction during late pregnancy on the cell apoptosis and related gene expression in ovine fetal liver.

    Science.gov (United States)

    Liu, Yingchun; Ma, Chi; Li, Hui; Li, Lingyao; Gao, Feng; Ao, Changjin

    2017-03-01

    This study investigated the effect of intrauterine growth restriction (IUGR) during late pregnancy on the cell apoptosis and related gene expression in ovine fetal liver. Eighteen time-mated Mongolian ewes with singleton fetuses were allocated to three groups at d 90 of pregnancy: Restricted Group 1 (RG1, 0.18 MJ ME kg BW -0.75  d -1 , n = 6), Restricted Group 2 (RG2, 0.33 MJ ME kg BW -0.75  d -1 , n = 6) and a Control Group (CG, ad libitum, 0.67 MJ ME kg BW -0.75  d -1 , n = 6). Fetuses were recovered at slaughter on d 140. Fetal liver weight, DNA content and protein/DNA ratio, proliferation index, cytochrome c, activities of Caspase-3, 8, and 9 were examined, along with relative expression of genes related to apoptosis. Fetuses in both restricted groups exhibited decreased BW, hepatic weight, DNA content, and protein/DNA ratio when compared to CG (P restricted groups (P  0.05). Hepatic expression of gene related to apoptosis showed reduced protein 21 (P21), B-cell lymphoma 2 (Bcl-2) and apoptosis antigen 1 ligand (FasL) expression in RG1 and RG2 (P < 0.05). In contrast, the increased hepatic expression of protein 53 (P53), Bcl-2 associated X protein (Bax) and apoptosis antigen 1 (Fas) in both IUGR fetuses were found (P < 0.05). These results indicate that the fetal hepatocyte proliferation were arrested in G1 cell cycle, and the fetal hepatocyte apoptosis was sensitive to the IUGR resulted from maternal undernutrition. The cell apoptosis in IUGR fetal liver were the potential mechanisms for its retarded proliferation and impaired development. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Clinical study of fetal liver transplantation in treatment of four cases of accidental or therapeutic acute radiation sickness

    International Nuclear Information System (INIS)

    1989-01-01

    This report summarized the clinical experience of fetal liver transplantation (FLT) in the medical handling of accidental (case 1) or therapeutic (cases 2-4) acute radiation sickness of severe haemopoietic form. In addition to receiving 80 mg/kg of cyclophosphamide, cases 2, 3 and 4 were exposed to total body single irradiation of 5.5, 5.0 and 5.0 Gy, respectively; while case 1 was exposed to whole body irradiation of 5.2 Gy only. The total number of nucleated fetal liver cells transplanted was 2.26-4.1 x 10 8 /kg. Only 2-5% of peripheral blood cells of cases 2, 3 and 4 were found to have allogeneic marker. The author points out that FLT may be beneficial in those cases of accidental irradiation or patients with acute leukemia when there were no HLA-identical bone marrow donors available

  16. Protection of lethally irradiated mice with allogeneic fetal liver cells: influence of irradiation dose on immunologic reconstitution

    International Nuclear Information System (INIS)

    Tulunay, O.; Good, R.A.; Yunis, E.J.

    1975-01-01

    After lethal irradiation long-lived, immunologically vigorous C3Hf mice were produced by treatment with syngeneic fetal liver cells or syngeneic newborn or adult spleen cells. Treatment of lethally irradiated mice with syngeneic or allogeneic newborn thymus cells or allogeneic newborn or adult spleen cells regularly led to fatal secondary disease or graft-versus-host reactions. Treatment of the lethally irradiated mice with fetal liver cells regularly yielded long-lived, immunologically vigorous chimeras. The introduction of the fetal liver cells into the irradiated mice appeared to be followed by development of immunological tolerance of the donor cells. The findings suggest that T-cells at an early stage of differentiation are more susceptible to tolerance induction than are T-lymphocytes at later stages of differentiation. These investigations turned up a perplexing paradox which suggests that high doses of irradiation may injure the thymic stroma, rendering it less capable of supporting certain T-cell populations in the peripheral lymphoid tissue. Alternatively, the higher and not the lower dose of irradiation may have eliminated a host cell not readily derived from fetal liver precursors which represents an important helper cell in certain cell-mediated immune functions, e.g., graft-versus-host reactions, but which is not important in others, e.g., allograft rejections. The higher dose of lethal irradiation did not permit development or maintenance of a population of spleen cells that could initiate graft-versus-host reactions but did permit the development of a population of donor cells capable of achieving vigorous allograft rejection

  17. Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development.

    Directory of Open Access Journals (Sweden)

    Keith M Godfrey

    Full Text Available Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001 and at age 4 years (r = 0.16, P = 0.02. In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02. This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04. We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fat.

  18. Maternal-fetal hepatic and placental metabolome profiles are associated with reduced fetal growth in a rat model of maternal obesity

    DEFF Research Database (Denmark)

    Mumme, Karen; Gray, Clint; Reynolds, Clare M.

    2016-01-01

    : Metabolomic profiling was used to reveal altered maternal and fetal metabolic pathways in a model of diet induced obesity during pregnancy, leading to reduced fetal growth. Methods: We examined the metabolome of maternal and fetal livers, and placenta following a high fat and salt intake. Sprague–Dawley rats...

  19. Acute alcohol-induced liver injury

    Directory of Open Access Journals (Sweden)

    Gavin Edward Arteel

    2012-06-01

    Full Text Available Alcohol consumption is customary in most cultures and alcohol abuse is common worldwide. For example, more than 50% of Americans consume alcohol, with an estimated 23.1% of Americans participating in heavy and/or binge drinking at least once a month. A safe and effective therapy for alcoholic liver disease (ALD in humans is still elusive, despite significant advances in our understanding of how the disease is initiated and progresses. It is now clear that acute alcohol binges not only can be acutely toxic to the liver, but also can contribute to the chronicity of ALD. Potential mechanisms by which acute alcohol causes damage include steatosis, dysregulated immunity and inflammation and altered gut permeability. Recent interest in modeling acute alcohol exposure has yielded new insights into potential mechanisms of acute injury, that also may well be relevant for chronic ALD. Recent work by this group on the role of PAI-1 and fibrin metabolism in mediating acute alcohol-induced liver damage serve as an example of possible new targets that may be useful for alcohol abuse, be it acute or chronic.

  20. Maternal endotoxin-induced fetal growth restriction in rats: Fetal responses in toll-like receptor

    Directory of Open Access Journals (Sweden)

    Banun Kusumawardani

    2012-09-01

    Full Text Available Background: Porphyromonas gingivalis as a major etiology of periodontal disease can produce virulence factor, lipopolysaccharide/LPS, which is expected to play a role in the intrauterine fetal growth. Trophoblast at the maternal-fetal interface actively participates in response to infection through the expression of a family of natural immune receptors, toll-like receptor (TLR. Purpose: the aims of study were to identify endotoxin concentration in maternal blood serum of Porphyromonas gingivalis-infected pregnant rats, to characterize the TLR-4 expression in trophoblast cells, and to determine its effect on fetal growth. Methods: Female rats were infected with live-Porphyromonas gingivalis at concentration of 2 x 109 cells/ml into subgingival sulcus area of the maxillary first molar before and/or during pregnancy. They were sacrified on 14th and 20th gestational day. Fetuses were evaluated for weight and length. Endotoxin was detected by limulus amebocyte lysate assay in the maternal blood serum. The TLR-4 expression in trophoblast cells was detected by immunohistochemistry.

  1. IL-27 induces a pro-inflammatory response in human fetal membranes mediating preterm birth.

    Science.gov (United States)

    Yin, Nanlin; Wang, Hanbing; Zhang, Hua; Ge, Huisheng; Tan, Bing; Yuan, Yu; Luo, Xiaofang; Olson, David M; Baker, Philip N; Qi, Hongbo

    2017-09-01

    Inflammation at the maternal-fetal interface has been shown to be involved in the pathogenesis of preterm birth. Interleukin 27 (IL-27), a heterodimeric cytokine, is known to mediate an inflammatory response in some pregnancy complications. In this study, we aimed to determine whether IL-27 could induce an inflammatory reaction at the maternal-fetal interface that would mediate the onset of preterm birth. We found elevated expression of IL-27 in human peripheral serum and elevated expression of its specific receptor (wsx-1) on fetal membranes in cases of preterm birth. Moreover, the release of inflammatory markers (CXCL10, IFN-γ, MCP-1, IL-6, IL-1β and TNF-α), especially CXCL10, was markedly augmented upon stimulation of IL-27 in the fetal membranes. Additionally, IL-27 and IFN-γ cooperated to amplify the expression of CXCL10 in the fetal membranes. Moreover, the production of CXCL10 was increased in IL-27-treated fetal membrane through JNK, PI3K or Erk signaling pathways. Finally, MMP2 and MMP9 were activated by IL-27 in human fetal membranes, which may be related to the onset of preterm premature rupture of membranes (pPROM). In conclusion, for the first time, we reported that the aberrant expression of IL-27 could mediate an excessive inflammatory response in fetal membranes through the JNK, PI3K or Erk signaling pathways, which contributes to preterm birth. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Traditional Chinese Medicine and Herb-induced Liver Injury: Comparison with Drug-induced Liver Injury.

    Science.gov (United States)

    Jing, Jing; Teschke, Rolf

    2018-03-28

    Cases of suspected herb-induced liver injury (HILI) caused by herbal Traditional Chinese Medicines (TCMs) and of drug-induced liver injury (DILI) are commonly published in the scientific literature worldwide. As opposed to the multiplicity of botanical chemicals in herbal TCM products, which are often mixtures of several herbs, conventional Western drugs contain only a single synthetic chemical. It is therefore of interest to study how HILI by TCM and DILI compare with each other, and to what extent results from each liver injury type can be transferred to the other. China is among the few countries with a large population using synthetic Western drugs as well as herbal TCM. Therefore, China is well suited to studies of liver injury comparing drugs with TCM herbs. Despite some concordance, recent analyses of liver injury cases with verified causality, using the Roussel Uclaf Causality Assessment Method, revealed major differences in HILI caused by TCMs as compared to DILI with respect to the following features: HILI cases are less frequently observed as compared to DILI, have a smaller proportion of females and less unintentional rechallenge events, and present a higher rate of hepatocellular injury features. Since many results were obtained among Chinese residents who had access to and had used Western drugs and TCM herbs, such ethnic homogeneity supports the contention that the observed differences of HILI and DILI in the assessed population are well founded.

  3. Disruption of polyubiquitin gene Ubc leads to defective proliferation of hepatocytes and bipotent fetal liver epithelial progenitor cells

    Energy Technology Data Exchange (ETDEWEB)

    Park, Hyejin; Yoon, Min-Sik; Ryu, Kwon-Yul, E-mail: kyryu@uos.ac.kr

    2013-06-07

    Highlights: •Proliferation capacity of Ubc{sup −/−} FLCs was reduced during culture in vitro. •Ubc is required for proliferation of both hepatocytes and bipotent FLEPCs. •Bipotent FLEPCs exhibit highest Ubc transcription and proliferation capacity. •Cell types responsible for Ubc{sup −/−} fetal liver developmental defect were identified. -- Abstract: We have previously demonstrated that disruption of polyubiquitin gene Ubc leads to mid-gestation embryonic lethality most likely due to a defect in fetal liver development, which can be partially rescued by ectopic expression of Ub. In a previous study, we assessed the cause of embryonic lethality with respect to the fetal liver hematopoietic system. We confirmed that Ubc{sup −/−} embryonic lethality could not be attributed to impaired function of hematopoietic stem cells, which raises the question of whether or not FLECs such as hepatocytes and bile duct cells, the most abundant cell types in the liver, are affected by disruption of Ubc and contribute to embryonic lethality. To answer this, we isolated FLCs from E13.5 embryos and cultured them in vitro. We found that proliferation capacity of Ubc{sup −/−} cells was significantly reduced compared to that of control cells, especially during the early culture period, however we did not observe the increased number of apoptotic cells. Furthermore, levels of Ub conjugate, but not free Ub, decreased upon disruption of Ubc expression in FLCs, and this could not be compensated for by upregulation of other poly- or mono-ubiquitin genes. Intriguingly, the highest Ubc expression levels throughout the entire culture period were observed in bipotent FLEPCs. Hepatocytes and bipotent FLEPCs were most affected by disruption of Ubc, resulting in defective proliferation as well as reduced cell numbers in vitro. These results suggest that defective proliferation of these cell types may contribute to severe reduction of fetal liver size and potentially mid

  4. Forskolin and the meiosis inducing substance synergistically initiate meiosis in fetal male germ cells

    DEFF Research Database (Denmark)

    Byskov, A G; Fenger, M; Westergaard, L

    1993-01-01

    We have shown that Meiosis Inducing Substance (MIS) and forskolin synergistically and dose dependently induce meiosis in germ cells of cultured fetal mouse testes. We used a bioassay which consists of fetal mouse testes and ovaries cultured for 6 days. In this study MIS media are spent culture...... are fixed, squashed, and DNA-stained. In these preparations germ cells and somatic cells can be distinguished, and the number of germ cells in the different stages of meiosis is counted as is the number of somatic cells in mitosis. MIS activity is defined to be present in a medium when meiosis is induced...... in male germ cells during culture. We found that MIS media as well as forskolin induced meiosis in fetal male germ cells in a dose-dependent manner. In addition, MIS media and forskolin acted synergistically by inducing meiosis. Female germ cells seem to be unaffected by the various culture media...

  5. Hemolysis, Elevated Liver Enzymes, and Low Platelets, Severe Fetal Growth Restriction, Postpartum Subarachnoid Hemorrhage, and Craniotomy: A Rare Case Report and Systematic Review

    Directory of Open Access Journals (Sweden)

    Shadi Rezai

    2017-01-01

    Full Text Available Introduction. Hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome is a relatively uncommon but traumatic condition occurring in the later stage of pregnancy as a complication of severe preeclampsia or eclampsia. Prompt brain computed tomography (CT or magnetic resonance imaging (MRI and a multidisciplinary management approach are required to improve perinatal outcome. Case. A 37-year-old, Gravida 6, Para 1-0-4-1, Hispanic female with a history of chronic hypertension presented at 26 weeks and 6 days of gestational age. She was noted to have hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome accompanied by fetal growth restriction (FGR, during ultrasound evaluation, warranting premature delivery. The infant was delivered in stable condition suffering no permanent neurological deficit. Conclusion. HELLP syndrome is an uncommon and traumatic obstetric event which can lead to neurological deficits if not managed in a responsive and rapid manner. The central aggravating factor seems to be hypertension induced preeclamptic or eclamptic episode and complications thereof. The syndrome itself is manifested by hemolytic anemia, increased liver enzymes, and decreasing platelet counts with a majority of neurological defects resulting from hemorrhagic stroke or subarachnoid hemorrhage (SAH. To minimize adverse perinatal outcomes, obstetric management of this medical complication must include rapid clinical assessment, diagnostic examination, and neurosurgery consultation.

  6. Fetal injury induced by Ca-DTPA in dogs

    International Nuclear Information System (INIS)

    Taylor, G.N.; Mays, C.W.

    1978-01-01

    The chelating agent Ca-DTPA, used to remove plutonium from the body, has produced fetal deaths and deformities in mice and rats. Damage is caused by depletion of essential trace elements, particularly zinc and manganese. It is suggested that a relationship may exist between the daily amount of Ca-DTPA,per kg body weight needed,to produce fetal toxicity and the daily intake of dietary zinc per kg body weight, and that this relationship could be used to predict fetal toxicity thresholds in various species. Results of a study on beagles are presented. Ca-DTPA treatment at the dose levels used in human therapy did not produce any symptoms in the pregnant dams but the fetuses showed depressed birth weight, abnormal hair colour due to pigmentary deficiency, brain damage and neutropenia. Extrapolation from dogs to humans predicts a toxic fetal dose less that one sixth of the daily dosage presently used for an adult woman, and emphasizes the hazards of Ca-DTPA therapy during pregnancy. (author)

  7. Drug-induced liver injury due to antibiotics.

    Science.gov (United States)

    Björnsson, Einar S

    Drug-induced liver injury (DILI) is an important differential diagnosis in patients with abnormal liver tests and normal hepatobiliary imaging. Of all known liver diseases, the diagnosis of DILI is probably one of the most difficult one to be established. In all major studies on DILI, antibiotics are the most common type of drugs that have been reported. The clinical phenotype of different types of antibiotics associated with liver injury is highly variable. Some widely used antibiotics such as amoxicillin-clavulanate have been shown to have a delayed onset on liver injury and recently cefazolin has been found to lead to liver injury 1-3 weeks after exposure of a single infusion. The other extreme is the nature of nitrofurantoin-induced liver injury, which can occur after a few years of treatment and lead to acute liver failure (ALF) or autoimmune-like reaction. Most patients with liver injury associated with use of antibiotics have a favorable prognosis. However, patients with jaundice have approximately 10% risk of death from liver failure and/or require liver transplantation. In rare instances, the hepatoxicity can lead to chronic injury and vanishing bile duct syndrome. Given, sometimes very severe consequences of the adverse liver reactions, it cannot be over emphasized that the indication for the different antibiotics should be evidence-based and symptoms and signs of liver injury from the drugs should lead to prompt cessation of therapy.

  8. Sex-specific differences in fetal germ cell apoptosis induced by ionizing radiation

    Energy Technology Data Exchange (ETDEWEB)

    Guerquin, M.J.; Duquenne, C.; Coffigny, H.; Rouiller-Fabre, V.; Lambrot, R.; Habert, R.; Livera, G. [CEA, DSV/DRR/SEGG/LDRG, Laboratory of Differentiation and Radiobiology of the Gonads, Unit of Gametogenesis and Genotoxicity, F-92265 Fontenay aux Roses (France); Guerquin, M.J.; Duquenne, C.; Coffigny, H.; Rouiller-Fabre, V.; Lambrot, R.; Habert, R.; Livera, G. [Univ. Paris 7-Denis Diderot, UFR of Biology, UMR-S 566, F-92265 Fontenay aux Roses (France); Guerquin, M.J.; Duquenne, C.; Coffigny, H.; Rouiller-Fabre, V.; Lambrot, R.; Habert, R.; Livera, G. [INSERM, U566, F-92265 Fontenay aux Roses (France); Bakalska, M. [Institute of Experimental Morphology and Anthropology, Bulgarian Academy of Sciences, Sofia (Bulgaria); Frydman, R. [Univ Paris-Sud, Clamart F-92140 (France); Frydman, R. [AP-HP, Service de Gynecologie-Obstetrique et Medecine de la Reproduction, Hopital Antoine Beclere, Clamart F-92141 (France); Frydman, R. [INSERM, U782, Clamart F-92140 (France)

    2009-07-01

    Background: We have previously shown that male human fetal germ cells are highly radiosensitive and that their death depends on p53 activation. Male germ cell apoptosis was initiated with doses as low as 0.1 Gy and was prevented by pifithrin {alpha}, a p53 inhibitor. In this study, we investigated the radiosensitivity of early female and male fetal proliferating germ cells. Methods and results: Both male and female fetal germ cells displayed a similar number of {gamma}H2AX foci in response to ionizing radiation (IR). In organ culture of human fetal ovaries, the germ cells underwent apoptosis only when exposed to high doses of IR (1.5 Gy and above). Accumulation of p53 was detected in irradiated male human fetal germ cells but not in female ones. Inhibition of p53 with pifithrin {alpha} did not affect oogonia apoptosis following irradiation. IR induced apoptosis similarly in mouse fetal ovaries in organ culture and in vivo during oogonial proliferation. Germ cell survival in testes from p53 knockout or p63 knockout mice exposed to IR was better than wild-type, whereas female germ cell survival was unaffected by p53 or p63 knockout. Conclusions: These findings show that pre-meiotic male and female fetal germ cells behave differently in response to a genotoxic stress-irradiation with oogonia being less sensitive and undergoing p53-independent apoptosis. (authors)

  9. Sex-specific differences in fetal germ cell apoptosis induced by ionizing radiation

    International Nuclear Information System (INIS)

    Guerquin, M.J.; Duquenne, C.; Coffigny, H.; Rouiller-Fabre, V.; Lambrot, R.; Habert, R.; Livera, G.; Guerquin, M.J.; Duquenne, C.; Coffigny, H.; Rouiller-Fabre, V.; Lambrot, R.; Habert, R.; Livera, G.; Guerquin, M.J.; Duquenne, C.; Coffigny, H.; Rouiller-Fabre, V.; Lambrot, R.; Habert, R.; Livera, G.; Bakalska, M.; Frydman, R.; Frydman, R.; Frydman, R.

    2009-01-01

    Background: We have previously shown that male human fetal germ cells are highly radiosensitive and that their death depends on p53 activation. Male germ cell apoptosis was initiated with doses as low as 0.1 Gy and was prevented by pifithrin α, a p53 inhibitor. In this study, we investigated the radiosensitivity of early female and male fetal proliferating germ cells. Methods and results: Both male and female fetal germ cells displayed a similar number of γH2AX foci in response to ionizing radiation (IR). In organ culture of human fetal ovaries, the germ cells underwent apoptosis only when exposed to high doses of IR (1.5 Gy and above). Accumulation of p53 was detected in irradiated male human fetal germ cells but not in female ones. Inhibition of p53 with pifithrin α did not affect oogonia apoptosis following irradiation. IR induced apoptosis similarly in mouse fetal ovaries in organ culture and in vivo during oogonial proliferation. Germ cell survival in testes from p53 knockout or p63 knockout mice exposed to IR was better than wild-type, whereas female germ cell survival was unaffected by p53 or p63 knockout. Conclusions: These findings show that pre-meiotic male and female fetal germ cells behave differently in response to a genotoxic stress-irradiation with oogonia being less sensitive and undergoing p53-independent apoptosis. (authors)

  10. Prenatal MRI fetal lung volumes and percent liver herniation predict pulmonary morbidity in congenital diaphragmatic hernia (CDH).

    Science.gov (United States)

    Zamora, Irving J; Olutoye, Oluyinka O; Cass, Darrell L; Fallon, Sara C; Lazar, David A; Cassady, Christopher I; Mehollin-Ray, Amy R; Welty, Stephen E; Ruano, Rodrigo; Belfort, Michael A; Lee, Timothy C

    2014-05-01

    The purpose of this study was to determine whether prenatal imaging parameters are predictive of postnatal CDH-associated pulmonary morbidity. The records of all neonates with CDH treated from 2004 to 2012 were reviewed. Patients requiring supplemental oxygen at 30 days of life (DOL) were classified as having chronic lung disease (CLD). Fetal MRI-measured observed/expected total fetal lung volume (O/E-TFLV) and percent liver herniation (%LH) were recorded. Receiver operating characteristic (ROC) curves and multivariate regression were applied to assess the prognostic value of O/E-TFLV and %LH for development of CLD. Of 172 neonates with CDH, 108 had fetal MRIs, and survival was 76%. 82% (89/108) were alive at DOL 30, 46 (52%) of whom had CLD. Neonates with CLD had lower mean O/E-TFLV (30 vs.42%; p=0.001) and higher %LH (21.3±2.8 vs.7.1±1.8%; p20% (AUC=0.78; p20% were highly associated with indicators of long-term pulmonary sequelae. On multivariate analysis, %LH was the strongest predictor of CLD in patients with CDH (OR: 10.96, 95%CI: 2.5-48.9, p=0.002). Prenatal measurement of O/E-TFLV and %LH is predictive of CDH pulmonary morbidity and can aid in establishing parental expectations of postnatal outcomes. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Enhancement of the grafting efficiency by the new method of fetal liver-bone marrow scheduled transplantation

    International Nuclear Information System (INIS)

    Xiang Yingsong; Yang Rujun; Yang Ping; Cai Jianming; Min Rui

    2000-01-01

    To enhance the grafting efficiency of bone marrow transplantation, lethally Irradiated recipient Kunming mice were transplantation with fetal liver-bone marrow scheduled transplantation. (FL-BMST) The numbers of WBC, nucleated cells were near to normal level 17 d after irradiation in FL-BMST group transplantation with 1 x 10 6 bone marrow cells, the indexes of CFU-E, CFU-GM, CFU-F, CFU-S, were returned to normal; the degree of GVHD in the FL-BMST group was slighter than that in sing bone marrow transplantation group; and the survival rate of mice was 60%, which was significantly higher than that of routine single bone marrow transplantation group. 'Niches' vacated each time could be fully used and be improved, be increased by fetal liver-bone marrow scheduled transplantation, so the homing of stem cells was increased, and the number of transplanted bone marrow cells could be decreased. So this new method was a better method than routine bone singe marrow transplantation

  12. Acute liver injury induced by weight-loss herbal supplements.

    Science.gov (United States)

    Chen, Gary C; Ramanathan, Vivek S; Law, David; Funchain, Pauline; Chen, George C; French, Samuel; Shlopov, Boris; Eysselein, Viktor; Chung, David; Reicher, Sonya; Pham, Binh V

    2010-11-27

    We report three cases of patients with acute liver injury induced by weight-loss herbal supplements. One patient took Hydroxycut while the other two took Herbalife supplements. Liver biopsies for all patients demonstrated findings consistent with drug-induced acute liver injury. To our knowledge, we are the first institute to report acute liver injury from both of these two types of weight-loss herbal supplements together as a case series. The series emphasizes the importance of taking a cautious approach when consuming herbal supplements for the purpose of weight loss.

  13. Dihydrotestosterone Potentiates EGF-Induced ERK Activation by Inducing SRC in Fetal Lung Fibroblasts

    Science.gov (United States)

    Smith, Susan M.; Murray, Sandy; Pham, Lucia D.; Minoo, Parviz; Nielsen, Heber C.

    2014-01-01

    Lung maturation is regulated by interactions between mesenchymal and epithelial cells, and is delayed by androgens. Fibroblast–Type II cell communications are dependent on extracellular signal-regulated kinases (ERK) 1/2 activation by the ErbB receptor ligands epidermal growth factor (EGF), transforming growth factor (TGF)-α, and neuregulin (Nrg). In other tissues, dihydrotestosterone (DHT) has been shown to activate SRC by a novel nontranscriptional mechanism, which phosphorylates EGF receptors to potentiate EGF-induced ERK1/2 activation. This study sought to determine if DHT potentiates EGFR signaling by a nontranscriptional mechanism. Embryonic day (E)17 fetal lung cells were isolated from dams treated with or without DHT since E12. Cells were exposed to 30 ng/ml DHT for periods of 30 minutes to 3 days before being stimulated with 100 ng/ml EGF, TGF-α, or Nrg for up to 30 minutes. Lysates were immunoblotted for ErbB and SRC pathway signaling intermediates. DHT increased ERK1/2 activation by EGF, TGF-α, and Nrg in fibroblasts and Type II cells. Characterization in fibroblasts showed that potentiation of the EGF pathway was significant after 60 minutes of DHT exposure and persisted in the presence of the translational inhibitor cycloheximide. SRC and EGF receptor phosphorylation was increased by DHT, as was EGF-induced SHC1 phosphorylation and subsequent association with GRB2. Finally, SRC silencing, SRC inhibition with PP2, and overexpression of a dominant-negative SRC each prevented DHT from increasing EGF-induced ERK1/2 phosphorylation. These results suggest that DHT activates SRC to potentiate the signaling pathway leading from the EGF receptor to ERK activation in primary fetal lung fibroblasts. PMID:24484548

  14. A Case of Alloimmune Thrombocytopenia, Hemorrhagic Anemia-Induced Fetal Hydrops, Maternal Mirror Syndrome, and Human Chorionic Gonadotropin–Induced Thyrotoxicosis

    Directory of Open Access Journals (Sweden)

    Venu Jain

    2013-05-01

    Full Text Available Fetal/neonatal alloimmune thrombocytopenia (FNAIT can be a cause of severe fetal thrombocytopenia, with the common presentation being intracranial hemorrhage in the fetus, usually in the third trimester. A very unusual case of fetal anemia progressed to hydrops. This was further complicated by maternal Mirror syndrome and human chorionic gonadotropin–induced thyrotoxicosis. Without knowledge of etiology, and possibly due to associated cardiac dysfunction, fetal transfusion resulted in fetal demise. Subsequent testing revealed FNAIT as the cause of severe hemorrhagic anemia. In cases with fetal anemia without presence of red blood cell antibodies, FNAIT must be ruled out as a cause prior to performing fetal transfusion. Fetal heart may adapt differently to acute hemorrhagic anemia compared with a more subacute hemolytic anemia.

  15. Moderate nutrient restriction influences transcript abundance of genes impacting production efficiencies of beef cattle in fetal liver, muscle, and cerebrum by d 50 of gestation

    Science.gov (United States)

    We hypothesized that a moderate maternal nutrient restriction during the first 50 d of gestation in beef heifers would affect transcript abundance of genes impacting production efficiency phenotypes in fetal liver, muscle, and cerebrum. Fourteen Angus-cross heifers were estrus synchronized and assig...

  16. Moderate nutrient restriction influences expression of genes impacting production efficiencies of beef cattle in fetal liver, muscle and cerebrum by day 50 of gestation

    Science.gov (United States)

    We hypothesized that a moderate maternal nutrient restriction during the first 50 days of gestation in beef heifers would affect expression of genes impacting production efficiency phenotypes in the fetal liver, muscle and cerebrum. Fourteen Angus-cross heifers were estrus synchronized and assigned ...

  17. Cloning of a novel cell type from human fetal liver expressing cytoplasmic CD3 delta and epsilon but not membrane CD3

    NARCIS (Netherlands)

    Hori, T.; de Waal Malefyt, R.; Duncan, B. W.; Harrison, M. R.; Roncarolo, M. G.; Spits, H.

    1991-01-01

    Seventeen-week human fetal liver cells cultured with a feeder cell mixture of irradiated PBL, irradiated JY cells (an EBV-transformed B cell line) and PHA contained a subpopulation of CD3- cells in addition to a major population of T cells with the mature phenotype. After 12 days in culture, CD3-

  18. Acetaminophen-induced acute liver injury in HCV transgenic mice

    International Nuclear Information System (INIS)

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U.; Tech, Katherine; Macdonald, Jeffrey M.; Boorman, Gary A.; Chatterjee, Saurabh; Mason, Ronald P.; Melnyk, Stepan B.; Tryndyak, Volodymyr P.; Pogribny, Igor P.; Rusyn, Ivan

    2013-01-01

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

  19. Acetaminophen-induced acute liver injury in HCV transgenic mice

    Energy Technology Data Exchange (ETDEWEB)

    Uehara, Takeki; Kosyk, Oksana; Jeannot, Emmanuelle; Bradford, Blair U. [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Tech, Katherine; Macdonald, Jeffrey M. [Department of Biomedical Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States); Boorman, Gary A. [Covance, Chantilly, VA 20151 (United States); Chatterjee, Saurabh; Mason, Ronald P. [Laboratory of Toxicology and Pharmacology, National Institute of Environmental Health Sciences, RTP, NC 27713 (United States); Melnyk, Stepan B. [Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72201 (United States); Tryndyak, Volodymyr P.; Pogribny, Igor P. [Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR 72079 (United States); Rusyn, Ivan, E-mail: iir@unc.edu [Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599 (United States)

    2013-01-15

    The exact etiology of clinical cases of acute liver failure is difficult to ascertain and it is likely that various co-morbidity factors play a role. For example, epidemiological evidence suggests that coexistent hepatitis C virus (HCV) infection increased the risk of acetaminophen-induced acute liver injury, and was associated with an increased risk of progression to acute liver failure. However, little is known about possible mechanisms of enhanced acetaminophen hepatotoxicity in HCV-infected subjects. In this study, we tested a hypothesis that HCV-Tg mice may be more susceptible to acetaminophen hepatotoxicity, and also evaluated the mechanisms of acetaminophen-induced liver damage in wild type and HCV-Tg mice expressing core, E1 and E2 proteins. Male mice were treated with a single dose of acetaminophen (300 or 500 mg/kg in fed animals; or 200 mg/kg in fasted animals; i.g.) and liver and serum endpoints were evaluated at 4 and 24 h after dosing. Our results suggest that in fed mice, liver toxicity in HCV-Tg mice is not markedly exaggerated as compared to the wild-type mice. In fasted mice, greater liver injury was observed in HCV-Tg mice. In fed mice dosed with 300 mg/kg acetaminophen, we observed that liver mitochondria in HCV-Tg mice exhibited signs of dysfunction showing the potential mechanism for increased susceptibility. -- Highlights: ► Acetaminophen-induced liver injury is a significant clinical challenge. ► HCV-infected subjects may be at higher risk for acetaminophen-induced liver injury. ► We used HCV transgenics to test if liver injury due to acetaminophen is exacerbated.

  20. Maternal Sevoflurane Exposure Causes Abnormal Development of Fetal Prefrontal Cortex and Induces Cognitive Dysfunction in Offspring

    Directory of Open Access Journals (Sweden)

    Ruixue Song

    2017-01-01

    Full Text Available Maternal sevoflurane exposure during pregnancy is associated with increased risk for behavioral deficits in offspring. Several studies indicated that neurogenesis abnormality may be responsible for the sevoflurane-induced neurotoxicity, but the concrete impact of sevoflurane on fetal brain development remains poorly understood. We aimed to investigate whether maternal sevoflurane exposure caused learning and memory impairment in offspring through inducing abnormal development of the fetal prefrontal cortex (PFC. Pregnant mice at gestational day 15.5 received 2.5% sevoflurane for 6 h. Learning function of the offspring was evaluated with the Morris water maze test at postnatal day 30. Brain tissues of fetal mice were subjected to immunofluorescence staining to assess differentiation, proliferation, and cell cycle dynamics of the fetal PFC. We found that maternal sevoflurane anesthesia impaired learning ability in offspring through inhibiting deep-layer immature neuron output and neuronal progenitor replication. With the assessment of cell cycle dynamics, we established that these effects were mediated through cell cycle arrest in neural progenitors. Our research has provided insights into the cell cycle-related mechanisms by which maternal sevoflurane exposure can induce neurodevelopmental abnormalities and learning dysfunction and appeals people to consider the neurotoxicity of anesthetics when considering the benefits and risks of nonobstetric surgical procedures.

  1. Immunohistochemical study on the fetal rat pituitary in hyperthermia-induced exencephaly

    OpenAIRE

    Watanabe, Yuichi G.; 渡辺, 勇一

    2002-01-01

    Hyperthermia of fetal rats is known to cause malformations of various organs including brain. The present study was carried out to investigate the effect of the hyperthermia-induced brain damages on the development of the adenohypophysis. Mother rats of Day 9.5 of pregnancy were anesthetized and immersed in hot water (43℃) for 15 min. At Day 21.5 of gestation, fetuses were removed by caesarian section and examined for exencephaly. Hyperthermal stress induced varying degrees of exencephaly in ...

  2. Fingolimod against endotoxin-induced fetal brain injury in a rat model.

    Science.gov (United States)

    Yavuz, And; Sezik, Mekin; Ozmen, Ozlem; Asci, Halil

    2017-11-01

    Fingolimod is a sphingosine-1-phosphate receptor modulator used for multiple sclerosis treatment and acts on cellular processes such as apoptosis, endothelial permeability, and inflammation. We hypothesized that fingolimod has a positive effect on alleviating preterm fetal brain injury. Sixteen pregnant rats were divided into four groups of four rats each. On gestational day 17, i.p. endotoxin was injected to induce fetal brain injury, followed by i.p. fingolimod (4 mg/kg maternal weight). Hysterotomy for preterm delivery was performed 6 h after fingolimod. The study groups included (i) vehicle controls (i.p. normal saline only); (ii) positive controls (endotoxin plus saline); (iii) saline plus fingolimod; and (iv) endotoxin plus fingolimod treatment. Brain tissues of the pups were dissected for evaluation of interleukin (IL)-6, caspase-3, and S100β on immunohistochemistry. Maternal fingolimod treatment attenuated endotoxin-related fetal brain injury and led to lower immunoreactions for IL-6, caspase-3, and S100β compared with endotoxin controls (P < 0.0001 for all comparisons). Antenatal maternal fingolimod therapy had fetal neuroprotective effects by alleviating preterm birth-related fetal brain injury with inhibitory effects on inflammation and apoptosis. © 2017 Japan Society of Obstetrics and Gynecology.

  3. Human fetal liver stromal cells that overexpress bFGF support growth and maintenance of human embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Jiafei Xi

    Full Text Available In guiding hES cell technology toward the clinic, one key issue to be addressed is to culture and maintain hES cells much more safely and economically in large scale. In order to avoid using mouse embryonic fibroblasts (MEFs we isolated human fetal liver stromal cells (hFLSCs from 14 weeks human fetal liver as new human feeder cells. hFLSCs feeders could maintain hES cells for 15 passages (about 100 days. Basic fibroblast growth factor (bFGF is known to play an important role in promoting self-renewal of human embryonic stem (hES cells. So, we established transgenic hFLSCs that stably express bFGF by lentiviral vectors. These transgenic human feeder cells--bFGF-hFLSCs maintained the properties of H9 hES cells without supplementing with any exogenous growth factors. H9 hES cells culturing under these conditions maintained all hES cell features after prolonged culture, including the developmental potential to differentiate into representative tissues of all three embryonic germ layers, unlimited and undifferentiated proliferative ability, and maintenance of normal karyotype. Our results demonstrated that bFGF-hFLSCs feeder cells were central to establishing the signaling network among bFGF, insulin-like growth factor 2 (IGF-2, and transforming growth factor β (TGF-β, thereby providing the framework in which hES cells were instructed to self-renew or to differentiate. We also found that the conditioned medium of bFGF-hFLSCs could maintain the H9 hES cells under feeder-free conditions without supplementing with bFGF. Taken together, bFGF-hFLSCs had great potential as feeders for maintaining pluripotent hES cell lines more safely and economically.

  4. T lymphocytes from irradiation chimeras repopulated with 13-day fetal liver cells recognize antigens only in association with self-MHC products

    International Nuclear Information System (INIS)

    Nisbet-Brown, E.; Diener, E.

    1986-01-01

    The restriction specificities of maturing thymocytes are determined by the Class II MHC antigens expressed by non-lymphoid thymic tissues. The proliferative response of mature T lymphocytes to antigen-presenting cells (APC) and antigen requires that the APC express the same MHC antigens as the thymus in which the T cells differentiated. Thus, in the two-way bone marrow chimera [A + B----(A x B)F1], T lymphocyte populations of A and B haplotypes have each acquired the potential to recognize antigens associated with either parental haplotype. In spite of the large body of work on MHC restriction, we still do not have a clear understanding of the mechanisms which impose self restriction. The chimeric model systems used previously to study MHC restriction have used adult bone marrow cells as the source of lymphoid precursors. During normal ontogeny, T cells are derived from precursors in the fetal liver and we felt that a direct comparison of T cells from fetal liver and bone marrow-repopulated animals would shed light on the development of MHC restriction specificities during T cell ontogeny in the thymus or prethymically. We found that parental T lymphocyte populations isolated from two-way fetal liver chimeras cooperated only with syngeneic APC, while those from bone marrow chimeras cooperated with APC of either parental haplotype. This suggests that fetal liver and bone marrow may not be equivalent sources of stem cells. Our results may be due to fundamental differences between thymocyte precursors in fetal liver and bone marrow, including the time course of their expression of T cell receptor gene products

  5. Inability to fully suppress sterol synthesis rates with exogenous sterol in embryonic and extraembyronic fetal tissues

    OpenAIRE

    Yao, Lihang; Jenkins, Katie; Horn, Paul S.; Lichtenberg, M. Hayden; Woollett, Laura A.

    2007-01-01

    The requirement for cholesterol is greater in developing tissues (fetus, placenta, and yolk sac) as compared to adult tissues. Here, we compared cholesterol-induced suppression of sterol synthesis rates in the adult liver to the fetal liver, fetal body, placenta, and yolk sac of the Golden Syrian hamster. Sterol synthesis rates were suppressed maximally in non-pregnant adult livers when cholesterol concentrations were increased. In contrast, sterol synthesis rates were suppressed only margina...

  6. Prenatal caffeine exposure induced a lower level of fetal blood leptin mainly via placental mechanism

    International Nuclear Information System (INIS)

    Wu, Yi-meng; Luo, Han-wen; Kou, Hao; Wen, Yin-xian; Shen, Lang; Pei, Ling-guo; Zhou, Jin; Zhang, Yuan-zhen; Wang, Hui

    2015-01-01

    It's known that blood leptin level is reduced in intrauterine growth retardation (IUGR) fetus, and placental leptin is the major source of fetal blood leptin. This study aimed to investigate the decreased fetal blood leptin level by prenatal caffeine exposure (PCE) and its underlying placental mechanisms. Pregnant Wistar rats were intragastrically administered caffeine (30–120 mg/kg day) from gestational day 9 to 20. The level of fetal serum leptin and the expression of placental leptin-related genes were analyzed. Furthermore, we investigated the molecular mechanism of the reduced placental leptin's expression by treatment with caffeine (0.8–20 μM) in the BeWo cells. In vivo, PCE significantly decreased fetal serum leptin level in caffeine dose-dependent manner. Meanwhile, placental mRNA expression of adenosine A2a receptor (Adora2a), cAMP-response element binding protein (CREB), a short-type leptin receptor (Ob-Ra) and leptin was reduced in the PCE groups. In vitro, caffeine significantly decreased the mRNA expression of leptin, CREB and ADORA2A in concentration and time-dependent manners. The addition of ADORA2A agonist or adenylyl cyclase (AC) agonist reversed the inhibition of leptin expression induced by caffeine. PCE induced a lower level of fetal blood leptin, which the primary mechanism is that caffeine inhibited antagonized Adora2a and AC activities to decreased cAMP synthesis, thus inhibited the expression of the transcription factor CREB and target gene leptin in the placenta. Meantime, the reduced transportation of maternal leptin by placental Ob-Ra also contributed to the reduced fetal blood leptin. Together, PCE decreased fetal blood leptin mainly via reducing the expression and transportation of leptin in the placenta. - Highlights: • Caffeine reduced fetal blood leptin level. • Caffeine inhibited placental leptin production and transport. • Caffeine down-regulated placental leptin expression via antagonizing ADORA2.

  7. Prenatal caffeine exposure induced a lower level of fetal blood leptin mainly via placental mechanism

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Yi-meng [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Luo, Han-wen [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Kou, Hao [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Wen, Yin-xian [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Shen, Lang; Pei, Ling-guo; Zhou, Jin [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Zhang, Yuan-zhen [Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071 (China); Wang, Hui, E-mail: wanghui19@whu.edu.cn [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071 (China)

    2015-11-15

    It's known that blood leptin level is reduced in intrauterine growth retardation (IUGR) fetus, and placental leptin is the major source of fetal blood leptin. This study aimed to investigate the decreased fetal blood leptin level by prenatal caffeine exposure (PCE) and its underlying placental mechanisms. Pregnant Wistar rats were intragastrically administered caffeine (30–120 mg/kg day) from gestational day 9 to 20. The level of fetal serum leptin and the expression of placental leptin-related genes were analyzed. Furthermore, we investigated the molecular mechanism of the reduced placental leptin's expression by treatment with caffeine (0.8–20 μM) in the BeWo cells. In vivo, PCE significantly decreased fetal serum leptin level in caffeine dose-dependent manner. Meanwhile, placental mRNA expression of adenosine A2a receptor (Adora2a), cAMP-response element binding protein (CREB), a short-type leptin receptor (Ob-Ra) and leptin was reduced in the PCE groups. In vitro, caffeine significantly decreased the mRNA expression of leptin, CREB and ADORA2A in concentration and time-dependent manners. The addition of ADORA2A agonist or adenylyl cyclase (AC) agonist reversed the inhibition of leptin expression induced by caffeine. PCE induced a lower level of fetal blood leptin, which the primary mechanism is that caffeine inhibited antagonized Adora2a and AC activities to decreased cAMP synthesis, thus inhibited the expression of the transcription factor CREB and target gene leptin in the placenta. Meantime, the reduced transportation of maternal leptin by placental Ob-Ra also contributed to the reduced fetal blood leptin. Together, PCE decreased fetal blood leptin mainly via reducing the expression and transportation of leptin in the placenta. - Highlights: • Caffeine reduced fetal blood leptin level. • Caffeine inhibited placental leptin production and transport. • Caffeine down-regulated placental leptin expression via antagonizing ADORA2.

  8. Role of IRAK-M in alcohol induced liver injury.

    Directory of Open Access Journals (Sweden)

    Yipeng Wang

    Full Text Available Increasing evidence suggests that innate immunity plays an important role in alcohol-induced liver injury and most studies have focused on positive regulation of innate immunity. The main objective of this study was to investigate the negative regulator of innate immunity, IL-1/Toll-like receptor (TLR signaling pathways and interleukin receptor-associated kinase-M (IRAK-M in alcoholic liver injury. We established an alcohol-induced liver injury model using wild type and IRAK-M deficient B6 mice and investigated the possible mechanisms. We found that in the absence of IRAK-M, liver damage by alcohol was worse with higher alanine transaminase (ALT, more immune cell infiltration and increased numbers of IFNγ producing cells. We also found enhanced phagocytic activity in CD68(+ cells. Moreover, our results revealed altered gut bacteria after alcohol consumption and this was more striking in the absence of IRAK-M. Our study provides evidence that IRAK-M plays an important role in alcohol-induced liver injury and IRAK-M negatively regulates the innate and possibly the adaptive immune response in the liver reacting to acute insult by alcohol. In the absence of IRAK-M, the hosts developed worse liver injury, enhanced gut permeability and altered gut microbiota.

  9. Immortalization of Human Fetal Hepatocyte by Ectopic Expression of Human Telomerase Reverse Transcriptase, Human Papilloma Virus (E7) and Simian Virus 40 Large T (SV40 T) Antigen Towards Bioartificial Liver Support.

    Science.gov (United States)

    Giri, Shibashish; Bader, Augustinus

    2014-09-01

    Generation of genetically stable and non-tumoric immortalization cell line from primary cells would be enormously useful for research and therapeutic purposes, but progress towards this goal has so far been limited. It is now universal acceptance that immortalization of human fetal hepatocytes based on recent advances of telomerase biology and oncogene, lead to unlimited population doubling could be the possible source for bioartificial liver device. Immortalization of human fetal hepatocytes cell line by ectopic expression of human telomerase reverse transcriptase (hTERT), human papilloma virus gene (E7) and simian virus 40 large T (SV40 T) antigens is main goal of present study. We used an inducible system containing human telomerase and E7, both of which are cloned into responder constructs controlled by doxycycline transactivator. We characterized the immortalized human fetal hepatocyte cells by analysis of green fluorescent cells (GFP) positive cells using flow cytometry (FACs) cell sorting and morphology, proliferative rate and antigen expression by immunohistochemical analysis. In addition to we analysized lactate formation, glucose consumption, albumin secretion and urea production of immortalized human fetal hepatocyte cells. After 25 attempts for transfection of adult primary hepatocytes by human telomerase and E7 to immortalize them, none of the transfection systems resulted in the production of a stable, proliferating cell line. Although the transfection efficiency was more than 70% on the first day, the vast majority of the transfected hepatocytes lost their signal within the first 5-7 days. The remaining transfected hepatocytes persisted for 2-4 weeks and divided one or two times without forming a clone. After 10 attempts of transfection human fetal hepatocytes using the same transfection system, we obtained one stable human fetal hepatocytes cell line which was able albumin secretion urea production and glucose consumption. We established a

  10. Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis

    OpenAIRE

    Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

    2016-01-01

    AIM To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. METHODS Liver stiffness was measured in sixty-eight rabbits with CCl4-induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points...

  11. Crizotinib-induced fatal fulminant liver failure

    NARCIS (Netherlands)

    van Geel, Robin M J M; Hendrikx, Jeroen J M A; Vahl, Jelmer E.; van Leerdam, Monique E.; van den Broek, Daan; Huitema, Alwin D R; Beijnen, Jos H.; Schellens, Jan H M; Burgers, Sjaak A.

    2016-01-01

    Herein we describe a case of a 62-year-old female in good clinical condition with non-small-cell lung cancer who was treated with crizotinib. After 24 days of crizotinib therapy she presented with acute liver failure. Serum aspartate aminotransferase and alanine aminotransferase levels had increased

  12. Induced pluripotent stem (iPS) cells from human fetal stem cells

    OpenAIRE

    Guillot, P. V.

    2016-01-01

    Pluripotency defines the ability of stem cells to differentiate into all the lineages of the three germ layers and self-renew indefinitely. Somatic cells can regain the developmental potential of embryonic stem cells following ectopic expression of a set of transcription factors or, in certain circumstances, via modulation of culture conditions and supplementation with small molecule, that is, induced pluripotent stem (iPS) cells. Here, we discuss the use of fetal tissues for reprogramming, f...

  13. Diphenhydramine as a Cause of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Yunseok Namn

    2017-01-01

    Full Text Available Drug-induced liver injury (DILI is the most common cause of acute liver failure in the Unites States and accounts for 10% of acute hepatitis cases. We report the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. A 28-year-old man with history of 13/14-chromosomal translocation presented with fevers, vomiting, and jaundice. Aspartate-aminotransferase and alanine-aminotransferase levels peaked above 20,000 IU/L and 5,000 IU/L, respectively. He developed coagulopathy but without altered mental status. Patient reported taking up to 400 mg diphenhydramine nightly, without concomitant acetaminophen, for insomnia. He denied taking other medications, supplements, antibiotics, and herbals. A thorough workup of liver injury ruled out viral hepatitis (including A, B, C, and E, autoimmune, toxic, ischemic, and metabolic etiologies including Wilson’s disease. A liver biopsy was consistent with DILI without evidence of iron or copper deposition. Diphenhydramine was determined to be the likely culprit. This is the first reported case of diphenhydramine-induced liver injury without concomitant use of acetaminophen.

  14. Maternal L-glutamine supplementation prevents prenatal alcohol exposure-induced fetal growth restriction in an ovine model.

    Science.gov (United States)

    Sawant, Onkar B; Wu, Guoyao; Washburn, Shannon E

    2015-06-01

    Prenatal alcohol exposure is known to cause fetal growth restriction and disturbances in amino acid bioavailability. Alterations in these parameters can persist into adulthood and low birth weight can lead to altered fetal programming. Glutamine has been associated with the synthesis of other amino acids, an increase in protein synthesis and it is used clinically as a nutrient supplement for low birth weight infants. The aim of this study was to explore the effect of repeated maternal alcohol exposure and L-glutamine supplementation on fetal growth and amino acid bioavailability during the third trimester-equivalent period in an ovine model. Pregnant sheep were randomly assigned to four groups, saline control, alcohol (1.75-2.5 g/kg), glutamine (100 mg/kg, three times daily) or alcohol + glutamine. In this study, a weekend binge drinking model was followed where treatment was done 3 days per week in succession from gestational day (GD) 109-132 (normal term ~147). Maternal alcohol exposure significantly reduced fetal body weight, height, length, thoracic girth and brain weight, and resulted in decreased amino acid bioavailability in fetal plasma and placental fluids. Maternal glutamine supplementation successfully mitigated alcohol-induced fetal growth restriction and improved the bioavailability of glutamine and glutamine-related amino acids such as glycine, arginine, and asparagine in the fetal compartment. All together, these findings show that L-glutamine supplementation enhances amino acid availability in the fetus and prevents alcohol-induced fetal growth restriction.

  15. Liver injury from Herbals and Dietary Supplements in the US Drug Induced Liver Injury Network

    Science.gov (United States)

    Navarro, Victor J.; Barnhart, Huiman; Bonkovsky, Herbert L.; Davern, Timothy; Fontana, Robert J.; Grant, Lafaine; Reddy, K. Rajender; Seeff, Leonard B.; Serrano, Jose; Sherker, Averell H.; Stolz, Andrew; Talwalkar, Jayant; Vega, Maricruz; Vuppalanchi, Raj

    2014-01-01

    Background The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity due to conventional medications as well as herbals and dietary supplements (HDS). Rationale To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight US referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury due to HDS. Hepatotoxicity due to HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments including death and liver transplantation were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury due to bodybuilding HDS, 85 due to non-bodybuilding HDS, and 709 due to medications. Main Results Liver injury due to HDS increased from 7% to 20% (p Bodybuilding HDS caused prolonged jaundice (median 91 days) in young men but did not result in any fatalities or liver transplantation. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women and more frequently led to death or transplantation compared to injury from medications (13% vs. 3%, p bodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes; death and transplantation. PMID:25043597

  16. Hedgehog pathway mediates early acceleration of liver regeneration induced by a novel two-staged hepatectomy in mice.

    Science.gov (United States)

    Langiewicz, Magda; Schlegel, Andrea; Saponara, Enrica; Linecker, Michael; Borger, Pieter; Graf, Rolf; Humar, Bostjan; Clavien, Pierre A

    2017-03-01

    ALPPS, a novel two-staged approach for the surgical removal of large/multiple liver tumors, combines portal vein ligation (PVL) with parenchymal transection. This causes acceleration of compensatory liver growth, enabling faster and more extensive tumor removal. We sought to identify the plasma factors thought to mediate the regenerative acceleration following ALPPS. We compared a mouse model of ALPPS against PVL and additional control surgeries (n=6 per group). RNA deep sequencing was performed to identify candidate molecules unique to ALPPS liver (n=3 per group). Recombinant protein and a neutralizing antibody combined with appropriate surgeries were used to explore candidate functions in ALPPS (n=6 per group). Indian hedgehog (IHH/Ihh) levels were assessed in human ALPPS patient plasma (n=6). ALPPS in mouse confirmed significant acceleration of liver regeneration relative to PVL (pIhh mRNA, coding for a secreted ligand inducing hedgehog signaling, was uniquely upregulated in ALPPS liver (pIhh plasma levels rose 4h after surgery (pIhh alone was sufficient to induce ALPPS-like acceleration of liver growth. Conversely, blocking Ihh markedly inhibited the accelerating effects of ALPPS. In the small cohort of ALPPS patients, IHH tended to be elevated early after surgery. Ihh and hedgehog pathway activation provide the first mechanistic insight into the acceleration of liver regeneration triggered by ALPPS surgery. The accelerating potency of recombinant Ihh, and its potential effect in human ALPPS may lead to a clinical role for this protein. ALPPS, a novel two-staged hepatectomy, accelerates liver regeneration, thereby helping to treat patients with otherwise unresectable liver tumors. The molecular mechanisms behind this accelerated regeneration are unknown. Here, we elucidate that Indian hedgehog, a secreted ligand important for fetal development, is a crucial mediator of the regenerative acceleration triggered by ALPPS surgery. Copyright © 2016. Published by

  17. Non-invasive evaluation of liver stiffness after splenectomy in rabbits with CCl4-induced liver fibrosis.

    Science.gov (United States)

    Wang, Ming-Jun; Ling, Wen-Wu; Wang, Hong; Meng, Ling-Wei; Cai, He; Peng, Bing

    2016-12-14

    To investigate the diagnostic performance of liver stiffness measurement (LSM) by elastography point quantification (ElastPQ) in animal models and determine the longitudinal changes in liver stiffness by ElastPQ after splenectomy at different stages of fibrosis. Liver stiffness was measured in sixty-eight rabbits with CCl 4 -induced liver fibrosis at different stages and eight healthy control rabbits by ElastPQ. Liver biopsies and blood samples were obtained at scheduled time points to assess liver function and degree of fibrosis. Thirty-one rabbits with complete data that underwent splenectomy at different stages of liver fibrosis were then included for dynamic monitoring of changes in liver stiffness by ElastPQ and liver function according to blood tests. LSM by ElastPQ was significantly correlated with histologic fibrosis stage ( r = 0.85, P fibrosis, moderate fibrosis, and cirrhosis, respectively. Longitudinal monitoring of the changes in liver stiffness by ElastPQ showed that early splenectomy (especially F1) may delay liver fibrosis progression. ElastPQ is an available, convenient, objective and non-invasive technique for assessing liver stiffness in rabbits with CCl 4 -induced liver fibrosis. In addition, liver stiffness measurements using ElastPQ can dynamically monitor the changes in liver stiffness in rabbit models, and in patients, after splenectomy.

  18. Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

    Directory of Open Access Journals (Sweden)

    Sathish Kumar Natarajan

    2018-01-01

    Full Text Available Acute fatty liver of pregnancy (AFLP, a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is highly associated with a fetal homozygous mutation (1528G>C in the gene that encodes for mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD. The mutation in LCHAD results in the accumulation of 3-hydroxy fatty acids, such as 3-hydroxy myristic acid, 3-hydroxy palmitic acid and 3-hydroxy dicarboxylic acid in the placenta, which are then shunted to the maternal circulation leading to the development of acute liver injury observed in patients with AFLP. In this review, we will discuss the mechanistic role of increased 3-hydroxy fatty acid in causing lipotoxicity to the liver and in inducing oxidative stress, mitochondrial dysfunction and hepatocyte lipoapoptosis. Further, we also review the role of 3-hydroxy fatty acids in causing placental damage, pancreatic islet β-cell glucolipotoxicity, brain damage, and retinal epithelial cells lipoapoptosis in patients with LCHAD deficiency.

  19. Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy

    Science.gov (United States)

    Ibdah, Jamal A.

    2018-01-01

    Acute fatty liver of pregnancy (AFLP), a catastrophic illness for both the mother and the unborn offspring, develops in the last trimester of pregnancy with significant maternal and perinatal mortality. AFLP is also recognized as an obstetric and medical emergency. Maternal AFLP is highly associated with a fetal homozygous mutation (1528G>C) in the gene that encodes for mitochondrial long-chain hydroxy acyl-CoA dehydrogenase (LCHAD). The mutation in LCHAD results in the accumulation of 3-hydroxy fatty acids, such as 3-hydroxy myristic acid, 3-hydroxy palmitic acid and 3-hydroxy dicarboxylic acid in the placenta, which are then shunted to the maternal circulation leading to the development of acute liver injury observed in patients with AFLP. In this review, we will discuss the mechanistic role of increased 3-hydroxy fatty acid in causing lipotoxicity to the liver and in inducing oxidative stress, mitochondrial dysfunction and hepatocyte lipoapoptosis. Further, we also review the role of 3-hydroxy fatty acids in causing placental damage, pancreatic islet β-cell glucolipotoxicity, brain damage, and retinal epithelial cells lipoapoptosis in patients with LCHAD deficiency. PMID:29361796

  20. Sexually dimorphic effects of maternal nutrient reduction on expression of genes regulating cortisol metabolism in fetal baboon adipose and liver tissues.

    Science.gov (United States)

    Guo, Chunming; Li, Cun; Myatt, Leslie; Nathanielsz, Peter W; Sun, Kang

    2013-04-01

    Maternal nutrient reduction (MNR) during fetal development may predispose offspring to chronic disease later in life. Increased regeneration of active glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in metabolic tissues is fundamental to the developmental programming of metabolic syndrome, but underlying mechanisms are unknown. Hexose-6-phosphate dehydrogenase (H6PD) generates NADPH, the cofactor for 11β-HSD1 reductase activity. CCAAT/enhancer binding proteins (C/EBPs) and the glucocorticoid receptor (GR) regulate 11β-HSD1 expression. We hypothesize that MNR increases expression of fetal C/EBPs, GR, and H6PD, thereby increasing expression of 11β-HSD1 and reductase activity in fetal liver and adipose tissues. Pregnant MNR baboons ate 70% of what controls ate from 0.16 to 0.9 gestation (term, 184 days). Cortisol levels in maternal and fetal circulations increased in MNR pregnancies at 0.9 gestation. MNR increased expression of 11β-HSD1; H6PD; C/EBPα, -β, -γ; and GR in female but not male perirenal adipose tissue and in male but not female liver at 0.9 gestation. Local cortisol level and its targets PEPCK1 and PPARγ increased correspondingly in adipose and liver tissues. C/EBPα and GR were found to be bound to the 11β-HSD1 promoter. In conclusion, sex- and tissue-specific increases of 11β-HSD1, H6PD, GR, and C/EBPs may contribute to sexual dimorphism in the programming of exaggerated cortisol regeneration in liver and adipose tissues and offsprings' susceptibility to metabolic syndrome.

  1. Maternal diets deficient in folic acid and related methyl donors modify mechanisms associated with lipid metabolism in the fetal liver of the rat.

    Science.gov (United States)

    McNeil, Christopher J; Hay, Susan M; Rucklidge, Garry J; Reid, Martin D; Duncan, Gary J; Rees, William D

    2009-11-01

    Previously we have examined the effects of diets deficient in folic acid ( - F) or folate deficient with low methionine and choline ( - F LM LC) on the relative abundance of soluble proteins in the liver of the pregnant rat. In the present study we report the corresponding changes in the fetal liver at day 21 of gestation. The abundance of eighteen proteins increased when dams were fed the - F diet. When dams were fed the - F LM LC diet, thirty-three proteins increased and eight decreased. Many of the differentially abundant proteins in the fetal liver could be classified into the same functional groups as those previously identified in the maternal liver, namely protein synthesis, metabolism, lipid metabolism and proteins associated with the cytoskeleton and endoplasmic reticulum. The pattern was consistent with reduced cell proliferation in the - F LM LC group but not in the - F group. Metabolic enzymes associated with lipid metabolism changed in both the - F and - F LM LC groups. The mRNA for carnitine palmitoyl transferase were up-regulated and CD36 (fatty acid translocase) down-regulated in the - F group, suggesting increased mitochondrial oxidation of fatty acids as an indirect response to altered maternal lipid metabolism. In the - F LM LC group the mRNA for acetyl CoA carboxylase was down-regulated, suggesting reduced fatty acid synthesis. The mRNA for transcriptional regulators including PPARalpha and sterol response element-binding protein-1c were unchanged. These results suggest that an adequate supply of folic acid and the related methyl donors may benefit fetal development directly by improving lipid metabolism in fetal as well as maternal tissues.

  2. The in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheep.

    Science.gov (United States)

    Hogg, Kirsten; Wood, Charlotte; McNeilly, Alan S; Duncan, W Colin

    2011-01-01

    Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS). We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin-like growth factor (IGF) and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5) or testosterone propionate (TP; n = 9) twice weekly (100 mg; i.m) from d62-102 (gestation 147 days). In a novel treatment paradigm, a second cohort received a direct C (n = 4) or TP (20 mg; n = 7) fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (Pfetal intervention (C and TP) led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK) was up-regulated in the fetal controls (Pfetal TP (Pfetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.

  3. Differences between Angus and Holstein cattle in the Lupinus leucophyllus induced inhibition of fetal activity.

    Science.gov (United States)

    Green, Benedict T; Panter, Kip E; Lee, Stephen T; Welch, Kevin D; Pfister, James A; Gardner, Dale R; Stegelmeier, Bryan L; Davis, T Zane

    2015-11-01

    Calves with congenital defects born to cows that have grazed teratogenic Lupinus spp. during pregnancy can suffer from what is termed crooked calf syndrome. Crooked calf syndrome defects include cleft palate, spinal column defects and limb malformations formed by alkaloid-induced inhibition of fetal movement. In this study, we tested the hypothesis that there are differences in fetal activity of fetuses carried by Holstein verses Angus heifers orally dosed with 1.1 g/kg dried ground Lupinus leucophyllus. Fetal activity was monitored via transrectal ultrasonography and maternal serum was analyzed for specific lupine alkaloids. There were more (P Angus heifers at eight and 12 h after oral dosing. In addition to serum alkaloid toxicokinetic differences, the Holstein heifers had significantly lower serum concentrations of anagyrine at 2, 4, and 8 h after oral dosing than Angus heifers. Holstein heifers also had significantly greater serum concentrations of lupanine at 12, 18 and 24 h after dosing than the Angus heifers. These results suggest that there are breed differences in susceptibility to lupine-induced crooked calf syndrome. These differences may also be used to discover genetic markers that identify resistant animals, thus facilitating selective breeding of resistant herds. Published by Elsevier Ltd.

  4. The in utero programming effect of increased maternal androgens and a direct fetal intervention on liver and metabolic function in adult sheep.

    Directory of Open Access Journals (Sweden)

    Kirsten Hogg

    Full Text Available Epigenetic changes in response to external stimuli are fast emerging as common underlying causes for the pre-disposition to adult disease. Prenatal androgenization is one such model that results in reproductive and metabolic features that are present in conditions such as polycystic ovary syndrome (PCOS. We examined the effect of prenatal androgens on liver function and metabolism of adult sheep. As non-alcoholic fatty liver disease is increased in PCOS we hypothesized that this, and other important liver pathways including metabolic function, insulin-like growth factor (IGF and steroid receptivity, would be affected. Pregnant ewes received vehicle control (C; n = 5 or testosterone propionate (TP; n = 9 twice weekly (100 mg; i.m from d62-102 (gestation 147 days. In a novel treatment paradigm, a second cohort received a direct C (n = 4 or TP (20 mg; n = 7 fetal injection at d62 and d82. In adults, maternal TP exposure resulted in increased insulin secretion to glucose load (P<0.05 and the histological presence of fatty liver (P<0.05 independent of central obesity. Additionally, hepatic androgen receptor (AR; P<0.05, glucocorticoid receptor (GR; P<0.05, UDP- glucose ceramide glucosyltransferase (UGCG; P<0.05 and IGF1 (P<0.01 expression were upregulated. The direct fetal intervention (C and TP led to early fatty liver changes in all animals without differential changes in insulin secretion. Furthermore, hepatic phosphoenolpyruvate carboxykinase (PEPCK was up-regulated in the fetal controls (P<0.05 and this was opposed by fetal TP (P<0.05. Hepatic estrogen receptor (ERα; P<0.05 and mitogen activated protein kinase kinase 4 (MAP2K4; P<0.05 were increased following fetal TP exposure. Adult liver metabolism and signaling can be altered by early exposure to sex steroids implicating epigenetic regulation of metabolic disturbances that are common in PCOS.

  5. Induced pluripotent stem (iPS) cells from human fetal stem cells.

    Science.gov (United States)

    Guillot, Pascale V

    2016-02-01

    Pluripotency defines the ability of stem cells to differentiate into all the lineages of the three germ layers and self-renew indefinitely. Somatic cells can regain the developmental potential of embryonic stem cells following ectopic expression of a set of transcription factors or, in certain circumstances, via modulation of culture conditions and supplementation with small molecule, that is, induced pluripotent stem (iPS) cells. Here, we discuss the use of fetal tissues for reprogramming, focusing in particular on stem cells derived from human amniotic fluid, and the development of chemical reprogramming. We next address the advantages and disadvantages of deriving pluripotent cells from fetal tissues and the potential clinical applications. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Intra-amniotic Ureaplasma parvum-Induced Maternal and Fetal Inflammation and Immune Responses in Rhesus Macaques.

    Science.gov (United States)

    Senthamaraikannan, Paranthaman; Presicce, Pietro; Rueda, Cesar M; Maneenil, Gunlawadee; Schmidt, Augusto F; Miller, Lisa A; Waites, Ken B; Jobe, Alan H; Kallapur, Suhas G; Chougnet, Claire A

    2016-11-15

     Although Ureaplasma species are the most common organisms associated with prematurity, their effects on the maternal and fetal immune system remain poorly characterized.  Rhesus macaque dams at approximately 80% gestation were injected intra-amniotically with 10 7 colony-forming units of Ureaplasma parvum or saline (control). Fetuses were delivered surgically 3 or 7 days later. We performed comprehensive assessments of inflammation and immune effects in multiple fetal and maternal tissues.  Although U. parvum grew well in amniotic fluid, there was minimal chorioamnionitis. U. parvum colonized the fetal lung, but fetal systemic microbial invasion was limited. Fetal lung inflammation was mild, with elevations in CXCL8, tumor necrosis factor (TNF) α, and CCL2 levels in alveolar washes at day 7. Inflammation was not detected in the fetal brain. Significantly, U. parvum decreased regulatory T cells (Tregs) and activated interferon γ production in these Tregs in the fetus. It was detected in uterine tissue by day 7 and induced mild inflammation and increased expression of connexin 43, a gap junction protein involved with labor.  U. parvum colonized the amniotic fluid and caused uterine inflammation, but without overt chorioamnionitis. It caused mild fetal lung inflammation but had a more profound effect on the fetal immune system, decreasing Tregs and polarizing them toward a T-helper 1 phenotype. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

  7. Comparative Analysis of the Hematopoietic Progenitor Cells from Placenta, Cord Blood, and Fetal Liver, Based on Their Immunophenotype

    Directory of Open Access Journals (Sweden)

    Maria D. Kuchma

    2015-01-01

    Full Text Available We have investigated the characteristics of human hematopoietic progenitor cells (HPCs with the CD34+CD45lowSSClow phenotype from full-term placental tissue (FTPT as compared to cord blood (CB and fetal liver (FL cells. We demonstrated the presence of cell subpopulations at various stages of the differentiation with such immunophenotypes as CD34+/lowCD45low/-, CD34++CD45low/-, CD34+++CD45low/-, CD34+/lowCD45hi, and CD34++CD45hi in both first trimester placental tissue (FiTPT and FTPT which implies their higher phenotypic heterogeneity compared to CB. HPCs of the FTPT origin expressed the CD90 antigen at a higher level compared to its expression by the CB HPCs and the CD133 antigen expression being at the same level in both cases. The HPCs compartment of FTPT versus CB contained higher number of myeloid and erythroid committed cells but lower number of myeloid and lymphoid ones compared to FL HPCs. HPCs of the FTPT and CB origin possess similar potentials for the multilineage differentiation in vitro and similar ratios of myeloid and erythroid progenitors among the committed cells. This observation suggests that the active hematopoiesis occurs in the FTPT. We obtained viable HPCs from cryopreserved placental tissue fragments allowing us to develop procedures for banking and testing of placenta-derived HPCs for clinical use.

  8. Distinct Molecular Signature of Murine Fetal Liver and Adult Hematopoietic Stem Cells Identify Novel Regulators of Hematopoietic Stem Cell Function.

    Science.gov (United States)

    Manesia, Javed K; Franch, Monica; Tabas-Madrid, Daniel; Nogales-Cadenas, Ruben; Vanwelden, Thomas; Van Den Bosch, Elisa; Xu, Zhuofei; Pascual-Montano, Alberto; Khurana, Satish; Verfaillie, Catherine M

    2017-04-15

    During ontogeny, fetal liver (FL) acts as a major site for hematopoietic stem cell (HSC) maturation and expansion, whereas HSCs in the adult bone marrow (ABM) are largely quiescent. HSCs in the FL possess faster repopulation capacity as compared with ABM HSCs. However, the molecular mechanism regulating the greater self-renewal potential of FL HSCs has not yet extensively been assessed. Recently, we published RNA sequencing-based gene expression analysis on FL HSCs from 14.5-day mouse embryo (E14.5) in comparison to the ABM HSCs. We reanalyzed these data to identify key transcriptional regulators that play important roles in the expansion of HSCs during development. The comparison of FL E14.5 with ABM HSCs identified more than 1,400 differentially expressed genes. More than 200 genes were shortlisted based on the gene ontology (GO) annotation term "transcription." By morpholino-based knockdown studies in zebrafish, we assessed the function of 18 of these regulators, previously not associated with HSC proliferation. Our studies identified a previously unknown role for tdg, uhrf1, uchl5, and ncoa1 in the emergence of definitive hematopoiesis in zebrafish. In conclusion, we demonstrate that identification of genes involved in transcriptional regulation differentially expressed between expanding FL HSCs and quiescent ABM HSCs, uncovers novel regulators of HSC function.

  9. Lipocalin-2 in Fructose-Induced Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Jessica Lambertz

    2017-11-01

    Full Text Available The intake of excess dietary fructose most often leads to non-alcoholic fatty liver disease (NAFLD. Fructose is metabolized mainly in the liver and its chronic consumption results in lipogenic gene expression in this organ. However, precisely how fructose is involved in NAFLD progression is still not fully understood, limiting therapy. Lipocalin-2 (LCN2 is a small secreted transport protein that binds to fatty acids, phospholipids, steroids, retinol, and pheromones. LCN2 regulates lipid and energy metabolism in obesity and is upregulated in response to insulin. We previously discovered that LCN2 has a hepatoprotective effect during hepatic insult, and that its upregulation is a marker of liver damage and inflammation. To investigate if LCN2 has impact on the metabolism of fructose and thereby arising liver damage, we fed wild type and Lcn2−/− mice for 4 or 8 weeks on diets that were enriched in fructose either by adding this sugar to the drinking water (30% w/v, or by feeding a chow containing 60% (w/w fructose. Body weight and daily intake of food and water of these mice was then measured. Fat content in liver sections was visualized using Oil Red O stain, and expression levels of genes involved in fat and sugar metabolism were measured by qRT-PCR and Western blot analysis. We found that fructose-induced steatosis and liver damage was more prominent in female than in male mice, but that the most severe hepatic damage occurred in female mice lacking LCN2. Unexpectedly, consumption of elevated fructose did not induce de novo lipogenesis or fat accumulation. We conclude that LCN2 acts in a lipid-independent manner to protect the liver against fructose-induced damage.

  10. Effects of Radiofrequency Induced local Hyperthermia on Normal Canine Liver

    International Nuclear Information System (INIS)

    Suh, Chang Ok; Loh, John J. K.; Seong, Jin Sil

    1991-01-01

    In order to assess the effects of radiofrequency-induced local hyperthermia on the normal liver, histopathologic findings and biochemical changes after localized hyperthermia in canine liver were studied. Hyperthermia was externally administered using the Thermotron RF-8 (Yamamoto Vinyter Co., Japan; Capacitive type heating machine) with parallel opposed electrodes. Thirteen dogs were used and allocated into one control group (N=3) and two treatment groups according to the treatment temperature. Group I (N=5) was heated with 42.5±0.5.deg.C for 30 minutes, and Group(N=5) was heated with 45±0.5.deg.C for 15-30 minutes. Samples of liver tissue were obtained through a needle biopsy immediately after hyperthermia and 7, 14 and 28 days after treatment and examined for SGOT, SGPT and alkaline phosphatase. Although SGOT and SGPT were elevated after hyperthermia in both groups (three of five in each group), there was no liver cell necrosis or hyperthermia related mortality in Group I. A hydropic swelling of hepatocytes was prominent histologic finding. Hyperthermia with 45.deg.C for 30 minutes was fatal and showed extensive liver cell necrosis. In conclusion, liver damage day heat of 42.5±0.5.deg.C for 30 minutes is reversible, and liver damage by heat of 45±0.5.deg.C for 30 minutes can be fatal or irreversible. However, these results cannot be applied directly to human trial. Therefore, in order to apply hyperthermic treatment on human liver tumor safely, close observation of temperature with proper thermometry is mandatory. Hyperthermic treatment should be confined to the tumor area while sparing a normal liver as much as possible

  11. The study on morphologic alteration of fetal mice and the change of MeCP2 in fetal brain induced by ionizing radiation

    International Nuclear Information System (INIS)

    Chen Feng; Zhang Fengxiang; Tu Yu

    2012-01-01

    Objective: In order to investigate the effect and the possible mechanism of γ-rays on neuro development of fetal brain tissue as bystander effect organ. Methods: pregnant kunming mice were randomly divided into blank control group, 0.5 Gy whole-body exposed group, 0.5 Gy head exposed group, 1.0 Gy whole-body exposed group, 1.0 Gy head exposed group, 2.0 Gy whole-body exposed group and 2.0 Gy head exposed group. The exposed mice were exposed with a vertical single acute dose using 60 Co therapy apparatus on the 9 th day of pregnancy, and cesarean operation were performed to gain fetal mice on the 18 th day of pregnancy. The number, the size, stillbirth, birth defects and abortion, and get fetal brains from live births were observed. Western-blot assay was used to detect the expression of MeCP2 protein. Results: Compared with the blank control group, the rates of stillbirth, birth defects and abortion ascended as the increase of doses; the expression of MeCP2 were upregulated except 0.5 Gy whole-body exposed group, there were no significant differences between groups. Conclusion: When the pregnant mice were exposed to ionizing radiation in the first trimester, bystander effect in fetal brain tissue was induced, within a certain range, the incidence of deterministic effects and stochastic effects ascended as the increase of doses. (authors)

  12. Molecular Pathogenesis of Liver Steatosis Induced by Hepatitis C Virus

    Directory of Open Access Journals (Sweden)

    Cheng Jun

    2012-09-01

    Full Text Available Liver steatosis is a pathological hallmark in patients with chronic hepatitis C (CHC. Increased lipid uptake, decreased lipid secretion, increased lipid synthesis and decreased lipid degradation are all involved in pathogenesis of steatosis induced by hepatitic C virus (HCV infection. Level of low density lipoprotein receptor (LDL-R and activity of peroxisome proliferator-activated receptor (PPAR α is related to liver uptake of lipid from circulation, and affected by HCV. Secretion via microsomal triglyceride transfer protein (MTTP, and formation of very low density lipoprotein (VLDL have been hampered by HCV infection. Up-regulation of lipid synthesis related genes, such as sterol regulatory element-binding protein (SREBP-1, SREBP-2, SREBP-1c, fatty acid synthase (FASN, HMG CoA reductase (HMGCR, liver X receptor (LXR, acetyl-CoA carboxylase 1 (ACC1, hepatic CB (1 receptors, retinoid X receptor (RXR α, were the main stay of liver steatosis pathogenesis. Degradation of lipid in liver is decreased in patients with CHC. There is strong evidence that heterogeneity of HCV core genes of different genotypes affect their effects of liver steatosis induction. A mechanism in which steatosis is involved in HCV life cycle is emerging.

  13. Maternal nutrition induces gene expression changes in fetal muscle and adipose tissues in sheep.

    Science.gov (United States)

    Peñagaricano, Francisco; Wang, Xin; Rosa, Guilherme Jm; Radunz, Amy E; Khatib, Hasan

    2014-11-28

    Maternal nutrition during different stages of pregnancy can induce significant changes in the structure, physiology, and metabolism of the offspring. These changes could have important implications on food animal production especially if these perturbations impact muscle and adipose tissue development. Here, we evaluated the impact of different maternal isoenergetic diets, alfalfa haylage (HY; fiber), corn (CN; starch), and dried corn distillers grains (DG; fiber plus protein plus fat), on the transcriptome of fetal muscle and adipose tissues in sheep. Prepartum diets were associated with notable gene expression changes in fetal tissues. In longissimus dorsi muscle, a total of 224 and 823 genes showed differential expression (FDR ≤0.05) in fetuses derived from DG vs. CN and HY vs. CN maternal diets, respectively. Several of these significant genes affected myogenesis and muscle differentiation. In subcutaneous and perirenal adipose tissues, 745 and 208 genes were differentially expressed (FDR ≤0.05), respectively, between CN and DG diets. Many of these genes are involved in adipogenesis, lipogenesis, and adipose tissue development. Pathway analysis revealed that several GO terms and KEGG pathways were enriched (FDR ≤0.05) with differentially expressed genes associated with tissue and organ development, chromatin biology, and different metabolic processes. These findings provide evidence that maternal nutrition during pregnancy can alter the programming of fetal muscle and fat tissues in sheep. The ramifications of the observed gene expression changes, in terms of postnatal growth, body composition, and meat quality of the offspring, warrant future investigation.

  14. Long-term prognosis for transplant-free survivors of paracetamol-induced acute liver failure

    DEFF Research Database (Denmark)

    Jepsen, P; Schmidt, L E; Larsen, F S

    2010-01-01

    The prognosis for transplant-free survivors of paracetamol-induced acute liver failure remains unknown.......The prognosis for transplant-free survivors of paracetamol-induced acute liver failure remains unknown....

  15. Nrf2 activation prevents cadmium-induced acute liver injury

    International Nuclear Information System (INIS)

    Wu, Kai C.; Liu, Jie J.; Klaassen, Curtis D.

    2012-01-01

    Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H 2 DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice were

  16. Nrf2 activation prevents cadmium-induced acute liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Kai C. [Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Liu, Jie J. [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Klaassen, Curtis D., E-mail: cklaasse@kumc.edu [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States)

    2012-08-15

    Oxidative stress plays an important role in cadmium-induced liver injury. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that up-regulates cytoprotective genes in response to oxidative stress. To investigate the role of Nrf2 in cadmium-induced hepatotoxicity, Nrf2-null mice, wild-type mice, kelch-like ECH-associated protein 1-knockdown (Keap1-KD) mice with enhanced Nrf2, and Keap1-hepatocyte knockout (Keap1-HKO) mice with maximum Nrf2 activation were treated with cadmium chloride (3.5 mg Cd/kg, i.p.). Blood and liver samples were collected 8 h thereafter. Cadmium increased serum alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) activities, and caused extensive hepatic hemorrhage and necrosis in the Nrf2-null mice. In contrast, Nrf2-enhanced mice had lower serum ALT and LDH activities and less morphological alternations in the livers than wild-type mice. H{sub 2}DCFDA (2′,7′-dichlorodihydrofluoresein diacetate) staining of primary hepatocytes isolated from the four genotypes of mice indicated that oxidative stress was higher in Nrf2-null cells, and lower in Nrf2-enhanced cells than in wild-type cells. To further investigate the mechanism of the protective effect of Nrf2, mRNA of metallothionein (MT) and other cytoprotective genes were determined. Cadmium markedly induced MT-1 and MT-2 in livers of all four genotypes of mice. In contrast, genes involved in glutathione synthesis and reducing reactive oxygen species, including glutamate-cysteine ligase (Gclc), glutathione peroxidase-2 (Gpx2), and sulfiredoxin-1 (Srxn-1) were only induced in Nrf2-enhanced mice, but not in Nrf2-null mice. In conclusion, the present study shows that Nrf2 activation prevents cadmium-induced oxidative stress and liver injury through induction of genes involved in antioxidant defense rather than genes that scavenge Cd. -- Highlights: ► Cadmium caused extensive hepatic hemorrhage and necrosis in Nrf2-null mice. ► Keap1-KD and Keap1-HKO mice

  17. Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

    Science.gov (United States)

    Comish, Paul B; Drumond, Ana Luiza; Kinnell, Hazel L; Anderson, Richard A; Matin, Angabin; Meistrich, Marvin L; Shetty, Gunapala

    2014-01-01

    Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT) and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP) is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1) mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2%) and to 80% in the male offspring of L1 (control value 33%). These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼ 70% of control and induced atrophic seminiferous tubules in ∼ 30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i) DNA damage is a common mechanism leading to induction of testicular cancer, ii) increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii) children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.

  18. Fetal cyclophosphamide exposure induces testicular cancer and reduced spermatogenesis and ovarian follicle numbers in mice.

    Directory of Open Access Journals (Sweden)

    Paul B Comish

    Full Text Available Exposure to radiation during fetal development induces testicular germ cell tumors (TGCT and reduces spermatogenesis in mice. However, whether DNA damaging chemotherapeutic agents elicit these effects in mice remains unclear. Among such agents, cyclophosphamide (CP is currently used to treat breast cancer in pregnant women, and the effects of fetal exposure to this drug manifested in the offspring must be better understood to offer such patients suitable counseling. The present study was designed to determine whether fetal exposure to CP induces testicular cancer and/or gonadal toxicity in 129 and in 129.MOLF congenic (L1 mice. Exposure to CP on embryonic days 10.5 and 11.5 dramatically increased TGCT incidence to 28% in offspring of 129 mice (control value, 2% and to 80% in the male offspring of L1 (control value 33%. These increases are similar to those observed in both lines of mice by radiation. In utero exposure to CP also significantly reduced testis weights at 4 weeks of age to ∼ 70% of control and induced atrophic seminiferous tubules in ∼ 30% of the testes. When the in utero CP-exposed 129 mice reached adulthood, there were significant reductions in testicular and epididymal sperm counts to 62% and 70%, respectively, of controls. In female offspring, CP caused the loss of 77% of primordial follicles and increased follicle growth activation. The results indicate that i DNA damage is a common mechanism leading to induction of testicular cancer, ii increased induction of testis cancer by external agents is proportional to the spontaneous incidence due to inherent genetic susceptibility, and iii children exposed to radiation or DNA damaging chemotherapeutic agents in utero may have increased risks of developing testis cancer and having reduced spermatogenic potential or diminished reproductive lifespan.

  19. Metronidazole-induced encephalopathy in a patient with liver cirrhosis.

    Science.gov (United States)

    Cheong, Hyeong Cheol; Jeong, Taek Geun; Cho, Young Bum; Yang, Bong Joon; Kim, Tae Hyeon; Kim, Haak Cheoul; Cho, Eun-Young

    2011-06-01

    Encephalopathy is a disorder characterized by altered brain function, which can be attributed to various causes. Encephalopathy associated with metronidazole administration occurs rarely and depends on the cumulative metronidazole dose, and most patients with this condition recover rapidly after discontinuation of therapy. Because metronidazole is metabolized in the liver and can be transported by the cerebrospinal fluid and cross the blood-brain barrier, it may induce encephalopathy even at a low cumulative dose in patients with hepatic dysfunction. We experienced a patient who showed ataxic gait and dysarthric speech after receiving metronidazole for the treatment of hepatic encephalopathy that was not controlled by the administration of lactulose. The patient was diagnosed as metronidazole-induced encephalopathy, and stopping drug administration resulted in a complete recovery from encephalopathy. This case shows that caution should be exercised when administering metronidazole because even a low dose can induce encephalopathy in patients with liver cirrhosis.

  20. Dexamethasone-induced haptoglobin release by calf liver parenchymal cells.

    Science.gov (United States)

    Higuchi, H; Katoh, N; Miyamoto, T; Uchida, E; Yuasa, A; Takahashi, K

    1994-08-01

    Parenchymal cells were isolated from the liver of male calves, and monolayer cultures formed were treated with glucocorticoids to examine whether haptoglobin, appearance of which is associated with hepatic lipidosis (fatty liver) in cattle, is induced by steroid hormones. Without addition of dexamethasone, only trace amounts of haptoglobin were detected in culture medium. With addition of dexamethasone (10(-12) to 10(-4) M), considerable amounts of haptoglobin were released into the medium. Maximal release was observed at concentrations of 10(-8) to 10(-6) M dexamethasone. Haptoglobin release was similarly induced by cortisol, although the effect was less potent than that of dexamethasone. Actinomycin D (a known protein synthesis inhibitor) dose-dependently reduced amounts of haptoglobin released in response to 10(-8) M dexamethasone. Dexamethasone also induced annexin I, which is known to be synthesized in response to glucocorticoids. Dexamethasone treatment resulted in reduced protein kinase C activity in the cell cytosol, which has been shown to be an early event in dexamethasone-treated cells. Other than glucocorticoids, estradiol induced haptoglobin release, whereas progesterone was less effective. The association of haptoglobin with hepatic lipidosis can be reasonably explained by the fact that haptoglobin production by the liver is induced by glucocorticoids and estradiol, and these steroid hormones are triggers for development of hepatic lipidosis in cattle.

  1. Ethanol and liver: Recent insights into the mechanisms of ethanol-induced fatty liver

    Science.gov (United States)

    Liu, Jinyao

    2014-01-01

    Alcoholic fatty liver disease (AFLD), a potentially pathologic condition, can progress to steatohepatitis, fibrosis, and cirrhosis, leading to an increased probability of hepatic failure and death. Alcohol induces fatty liver by increasing the ratio of reduced form of nicotinamide adenine dinucleotide to oxidized form of nicotinamide adenine dinucleotide in hepatocytes; increasing hepatic sterol regulatory element-binding protein (SREBP)-1, plasminogen activator inhibitor (PAI)-1, and early growth response-1 activity; and decreasing hepatic peroxisome proliferator-activated receptor-α activity. Alcohol activates the innate immune system and induces an imbalance of the immune response, which is followed by activated Kupffer cell-derived tumor necrosis factor (TNF)-α overproduction, which is in turn responsible for the changes in the hepatic SREBP-1 and PAI-1 activity. Alcohol abuse promotes the migration of bone marrow-derived cells (BMDCs) to the liver and then reprograms TNF-α expression from BMDCs. Chronic alcohol intake triggers the sympathetic hyperactivity-activated hepatic stellate cell (HSC) feedback loop that in turn activates the HSCs, resulting in HSC-derived TNF-α overproduction. Carvedilol may block this feedback loop by suppressing sympathetic activity, which attenuates the progression of AFLD. Clinical studies evaluating combination therapy of carvedilol with a TNF-α inhibitor to treat patients with AFLD are warranted to prevent the development of alcoholic liver disease. PMID:25356030

  2. Maternal Obesity Induces Sustained Inflammation in Both Fetal and Offspring Large Intestine of Sheep

    Science.gov (United States)

    Yan, Xu; Huang, Yan; Wang, Hui; Du, Min; Hess, Bret W.; Ford, Stephen P.; Nathanielsz, Peter W.; Zhu, Mei-Jun

    2010-01-01

    Background Both maternal obesity and inflammatory bowel diseases (IBDs) are increasing. It was hypothesized that maternal obesity induces an inflammatory response in the fetal large intestine, predisposing offspring to IBDs. Methods Nonpregnant ewes were assigned to a control (Con, 100% of National Research Council [NRC] recommendations) or obesogenic (OB, 150% of NRC) diet from 60 days before conception. The large intestine was sampled from fetuses at 135 days (term 150 days) after conception and from offspring lambs at 22.5 ± 0.5 months of age. Results Maternal obesity enhanced mRNA expression tumor necrosis factor (TNF)α, interleukin (IL)1α, IL1β, IL6, IL8, and monocyte/macrophage chemotactic protein-1 (MCP1), as well as macrophage markers, CD11b, CD14, and CD68 in fetal gut. mRNA expression of Toll-like receptor (TLR) 2 and TLR4 was increased in OB versus Con fetuses; correspondingly, inflammatory NF-κB and JNK signaling pathways were also upregulated. Both mRNA expression and protein content of transforming growth factor (TGF) β was increased. The IL-17A mRNA expression and protein content was higher in OB compared to Con samples, which was associated with fibrosis in the large intestine of OB fetuses. Similar inflammatory responses and enhanced fibrosis were detected in OB compared to Con offspring. Conclusions Maternal obesity induced inflammation and enhanced expression of proinflammatory cytokines in fetal and offspring large intestine, which correlated with increased TGFβ and IL17 expression. These data show that maternal obesity may predispose offspring gut to IBDs. PMID:21674707

  3. Choriodecidual group B streptococcal inoculation induces fetal lung injury without intra-amniotic infection and preterm labor in Macaca nemestrina.

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    Kristina M Adams Waldorf

    Full Text Available BACKGROUND: Early events leading to intrauterine infection and fetal lung injury remain poorly defined, but may hold the key to preventing neonatal and adult chronic lung disease. Our objective was to establish a nonhuman primate model of an early stage of chorioamnionitis in order to determine the time course and mechanisms of fetal lung injury in utero. METHODOLOGY/PRINCIPAL FINDINGS: Ten chronically catheterized pregnant monkeys (Macaca nemestrina at 118-125 days gestation (term=172 days received one of two treatments: 1 choriodecidual and intra-amniotic saline (n=5, or 2 choriodecidual inoculation of Group B Streptococcus (GBS 1×10(6 colony forming units (n=5. Cesarean section was performed regardless of labor 4 days after GBS or 7 days after saline infusion to collect fetal and placental tissues. Only two GBS animals developed early labor with no cervical change in the remaining animals. Despite uterine quiescence in most cases, blinded review found histopathological evidence of fetal lung injury in four GBS animals characterized by intra-alveolar neutrophils and interstitial thickening, which was absent in controls. Significant elevations of cytokines in amniotic fluid (TNF-α, IL-8, IL-1β, IL-6 and fetal plasma (IL-8 were detected in GBS animals and correlated with lung injury (p<0.05. Lung injury was not directly caused by GBS, because GBS was undetectable in amniotic fluid (~10 samples tested/animal, maternal and fetal blood by culture and polymerase chain reaction. In only two cases was GBS cultured from the inoculation site in low numbers. Chorioamnionitis occurred in two GBS animals with lung injury, but two others with lung injury had normal placental histology. CONCLUSIONS/SIGNIFICANCE: A transient choriodecidual infection can induce cytokine production, which is associated with fetal lung injury without overt infection of amniotic fluid, chorioamnionitis or preterm labor. Fetal lung injury may, thus, occur silently without

  4. TAB2 Is Essential for Prevention of Apoptosis in Fetal Liver but Not for Interleukin-1 Signaling

    Science.gov (United States)

    Sanjo, Hideki; Takeda, Kiyoshi; Tsujimura, Tohru; Ninomiya-Tsuji, Jun; Matsumoto, Kunihiro; Akira, Shizuo

    2003-01-01

    The proinflammatory cytokine interleukin-1 (IL-1) transmits a signal via several critical cytoplasmic proteins such as MyD88, IRAKs and TRAF6. Recently, serine/threonine kinase TAK1 and TAK1 binding protein 1 and 2 (TAB1/2) have been identified as molecules involved in IL-1-induced TRAF6-mediated activation of AP-1 and NF-κB via mitogen-activated protein (MAP) kinases and IκB kinases, respectively. However, their physiological functions remain to be clarified. To elucidate their roles in vivo, we generated TAB2-deficient mice. The TAB2 deficiency was embryonic lethal due to liver degeneration and apoptosis. This phenotype was similar to that of NF-κB p65-, IKKβ-, and NEMO/IKKγ-deficient mice. However, the IL-1-induced activation of NF-κB and MAP kinases was not impaired in TAB2-deficient embryonic fibroblasts. These findings demonstrate that TAB2 is essential for embryonic development through prevention of liver apoptosis but not for the IL-1 receptor-mediated signaling pathway. PMID:12556483

  5. Drug-induced Liver Disease in Patients with Diabetes Mellitus

    OpenAIRE

    Iryna, Klyarytskaya; Helen, Maksymova; Elena, Stilidi

    2016-01-01

    The study presented here was accomplished to assess the course of drug-induced liver diseases in patient’s rheumatoid arthritis receiving long-term methotrexate therapy. Diabetes mellitus was revealed as the most significant risk factor. The combination of diabetes mellitus with other risk factors (female sex) resulted in increased hepatic fibrosis, degree of hepatic encephalopathy and reduction of hepatic functions. The effectiveness and safety of ursodeoxycholic acid and cytolytic type-with...

  6. An Update on Drug-induced Liver Injury.

    Science.gov (United States)

    Devarbhavi, Harshad

    2012-09-01

    Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of

  7. Zinc supplementation during pregnancy protects against lipopolysaccharide-induced fetal growth restriction and demise through its anti-inflammatory effect.

    Science.gov (United States)

    Chen, Yuan-Hua; Zhao, Mei; Chen, Xue; Zhang, Ying; Wang, Hua; Huang, Ying-Ying; Wang, Zhen; Zhang, Zhi-Hui; Zhang, Cheng; Xu, De-Xiang

    2012-07-01

    LPS is associated with adverse developmental outcomes, including preterm delivery, fetal death, teratogenicity, and intrauterine growth restriction (IUGR). Previous reports showed that zinc protected against LPS-induced teratogenicity. In the current study, we investigated the effects of zinc supplementation during pregnancy on LPS-induced preterm delivery, fetal death and IUGR. All pregnant mice except controls were i.p. injected with LPS (75 μg/kg) daily from gestational day (GD) 15 to GD17. Some pregnant mice were administered zinc sulfate through drinking water (75 mg elemental Zn per liter) throughout the pregnancy. As expected, an i.p. injection with LPS daily from GD15 to GD17 resulted in 36.4% (4/11) of dams delivered before GD18. In dams that completed the pregnancy, 63.2% of fetuses were dead. Moreover, LPS significantly reduced fetal weight and crown-rump length. Of interest, zinc supplementation during pregnancy protected mice from LPS-induced preterm delivery and fetal death. In addition, zinc supplementation significantly alleviated LPS-induced IUGR and skeletal development retardation. Further experiments showed that zinc supplementation significantly attenuated LPS-induced expression of placental inflammatory cytokines and cyclooxygenase-2. Zinc supplementation also significantly attenuated LPS-induced activation of NF-κB and MAPK signaling in mononuclear sinusoidal trophoblast giant cells of the labyrinth zone. It inhibited LPS-induced placental AKT phosphorylation as well. In conclusion, zinc supplementation during pregnancy protects against LPS-induced fetal growth restriction and demise through its anti-inflammatory effect.

  8. Propylthiouracil-induced liver failure and artificial liver support systems: a case report and review of the literature

    Directory of Open Access Journals (Sweden)

    Wu DB

    2017-01-01

    Full Text Available Dong-Bo Wu,1,2 En-Qiang Chen,1,2 Lang Bai,1,2 Hong Tang1,2 1Center of Infectious Diseases, West China Hospital of Sichuan University, 2Division of Molecular Biology of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, People’s Republic of China Background: Antithyroid drugs carry a potential risk of hepatotoxicity. Propylthiouracil (PTU is commonly prescribed for patients with hyperthyroidism. PTU, however, can induce liver injury, ranging from mild asymptomatic elevation of aminotransferases to acute liver failure (ALF.Case presentation: This case reports on a 16-year-old Chinese girl with hyperthyroidism, who was admitted to our hospital for jaundice, nausea, and fatigue associated with severe hyperbilirubinemia and coagulopathy. She had been prescribed PTU 5 months earlier. There was no history of hypersensitivity to drugs, viral liver diseases, blood transfusion, or surgery. On the basis of her symptoms and the clinical data, she was diagnosed with PTU-induced ALF. Due to the limited number of available donor organs for liver transplantation, she was started on treatment with artificial liver support system (ALSS. After four sessions of ALSS, her clinical signs and symptoms were found to be markedly improved, and she was discharged 25 days after admission. Four months later, her liver function normalized.Conclusion: Although PTU-induced liver failure is rare in clinical practice, liver function should be appropriately monitored during treatment with PTU. PTU-induced ALF in this patient was successfully managed with an ALSS, suggesting that the latter may be an alternative to liver transplantation. Keywords: propylthiouracil, liver injury, acute liver failure, artificial liver support systems 

  9. Fish oil prevents sucrose-induced fatty liver but exacerbates high-safflower oil-induced fatty liver in ddy mice.

    Science.gov (United States)

    Yamazaki, Tomomi; Nakamori, Akiko; Sasaki, Eriko; Wada, Satoshi; Ezaki, Osamu

    2007-12-01

    Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). We analyzed the effects of dietary fish oil on fatty liver induced by sucrose, safflower oil, and butter in ddY mice. In experiment I, mice were fed a high-starch diet [70 energy% (en%) starch] plus 20% (wt/wt) sucrose in the drinking water or fed a high-safflower oil diet (60 en%) for 11 weeks. As a control, mice were fed a high-starch diet with drinking water. Fish oil (10 en%) was either supplemented or not. Mice supplemented with sucrose or fed safflower oil showed a 1.7-fold or 2.2-fold increased liver triglyceride content, respectively, compared with that of control mice. Fish oil completely prevented sucrose-induced fatty liver, whereas it exacerbated safflower oil-induced fatty liver. Sucrose increased SREBP-1c and target gene messenger RNAs (mRNAs), and fish oil completely inhibited these increases. In experiment II, mice were fed a high-safflower oil or a high-butter diet, with or without fish oil supplementation. Fish oil exacerbated safflower oil-induced fatty liver but did not affect butter-induced fatty liver. Fish oil increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and target CD36 mRNA in safflower oil-fed mice. These increases were not observed in sucrose-supplemented or butter-fed mice. The effects of dietary fish oil on fatty liver differ according to the cause of fatty liver; fish oil prevents sucrose-induced fatty liver but exacerbates safflower oil-induced fatty liver. The exacerbation of fatty liver may be due, at least in part, to increased expression of liver PPARgamma.

  10. Rapamycin Induces Heme Oxygenase-1 in Liver but Inhibits Bile Flow Recovery after Ischemia

    NARCIS (Netherlands)

    Kist, Alwine; Wakkie, Joris; Madu, Max; Versteeg, Ruth; ten Berge, Judith; Nikolic, Andrej; Nieuwenhuijs, Vincent B.; Porte, Robert J.; Padbury, Robert T. A.; Barritt, Greg J.

    Background/Aims. Rapamycin, which is employed in the management of patients undergoing liver surgery, induces the synthesis of heme oxygenase-1 (HO-1) in some non-liver cell types. The aim was to investigate whether rapamycin can induce HO-1 expression in the liver, and to test the effects of

  11. Antenatal dexamethasone before asphyxia promotes cystic neural injury in preterm fetal sheep by inducing hyperglycemia.

    Science.gov (United States)

    Lear, Christopher A; Davidson, Joanne O; Mackay, Georgia R; Drury, Paul P; Galinsky, Robert; Quaedackers, Josine S; Gunn, Alistair J; Bennet, Laura

    2018-04-01

    Antenatal glucocorticoid therapy significantly improves the short-term systemic outcomes of prematurely born infants, but there is limited information available on their impact on neurodevelopmental outcomes in at-risk preterm babies exposed to perinatal asphyxia. Preterm fetal sheep (0.7 of gestation) were exposed to a maternal injection of 12 mg dexamethasone or saline followed 4 h later by asphyxia induced by 25 min of complete umbilical cord occlusion. In a subsequent study, fetuses received titrated glucose infusions followed 4 h later by asphyxia to examine the hypothesis that hyperglycemia mediated the effects of dexamethasone. Post-mortems were performed 7 days after asphyxia for cerebral histology. Maternal dexamethasone before asphyxia was associated with severe, cystic brain injury compared to diffuse injury after saline injection, with increased numbers of seizures, worse recovery of brain activity, and increased arterial glucose levels before, during, and after asphyxia. Glucose infusions before asphyxia replicated these adverse outcomes, with a strong correlation between greater increases in glucose before asphyxia and greater neural injury. These findings strongly suggest that dexamethasone exposure and hyperglycemia can transform diffuse injury into cystic brain injury after asphyxia in preterm fetal sheep.

  12. Protective effects of C-phycocyanin on alcohol-induced acute liver injury in mice

    Science.gov (United States)

    Xia, Dong; Liu, Bing; Luan, Xiying; Sun, Junyan; Liu, Nana; Qin, Song; Du, Zhenning

    2016-03-01

    Excessive alcohol consumption leads to liver disease. Extensive evidence suggests that C-phycocyanin (C-PC), a chromophore phycocyanobilin derived from Spirulina platensis, exerts protective effects against chemical-induced organ damage. In this study, we investigated whether C-PC could protect against ethanol-induced acute liver injury. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (CHOL), low-density lipoprotein (LDL), liver homogenate malondialdehyde (MDA), superoxide dismutase (SOD) content were measured, and pathological examination of liver sections were examined. C-PC showed obvious inhibitory effects on serum ALT, AST, TG, CHOL, LDL and MDA, and SOD content significantly increased in the liver. The structure of hepatic lobules was clear, liver sinus returned to normal, and liver cell cords were arranged in neat rows. Cloudiness, swelling, inflammatory cell infiltration and spotty necrosis of liver cells were significantly reduced. Therefore, C-PC can significantly protect against ethanol-induced acute liver injury.

  13. Mouse Precision-Cut Liver Slices as an ex Vivo Model To Study Idiosyncratic Drug-Induced Liver Injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Chen, Yixi; Starokozhko, Viktoriia; Groothuis, Geny M. M.; Merema, M.T.

    Idiosyncratic drug-induced liver injury (IDILI) has been the top reason for withdrawing drugs from the market or for black box warnings. IDILI may arise from the interaction of a drug's reactive metabolite with a mild inflammation that renders the liver more sensitive to injury resulting in

  14. Cobalamin Concentrations in Fetal Liver Show Gender Differences: A Result from Using a High-Pressure Liquid Chromatography-Inductively Coupled Plasma Mass Spectrometry as an Ultratrace Cobalt Speciation Method.

    Science.gov (United States)

    Bosle, Janine; Goetz, Sven; Raab, Andrea; Krupp, Eva M; Scheckel, Kirk G; Lombi, Enzo; Meharg, Andrew A; Fowler, Paul A; Feldmann, Jörg

    2016-12-20

    Maternal diet and lifestyle choices may affect placental transfer of cobalamin (Cbl) to the fetus. Fetal liver concentration of Cbl reflects nutritional status with regards to vitamin B12, but at these low concentration current Cbl measurement methods lack robustness. An analytical method based on enzymatic extraction with subsequent reversed-phase-high-pressure liquid chromatography (RP-HPLC) separation and parallel ICPMS and electrospray ionization (ESI)-Orbitrap-MS to determine specifically Cbl species in liver samples of only 10-50 mg was developed using 14 pig livers. Subsequently 55 human fetal livers were analyzed. HPLC-ICPMS analysis for cobalt (Co) and Cbl gave detection limits of 0.18 ng/g and 0.88 ng/g d.m. in liver samples, respectively, with a recovery of >95%. Total Co (Co t ) concentration did not reflect the amount of Cbl or vitamin B12 in the liver. Cbl bound Co contributes only 45 ± 15% to Co t . XRF mapping and μXANES analysis confirmed the occurrence of non-Cbl cobalt in pig liver hot spots indicating particular Co. No correlations of total cobalt nor Cbl with fetal weight or weeks of gestation were found for the human fetal livers. Although no gender difference could be identified for total Co concentration, female livers were significantly higher in Cbl concentration (24.1 ± 7.8 ng/g) than those from male fetuses (19.8 ± 7.1 ng/g) (p = 0.04). This HPLC-ICPMS method was able to quantify total Co t and Cbl in fetus liver, and it was sensitive and precise enough to identify this gender difference.

  15. Dietary fructose augments ethanol-induced liver pathology.

    Science.gov (United States)

    Thomes, Paul G; Benbow, Jennifer H; Brandon-Warner, Elizabeth; Thompson, Kyle J; Jacobs, Carl; Donohue, Terrence M; Schrum, Laura W

    2017-05-01

    Certain dietary components when combined with alcohol exacerbate alcohol-induced liver injury (ALI). Here, we tested whether fructose, a major ingredient of the western diet, enhances the severity of ALI. We fed mice ethanol for 8 weeks in the following Lieber-DeCarli diets: (a) Regular (contains olive oil); (b) corn oil (contains corn oil); (c) fructose (contains fructose and olive oil) and (d) corn+fructose (contains fructose and corn oil). We compared indices of metabolic function and liver pathology among the different groups. Mice fed fructose-free and fructose-containing ethanol diets exhibited similar levels of blood alcohol, blood glucose and signs of disrupted hepatic insulin signaling. However, only mice given fructose-ethanol diets showed lower insulin levels than their respective controls. Compared with their respective pair-fed controls, all ethanol-fed mice exhibited elevated levels of serum ALT; the inflammatory cytokines TNF-α, MCP-1 and MIP-2; hepatic lipid peroxides and triglycerides. All the latter parameters were significantly higher in mice given fructose-ethanol diets than those fed fructose-free ethanol diets. Mice given fructose-free or fructose-containing ethanol diets each had higher levels of hepatic lipogenic enzymes than controls. However, the level of the lipogenic enzyme fatty acid synthase (FAS) was significantly higher in livers of mice given fructose control and fructose-ethanol diets than in all other groups. Our findings indicate that dietary fructose exacerbates ethanol-induced steatosis, oxidant stress, inflammation and liver injury, irrespective of the dietary fat source, to suggest that inclusion of fructose in or along with alcoholic beverages increases the risk of more severe ALI in heavy drinkers. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Hypoglycemia and the origin of hypoxia-induced reduction in human fetal growth.

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    Stacy Zamudio

    2010-01-01

    Full Text Available The most well known reproductive consequence of residence at high altitude (HA >2700 m is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA.Doppler and ultrasound were used to measure maternal uterine and fetal umbilical blood flows in 69 and 58 residents of 400 vs 3600 m. Arterial and venous blood samples from mother and fetus were collected at elective cesarean delivery and analyzed for glucose, lactate and insulin. Maternal delivery and fetal uptakes for oxygen and glucose were calculated.The maternal arterial - venous glucose concentration difference was greater at HA. However, umbilical venous and arterial glucose concentrations were markedly decreased, resulting in lower glucose delivery at 3600 m. Fetal glucose consumption was reduced by >28%, but strongly correlated with glucose delivery, highlighting the relevance of glucose concentration to fetal uptake. At altitude, fetal lactate levels were increased, insulin concentrations decreased, and the expression of GLUT1 glucose transporter protein in the placental basal membrane was reduced.Our results support that preferential anaerobic consumption of glucose by the placenta at high altitude spares oxygen for fetal use, but limits glucose availability for fetal growth. Thus reduced fetal growth at high altitude is associated with fetal hypoglycemia, hypoinsulinemia and a trend towards lactacidemia. Our data support that

  17. HIV-Antiretroviral Therapy Induced Liver, Gastrointestinal, and Pancreatic Injury

    Directory of Open Access Journals (Sweden)

    Manuela G. Neuman

    2012-01-01

    Full Text Available The present paper describes possible connections between antiretroviral therapies (ARTs used to treat human immunodeficiency virus (HIV infection and adverse drug reactions (ADRs encountered predominantly in the liver, including hypersensitivity syndrome reactions, as well as throughout the gastrointestinal system, including the pancreas. Highly active antiretroviral therapy (HAART has a positive influence on the quality of life and longevity in HIV patients, substantially reducing morbidity and mortality in this population. However, HAART produces a spectrum of ADRs. Alcohol consumption can interact with HAART as well as other pharmaceutical agents used for the prevention of opportunistic infections such as pneumonia and tuberculosis. Other coinfections that occur in HIV, such as hepatitis viruses B or C, cytomegalovirus, or herpes simplex virus, further complicate the etiology of HAART-induced ADRs. The aspect of liver pathology including liver structure and function has received little attention and deserves further evaluation. The materials used provide a data-supported approach. They are based on systematic review and analysis of recently published world literature (MedLine search and the experience of the authors in the specified topic. We conclude that therapeutic and drug monitoring of ART, using laboratory identification of phenotypic susceptibilities, drug interactions with other medications, drug interactions with herbal medicines, and alcohol intake might enable a safer use of this medication.

  18. Hypercholesterolemia Induces Differentiation of Regulatory T Cells in the Liver.

    Science.gov (United States)

    Mailer, Reiner K W; Gisterå, Anton; Polyzos, Konstantinos A; Ketelhuth, Daniel F J; Hansson, Göran K

    2017-05-26

    The liver is the central organ that responds to dietary cholesterol intake and facilitates the release and clearance of lipoprotein particles. Persistent hypercholesterolemia leads to immune responses against lipoprotein particles that drive atherosclerosis. However, the effect of hypercholesterolemia on hepatic T-cell differentiation remains unknown. To investigate hepatic T-cell subsets upon hypercholesterolemia. We observed that hypercholesterolemia elevated the intrahepatic regulatory T (Treg) cell population and increased the expression of transforming growth factor-β1 in the liver. Adoptive transfer experiments revealed that intrahepatically differentiated Treg cells relocated to the inflamed aorta in atherosclerosis-prone low-density lipoprotein receptor deficient ( Ldlr -/- ) mice. Moreover, hypercholesterolemia induced the differentiation of intrahepatic, but not intrasplenic, Th17 cells in wild-type mice, whereas the disrupted liver homeostasis in hypercholesterolemic Ldlr -/- mice led to intrahepatic Th1 cell differentiation and CD11b + CD11c + leukocyte accumulation. Our results elucidate a new mechanism that controls intrahepatic T-cell differentiation during atherosclerosis development and indicates that intrahepatically differentiated T cells contribute to the CD4 + T-cell pool in the atherosclerotic aorta. © 2017 American Heart Association, Inc.

  19. Melatonin reduces dimethylnitrosamine-induced liver fibrosis in rats.

    Science.gov (United States)

    Tahan, Veysel; Ozaras, Resat; Canbakan, Billur; Uzun, Hafize; Aydin, Seval; Yildirim, Beytullah; Aytekin, Huseyin; Ozbay, Gulsen; Mert, Ali; Senturk, Hakan

    2004-09-01

    Increased deposition of the extracellular matrix components, particularly collagen, is a central phenomenon in liver fibrosis. Stellate cells, the central mediators in the pathogenesis of fibrosis are activated by free radicals, and synthesize collagen. Melatonin is a potent physiological scavenger of hydroxyl radicals. Melatonin has also been shown to be involved in the inhibitory regulation of collagen content in tissues. At present, no effective treatment of liver fibrosis is available for clinical use. We aimed to test the effects of melatonin on dimethylnitrosamine (DMN)-induced liver damage in rats. Wistar albino rats were injected with DMN intraperitoneally. Following a single dose of 40 mg/kg DMN, either saline (DMN) or 100 mg/kg daily melatonin was administered for 14 days. In other rats, physiologic saline or melatonin were injected for 14 days, following a single injection of saline as control. Hepatic fibrotic changes were evaluated biochemically by measuring tissue hydroxyproline levels and histopathogical examination. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH) and superoxide dismutase (SOD) levels were evaluated in blood and tissue homogenates. DMN caused hepatic fibrotic changes, whereas melatonin suppressed these changes in five of 14 rats (P < 0.05). DMN administration resulted in increased hydroxyproline and MDA levels, and decreased GSH and SOD levels, whereas melatonin reversed these effects. When melatonin was administered alone, no significant changes in biochemical parameters were noted. In conclusion, the present study suggests that melatonin functions as a potent fibrosuppressant and antioxidant, and may be a therapeutic choice.

  20. Free methionine supplementation limits alcohol-induced liver damage in rats

    DEFF Research Database (Denmark)

    Parlesak, Alexandr; Bode, C.; Bode, J.C.

    1998-01-01

    Alcohol feeding to rats that were submitted to a jejunoileal bypass operation has been shown to result in liver damage being comparable with alcohol-induced liver disease in man. In the present study, a striking effect of free methionine consumption on histological liver injury, triglyceride accu...

  1. Chemical Inhibition of Histone Deacetylases 1 and 2 Induces Fetal Hemoglobin through Activation of GATA2.

    Directory of Open Access Journals (Sweden)

    Jeffrey R Shearstone

    Full Text Available Therapeutic intervention aimed at reactivation of fetal hemoglobin protein (HbF is a promising approach for ameliorating sickle cell disease (SCD and β-thalassemia. Previous studies showed genetic knockdown of histone deacetylase (HDAC 1 or 2 is sufficient to induce HbF. Here we show that ACY-957, a selective chemical inhibitor of HDAC1 and 2 (HDAC1/2, elicits a dose and time dependent induction of γ-globin mRNA (HBG and HbF in cultured primary cells derived from healthy individuals and sickle cell patients. Gene expression profiling of erythroid progenitors treated with ACY-957 identified global changes in gene expression that were significantly enriched in genes previously shown to be affected by HDAC1 or 2 knockdown. These genes included GATA2, which was induced greater than 3-fold. Lentiviral overexpression of GATA2 in primary erythroid progenitors increased HBG, and reduced adult β-globin mRNA (HBB. Furthermore, knockdown of GATA2 attenuated HBG induction by ACY-957. Chromatin immunoprecipitation and sequencing (ChIP-Seq of primary erythroid progenitors demonstrated that HDAC1 and 2 occupancy was highly correlated throughout the GATA2 locus and that HDAC1/2 inhibition led to elevated histone acetylation at well-known GATA2 autoregulatory regions. The GATA2 protein itself also showed increased binding at these regions in response to ACY-957 treatment. These data show that chemical inhibition of HDAC1/2 induces HBG and suggest that this effect is mediated, at least in part, by histone acetylation-induced activation of the GATA2 gene.

  2. Accuracy of liver function tests for predicting adverse maternal and fetal outcomes in women with preeclampsia: a systematic review

    NARCIS (Netherlands)

    Thangaratinam, Shakila; Koopmans, Corine M.; Iyengar, Shalini; Zamora, Javier; Ismail, Khaled M. K.; Mol, Ben W. J.; Khan, Khalid S.

    2011-01-01

    Background. Liver function tests are routinely performed in women as part of a battery of investigations to assess severity at admission and later to guide appropriate management. Objective. To determine the accuracy with which liver function tests predict complications in women with preeclampsia by

  3. Accuracy of liver function tests for predicting adverse maternal and fetal outcomes in women with preeclampsia : a systematic review

    NARCIS (Netherlands)

    Thangaratinam, Shakila; Koopmans, Corine M.; Iyengar, Shalini; Zamora, Javier; Ismail, Khaled M. K.; Mol, Ben W. J.; Khan, Khalid S.

    Background. Liver function tests are routinely performed in women as part of a battery of investigations to assess severity at admission and later to guide appropriate management. Objective. To determine the accuracy with which liver function tests predict complications in women with preeclampsia by

  4. Saccharomyces boulardii Administration Changes Gut Microbiota and Attenuates D-Galactosamine-Induced Liver Injury

    OpenAIRE

    Yu, Lei; Zhao, Xue-ke; Cheng, Ming-liang; Yang, Guo-zhen; Wang, Bi; Liu, Hua-juan; Hu, Ya-xin; Zhu, Li-li; Zhang, Shuai; Xiao, Zi-wen; Liu, Yong-mei; Zhang, Bao-fang; Mu, Mao

    2017-01-01

    Growing evidence has shown that gut microbiome is a key factor involved in liver health. Therefore, gut microbiota modulation with probiotic bacteria, such as Saccharomyces boulardii, constitutes a promising therapy for hepatosis. In this study, we aimed to investigate the protective effects of S. boulardii on D-Galactosamine-induced liver injury in mice. Liver function test and histopathological analysis both suggested that the liver injury can be effectively attenuated by S. boulardii admin...

  5. Endotoxin induced chorioamnionitis prevents intestinal development during gestation in fetal sheep.

    Directory of Open Access Journals (Sweden)

    Tim G A M Wolfs

    junctional protein ZO-1, the immune defence and vascular function are immature at low GA and are further compromised by endotoxin-induced chorioamnionitis. This study suggests that both prematurity and inflammation in utero disturb fetal gut development, potentially predisposing to postnatal intestinal pathology.

  6. Proteomic profiling in incubation medium of mouse, rat and human precision-cut liver slices for biomarker detection regarding acute drug-induced liver injury

    NARCIS (Netherlands)

    van Swelm, Rachel P L; Hadi, Mackenzie; Laarakkers, Coby M M; Masereeuw, R.|info:eu-repo/dai/nl/155644033; Groothuis, Geny M M; Russel, Frans G M

    Drug-induced liver injury is one of the leading causes of drug withdrawal from the market. In this study, we investigated the applicability of protein profiling of the incubation medium of human, mouse and rat precision-cut liver slices (PCLS) exposed to liver injury-inducing drugs for biomarker

  7. Identification of Factors Interacting with hMSH2 and hMLH1 in the Fetal Liver and Investigations of how Mitochondrial Dysfunction Creates a Mutator Phenotype

    DEFF Research Database (Denmark)

    Rasmussen, Anne Karin

    mutations. Mutations in MMR genes cause hereditary non-polyposis colon cancer. In an effort to identify unidentified genes involved in MMR and tissue-specific MMRassociated factors, we employed the yeast two-hybrid system, using the human hMSH2 as bait and a human fetal liver cDNA library as prey. We...... between mitochondrial activity and genomic instability. Mitochondrial dysfunction and genetic instability are characteristic features of cancer cells. Furthermore, mitochondrial dysfunction is a key feature of aging due to accumulation of mutations in mtDNA. Our studies in a yeast model system suggest......Increased spontaneous mutation frequency is associated with increased cancer risk. However, the relative contribution of spontaneous endogenous mutagenesis to carcinogenesis is not known today. Defects in the postreplication DNA mismatch repair (MMR) pathway are recognized to increase spontaneous...

  8. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Uduak S. Udoh

    2015-10-01

    Full Text Available Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

  9. Surrogate markers of the kidney and liver in the assessment of gestational diabetes mellitus and fetal outcome.

    Science.gov (United States)

    Liu, Hong; Shao-Gang, Ma; Liang, Cheng; Feng, Bai; Wei, Xu

    2015-01-01

    To investigate whether serum levels of butyrylcho-linesterase activity, cystatin C, and pre-albumin has the potential value as γ-glutamyl transferase in reflecting gestational diabetes mellitus and its fetal outcome. Seventy-six gestational diabetes mellitus women and 76 pregnancies with normal glucose tolerance in the second trimester were enrolled. Maternal serum parameters of butyrylcholinesterase activity, γ-glutamyl transferase, cystatin C, and pre-albumin were detected and evaluated. The pregnant complications and fetal outcome were also evaluated. Levels of butyrylcholinesterase activity, γ-glutamyl transferase, cystatin C, pre-albumin and glycemic variables were higher in the gestational diabetes mellitus patients than in the controls. Levels of butyrylcholinesterase activity were significantly correlated to the levels of fasting plasma glucose, cystatin C, and γ- glutamyl transferase (p gestational diabetes mellitus group. There were statistical differences in cases of preterm delivery, preeclampsia and postpartum hemorrhage. Higher levels of γ-glutamyl transferase and pre-albumin were risk markers for gestational diabetes mellitus (p gestational diabetes mellitus status but not with the fetal outcome. Pre-albumin can be equivalent as γ-glutamyl transferase in reflecting the presence of gestational diabetes mellitus.

  10. Characterization of Chemically Induced Liver Injuries Using Gene Co-Expression Modules

    Science.gov (United States)

    2014-09-16

    evaluated the periportal fibrosis gene signature in the GEO dataset - GSE13747 [34]. In this dataset, liver fibrosis was induced by bile duct ...dataset, liver fibrosis was induced by bile duct ligation. Figure 10-D shows the observed correlation between log-ratios of periportal fibrosis...at 15 days of exposure obtained from TG-GATEs, and D) liver fibrosis produced by bile duct ligation obtained from GSE13747. doi:10.1371/journal.pone

  11. Liv. 52 protection against radiation induced lesions in mammalian liver

    International Nuclear Information System (INIS)

    Saini, M.R.; Saini, N.

    1985-01-01

    Effect of Liv. 52 on mammalian liver was studied after whole-body exposure to 5.5 Gy of 60 Co gamma radiation. It was found that the drug protected the organ against radiation-induced changes. The protective effect was manifested in the form of early recovery as indicated by the absence of pathological changes like cytoplasmic degranulation, loss of nulei from many cells and abnormal architecture at 10 days and restoration of normal structure by 4 weeks. Liv. 52 may neutralize the peroxides formed from water molecules after irradiation which are toxic and cause the damage to the organ. Thus it seems that the drug may act as detoxicating agent. (author)

  12. Reversal of aflatoxin induced liver damage by turmeric and curcumin.

    Science.gov (United States)

    Soni, K B; Rajan, A; Kuttan, R

    1992-09-30

    The effect of certain food additives on aflatoxin production by Aspergillus parasiticus has been studied in vitro. Extracts of turmeric (Curcuma longa), garlic (Allium sativum) and asafoetida (Ferula asafoetida) inhibited the aflatoxin production considerably (more than 90%) at concentrations of 5-10 mg/ml. Similar results were also seen using butylated hydroxytoluene, butylated hydroxyanisole and ellagic acid at concentration 0.1 mM. Curcumin, the antioxidant principle from Curcuma longa did not have any effect on aflatoxin production. Turmeric and curcumin were also found to reverse the aflatoxin induced liver damage produced by feeding aflatoxin B1 (AFB1) (5 micrograms/day per 14 days) to ducklings. Fatty changes, necrosis and biliary hyperplasia produced by AFB1 were considerably reversed by these food additives.

  13. Antituberculosis Drug-Induced Liver Injury with Autoimmune Features: Facing Diagnostic and Treatment Challenges

    Directory of Open Access Journals (Sweden)

    Maria Adriana Rangel

    2017-01-01

    Full Text Available The authors present a case report of antituberculosis drug-induced liver injury that offered diagnostic challenges (namely, the possibility of drug-induced autoimmune hepatitis and treatment difficulties.

  14. Comparative Study of Folic Acid and α-Naphthoflavone on Reducing TCDD-Induced Cleft Palate in Fetal Mice.

    Science.gov (United States)

    Yuan, Xingang; He, Xiaomeng; Zhang, Xuan; Liu, Cuiping; Wang, Chen; Qiu, Lin; Pu, Wei; Fu, Yuexian

    2017-03-01

      Tocompare the effect of folic acid (FA) and α-naphthoflavone on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced cleft palate in fetal mice.   Pregnant mice were randomly divided into seven groups. The mice treated with corn oil were used as a negative control. The mice in the other six groups were given a single dose of 28 μg/kg TCDD on GD 10 by gavage. For FA treatment, TCDD-treated mice were also dosed with 5, 10, and 15 mg/kg FA on GD 10, while for α-naphthoflavone treatment, the mice received a single dose of 50 μg/kg or 5 mg/kg α-naphthoflavone on GD 10.   Fetal mice palates were imaged using light and scanning electron microscopy on GD 13.5, GD 14.5, and GD 15.5, and cleft palate were recorded on GD 17.5. The expression of guanosine diphosphate dissociation inhibitor (GDI) in fetal mice palate on GD 15.5 was examined by immunohistochemistry.   TCDD successfully induced cleft palate. Ten mg/ml FA and 5 mg/ml α-naphthoflavone significantly reduced TCDD-induced cleft palate. FA and α-naphthoflavone partly reduced TCDD-induced cleft palate but did not affect the expression of Rho GDI.   FA and α-naphthoflavone may reduce the generation of reactive oxygen species, inhibit MEE apoptosis through anti-oxidation, and increase filopodia and MEE movement. This may result in restoration of the ultrastructure of the palatal surface to a normal state, leading to the fusion and formation of complete palate in TCDD-treated fetal mice.

  15. Temozolomide-induced liver damage. A case report

    Energy Technology Data Exchange (ETDEWEB)

    Becker, F.; Hecht, M.; Schmidtner, J.; Semrau, S.; Fietkau, R. [University of Erlangen-Nuremberg, Department of Radiation Oncology, Erlangen (Germany)

    2014-04-15

    Temozolomide (TMZ) is an alkylating agent used in chemoradiotherapy and adjuvant chemotherapy regimens for treatment of newly diagnosed or recurrent glioblastoma. In Germany alone, 900,000 daily doses of the drug are prescribed each year. Therefore, all severe side effects of TMZ, even those rarely observed, are relevant to radiotherapists. We report a case of severe drug-induced toxic hepatitis that developed during chemoradiotherapy with TMZ in a patient with glioblastoma multiforme. Transaminase elevation was observed after 5 weeks of TMZ treatment, followed by severe jaundice symptoms which only subsided 2 months later. These findings were consistent with diagnosis of the mixed hepatic/cholestatic type of drug-induced toxic hepatitis. Due to the early termination of treatment, no life-threatening complications occurred in our patient. However, rare reports of encephalopathy and fatality as complications of TMZ therapy can be found in the literature. When using TMZ for treatment of glioblastoma, monitoring of liver enzyme levels should be performed twice weekly to prevent fatal toxic hepatitis. In the case of any drug-induced hepatitis, TMZ must be discontinued immediately. (orig.)

  16. Anatomical, animal, and cellular evidence for Zika-induced pathogenesis of fetal microcephaly.

    Science.gov (United States)

    Wang, Jing-Zhang; Guo, Xin-Hua; Xu, Dian-Guo

    2017-04-01

    Several recent articles published by Brain and Development in 2016 demonstrated some rare, but innovative, genetic mechanisms for microcephaly. This concise mini-review presented another novel pathogenic mechanism for microcephaly, which has actually been a worldwide medical challenge since the World Health Organization (WHO) defined the outbreak of the Zika virus (ZIKV) as an International Public Health Emergency on 1 Feb, 2016. As a recent noteworthy clinical phenomenon, the ZIKV outbreak was accompanied by a dramatically increased number of microcephalus fetuses. However, no direct evidence supporting the suspected pathogenic effects of ZIKV on fetal microcephaly was shown previously before 2016. Herein, we evaluated the most important human pathological, animal developmental, and neuro-cytotoxic findings released in 2016, and highlighted the original experimental evidence that strengthens the potential link between ZIKV and the high incidence of microcephaly in new-born babies. Because killing mosquitoes via insecticides is currently the only effective way to suppress ZIKV-induced disorders, the animal and cellular models described in this mini-review are very beneficial to anti-ZIKV drug development and vaccine assessment. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  17. RUCAM in Drug and Herb Induced Liver Injury: The Update

    Directory of Open Access Journals (Sweden)

    Gaby Danan

    2015-12-01

    Full Text Available RUCAM (Roussel Uclaf Causality Assessment Method or its previous synonym CIOMS (Council for International Organizations of Medical Sciences is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI and herb induced liver injury (HILI. Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality

  18. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

    NARCIS (Netherlands)

    Gonzalez Ponce, Herson Antonio; Consolacion Martinez-Saldana, Maria; Rosa Rincon-Sanchez, Ana; Teresa Sumaya-Martinez, Maria; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juarez, Fernando

    2016-01-01

    Acetaminophen (APAP)-induced acute liver failure (ALF) is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC), the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients

  19. Possible gasoline-induced chronic liver injury due to occupational malpractice in a motor mechanic: a case report

    OpenAIRE

    Gunathilaka, Mahesh Lakmal; Niriella, Madunil Anuk; Luke, Nathasha Vihangi; Piyarathna, Chathura Lakmal; Siriwardena, Rohan Chaminda; De Silva, Arjuna Priyadarshin; de Silva, Hithanadura Janaka

    2017-01-01

    Background Hydrocarbon-induced occupational liver injury is a well-known clinical entity among petroleum industry workers. There are many types of hydrocarbon exposure, with inhalation being the most common. Hydrocarbon-induced occupational liver injury is a rarely suspected and commonly missed etiological agent for liver injury. We report a case of a non-petroleum industry worker with chronic liver disease secondary to hydrocarbon-induced occupational liver injury caused by chronic low-grade...

  20. Ontogenic differences in human liver 4-hydroxynonenal detoxification are associated with in vitro injury to fetal hematopoietic stem cells

    International Nuclear Information System (INIS)

    Gardner, James L.; Doi, Adriana M.; Pham, Robert T.; Huisden, Christiaan M.; Gallagher, Evan P.

    2003-01-01

    4-hydroxynonenal (4HNE) is a highly mutagenic and cytotoxic α,β-unsaturated aldehyde that can be produced in utero during transplacental exposure to prooxidant compounds. Cellular protection against 4HNE injury is provided by alcohol dehydrogenases (ADH), aldehyde reductases (ALRD), aldehyde dehydrogenases (ALDH), and glutathione S-transferases (GST). In the present study, we examined the comparative detoxification of 4HNE by aldehyde-metabolizing enzymes in a panel of adult and second-trimester prenatal liver tissues and report the toxicological ramifications of ontogenic 4HNE detoxification in vitro. The initial rates of 4HNE oxidation and reduction were two- to fivefold lower in prenatal liver subcellular fractions as compared to adult liver, and the rates of GST conjugation of 4HNE were not detectable in either prenatal or adult cytosolic fractions. GSH-affinity purification of hepatic cytosol yielded detectable and roughly equivalent rates of GST-4HNE conjugation for the two age groups. Consistent with the inefficient oxidative and reductive metabolism of 4HNE in prenatal liver, cytosolic fractions prepared from prenatal liver exhibited a decreased ability to protect against 4HNE-protein adduct formation relative to adults. Prenatal liver hematopoietic stem cells (HSC), which constitute a significant percentage of prenatal liver cell populations, exhibited ALDH activities toward 4HNE, but little reductive or conjugative capacity toward 4HNE through ALRD, ADH, and GST. Cultured HSC exposed to 5 μM 4HNE exhibited a loss in viability and readily formed one or more high molecular weight 4HNE-protein adduct(s). Collectively, our results indicate that second trimester prenatal liver has a lower ability to detoxify 4HNE relative to adults, and that the inefficient detoxification of 4HNE underlies an increased susceptibility to 4HNE injury in sensitive prenatal hepatic cell targets

  1. Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity.

    Science.gov (United States)

    Linder, Katarzyna; Schleger, Franziska; Ketterer, Caroline; Fritsche, Louise; Kiefer-Schmidt, Isabelle; Hennige, Anita; Häring, Hans-Ulrich; Preissl, Hubert; Fritsche, Andreas

    2014-06-01

    Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity. Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined. Maternal insulin increased from a fasting level of 67 ± 25 pmol/l (mean ± SD) to 918 ± 492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4 ± 0.3 to 7.4 ± 1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297 ± 99 to 235 ± 84 ms (p = 0.01) and then remained stable until 120 min (235 ± 84 vs 251 ± 91 ms, p = 0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r = 0.68, p = 0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283 ± 79 ms) than those of insulin-sensitive mothers (178 ± 46 ms, p = 0.03). Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development.

  2. Imatinib-induced fulminant liver failure in chronic myeloid leukemia: role of liver transplant and second-generation tyrosine kinase inhibitors: a case report.

    Science.gov (United States)

    Nacif, Lucas Souto; Waisberg, Daniel R; Pinheiro, Rafael Soares; Lima, Fabiana Roberto; Rocha-Santos, Vinicius; Andraus, Wellington; D'Albuquerque, Luiz Carneiro

    2018-03-10

    There is a worldwide problem of acute liver failure and mortality associated with remaining on the waiting for a liver transplant. In this study, we highlight results published in recent years by leading transplant centers in evaluating imatinib-induced acute liver failure in chronic myeloid leukemia and follow-up in liver transplantation. A 36-year-old brown-skinned woman (mixed Brazilian race) diagnosed 1 year earlier with chronic myeloid leukemia was started after delivery of a baby and continued for 6 months with imatinib mesylate (selective inhibitor of Bcr-Abl tyrosine kinase), which induced liver failure. We conducted a literature review using the PubMed database for articles published through September 2017, and we demonstrate a role of liver transplant in this situation for imatinib-induced liver failure. We report previously published results and a successful liver transplant after acute liver failure due to imatinib-induced in chronic myeloid leukemia treatment. We report a case of a successful liver transplant after acute liver failure resulting from imatinib-induced chronic myeloid leukemia treatment. The literature reveals the importance of prompt acute liver failure diagnosis and treatment with liver transplant in selected cases.

  3. Fetal abdominal magnetic resonance imaging

    International Nuclear Information System (INIS)

    Brugger, Peter C.; Prayer, Daniela

    2006-01-01

    This review deals with the in vivo magnetic resonance imaging (MRI) appearance of the human fetal abdomen. Imaging findings are correlated with current knowledge of human fetal anatomy and physiology, which are crucial to understand and interpret fetal abdominal MRI scans. As fetal MRI covers a period of more than 20 weeks, which is characterized not only by organ growth, but also by changes and maturation of organ function, a different MR appearance of the fetal abdomen results. This not only applies to the fetal intestines, but also to the fetal liver, spleen, and adrenal glands. Choosing the appropriate sequences, various aspects of age-related and organ-specific function can be visualized with fetal MRI, as these are mirrored by changes in signal intensities. Knowledge of normal development is essential to delineate normal from pathological findings in the respective developmental stages

  4. Fetal abdominal magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Brugger, Peter C. [Center of Anatomy and Cell Biology, Integrative Morphology Group, Medical University of Vienna, Waehringerstrasse 13, 1090 Vienna (Austria)]. E-mail: peter.brugger@meduniwien.ac.at; Prayer, Daniela [Department of Radiology, Medical University of Vienna, Waehringerguertel 18-20, 1090 Vienna (Austria)

    2006-02-15

    This review deals with the in vivo magnetic resonance imaging (MRI) appearance of the human fetal abdomen. Imaging findings are correlated with current knowledge of human fetal anatomy and physiology, which are crucial to understand and interpret fetal abdominal MRI scans. As fetal MRI covers a period of more than 20 weeks, which is characterized not only by organ growth, but also by changes and maturation of organ function, a different MR appearance of the fetal abdomen results. This not only applies to the fetal intestines, but also to the fetal liver, spleen, and adrenal glands. Choosing the appropriate sequences, various aspects of age-related and organ-specific function can be visualized with fetal MRI, as these are mirrored by changes in signal intensities. Knowledge of normal development is essential to delineate normal from pathological findings in the respective developmental stages.

  5. Risk factors of radiation-induced liver disease after three-dimensional conformal radiotherapy for primary liver carcinoma

    International Nuclear Information System (INIS)

    Liang Shixiong; Zhu Xiaodong; Lu Haijie; Pan Chaoyang; Huang Qifang; Li Fuxiang; Wang Anyu; Liang Guoliang; Fu Xiaolong

    2005-01-01

    Objective: To identify the risk factors of radiation-induced liver disease (RILD) after three-dimensional radiotherapy (3DCRT) for primary liver carcinoma (PLC) and the dosimetric threshold of RILD. Methods: Between April 1999 and August 2003, 128 PLC patients who were treated with 3DCRT received a mean dose of 53.6 ± 6.6 Gy with a 4-8 Gy/f, 3f/w, qod regimen. The relation between RILD and the possible clinical factors, such as gender, age, UICC/ AJCC T stage, GTV, HBV status, PTV, TACE, Child-Pugh grade of liver cirrhosis, BED calculated by LQ model and fraction size were analyzed. Among 84 patients who had full dose- volume histogram (DVH) data, the relation between RILD and dosimetric parameters were analyzed. Results: Nineteen patients (14.8%) developed RILD. It was found that T stage, GTV, PTV, Child-Pugh grade of liver cirrhosis and the acute hepatic toxicity proposed by common toxicity criteria version 2.0 (CTC2.0) were correlated with RILD (P=0.024, 0.002, 0.001, 0.000, 0.000, respectively). Multivariate analysis showed that only the Child-Pugh grade of liver cirrhosis was independent factor (P=0.000). The mean liver dose was significantly higher in patients with RILD (P=0.027). In patients with Child-Pugh grade A, V5 (percentage of normal liver volume with radiation dose > 5 Gy), V 10 and V 20 ≤81%, 69% and 42%, mean liver dose ≤28 Gy, RILD was not observed, whereas in patients with Child-Pugh grade B, the possibility of developing RILD was 53.3%(8/15). Conclusions: Comprehensive consideration of T stage, GTV, PTV and Child-Pugh grade of liver cirrhosis, especially the Child-Pugh grade of liver cirrhosis, when planning 3DCRT for PLC, may lower the incidence of RILD. (authors)

  6. Symbiotic formulation in experimentally induced liver fibrosis in rats: intestinal microbiota as a key point to treat liver damage?

    Science.gov (United States)

    D'Argenio, Giuseppe; Cariello, Rita; Tuccillo, Concetta; Mazzone, Giovanna; Federico, Alessandro; Funaro, Annalisa; De Magistris, Laura; Grossi, Enzo; Callegari, Maria L; Chirico, Marilena; Caporaso, Nicola; Romano, Marco; Morelli, Lorenzo; Loguercio, Carmela

    2013-05-01

    Evidence indicates that intestinal microbiota may participate in both the induction and the progression of liver damage. The aim of our research was the detection and evaluation of the effects of chronic treatment with a symbiotic formulation on CCl4 -induced rat liver fibrosis. CCl4 significantly increased gastric permeability in respect to basal values, and the treatment with symbiotic significantly decreased it. CCl4 per se induced a decrease in intestinal permeability. This effect was also seen in fibrotic rats treated with symbiotic and was still evident when normal rats were treated with symbiotic alone (P symbiotic treatment normalized the plasma levels of TNF-α and significantly enhanced anti-inflammatory cytokine IL 10. TNF-α, TGF-β, TLR4, TLR2, iNOS and α-SMA mRNA expression in the liver were up-regulated in rats with CCl4 -induced liver fibrosis and down-regulated by symbiotic treatment. Moreover, IL-10 and eNOS mRNA levels were increased in the CCL4 (+) symbiotic group. Symbiotic treatment of fibrotic rats normalized serum ALT, AST and improved histology and liver collagen deposition. DGGE analysis of faecal samples revealed that CCl4 administration and symbiotic treatment either alone or in combination produced modifications in faecal profiles vs controls. Our results provide evidence that in CCl4 -induced liver fibrosis, significant changes in gastro-intestinal permeability and in faecal flora occur. Treatment with a specific symbiotic formulation significantly affects these changes, leading to improvement in both liver inflammation and fibrosis. © 2013 John Wiley & Sons A/S.

  7. Radiation-induced adaptive response in fetal mice: a micro-array study

    International Nuclear Information System (INIS)

    Vares, G.; Bing, Wang; Mitsuru, Nenoi; Tetsuo, Nakajima; Kaoru, Tanaka; Isamu, Hayata

    2006-01-01

    may contribute to AR induction by shifting DSB end-joining activity from illegitimate error-prone rejoining to error-free direct ligation. For all these reasons, particular attention was given to the transcriptional behavior of p53-related genes in our model. Although average gene regulation fold was relatively small, a significant proportion of p53-related genes showed AR-specific modulation, indicating a role for directly and indirectly p53-related pathways in the induction of AR. Even though no evidence of specific DNA repair modulation at the transcriptional level was observed in adapted cells, a large amount of data suggested that induction of AR may result from modification of DNA repair activity. We studied H2AX kinetics following challenging irradiation in adapted and non-adapted cells. H2AX phosphorylation increased shortly after irradiation, and then decreased progressively during the subsequent 24 hours. No significant difference was observed between the rate of disappearance of H2AX in adapted and non-adapted cells, indicating that AR in this model seems not to be related with a modulation of DNA break rejoining speed. However, the peak of H2AX phosphorylation appeared slightly earlier in adapted than in non-adapted cells. In accordance with other data, these results are compatible with the hypothesis that the low adapting dose could induce a repair mechanism that, if activated at the time of challenging exposure with high doses of radiation, would lead to less residual damage. In conclusion, we observed transcriptional de-regulations resulting from exposure to low dose X-rays. Our results highlighted some specific transcriptional response of cells when the characteristics of irradiation were efficient for inducing AR, indicating that AR may result from specific molecular mechanisms induced b y exposure to priming dose of irradiation. To our knowledge and to date, this is the first report of AR-specific transcriptional de-regulations in fetal mouse

  8. Methionine sulfoxide reductase A deficiency exacerbates acute liver injury induced by acetaminophen

    International Nuclear Information System (INIS)

    Singh, Mahendra Pratap; Kim, Ki Young; Kim, Hwa-Young

    2017-01-01

    Acetaminophen (APAP) overdose induces acute liver injury via enhanced oxidative stress and glutathione (GSH) depletion. Methionine sulfoxide reductase A (MsrA) acts as a reactive oxygen species scavenger by catalyzing the cyclic reduction of methionine-S-sulfoxide. Herein, we investigated the protective role of MsrA against APAP-induced liver damage using MsrA gene-deleted mice (MsrA −/− ). We found that MsrA −/− mice were more susceptible to APAP-induced acute liver injury than wild-type mice (MsrA +/+ ). The central lobule area of the MsrA −/− liver was more impaired with necrotic lesions. Serum alanine transaminase, aspartate transaminase, and lactate dehydrogenase levels were significantly higher in MsrA −/− than in MsrA +/+ mice after APAP challenge. Deletion of MsrA enhanced APAP-induced hepatic GSH depletion and oxidative stress, leading to increased susceptibility to APAP-induced liver injury in MsrA-deficient mice. APAP challenge increased Nrf2 activation more profoundly in MsrA −/− than in MsrA +/+ livers. Expression and nuclear accumulation of Nrf2 and its target gene expression were significantly elevated in MsrA −/− than in MsrA +/+ livers after APAP challenge. Taken together, our results demonstrate that MsrA protects the liver from APAP-induced toxicity. The data provided herein constitute the first in vivo evidence of the involvement of MsrA in hepatic function under APAP challenge. - Highlights: • MsrA deficiency increases APAP-induced liver damage. • MsrA deletion enhances APAP-induced hepatic GSH depletion and oxidative stress. • MsrA deficiency induces more profound activation of Nrf2 in response to APAP. • MsrA protects the liver from APAP-induced toxicity.

  9. 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.

  10. Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network.

    Science.gov (United States)

    Navarro, Victor J; Barnhart, Huiman; Bonkovsky, Herbert L; Davern, Timothy; Fontana, Robert J; Grant, Lafaine; Reddy, K Rajender; Seeff, Leonard B; Serrano, Jose; Sherker, Averell H; Stolz, Andrew; Talwalkar, Jayant; Vega, Maricruz; Vuppalanchi, Raj

    2014-10-01

    The Drug-Induced Liver Injury Network (DILIN) studies hepatotoxicity caused by conventional medications as well as herbals and dietary supplements (HDS). To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight U.S. referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury caused by HDS. Hepatotoxicity caused by HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments, including death and liver transplantation (LT), were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury caused by bodybuilding HDS, 85 by nonbodybuilding HDS, and 709 by medications. Liver injury caused by HDS increased from 7% to 20% (P Bodybuilding HDS caused prolonged jaundice (median, 91 days) in young men, but did not result in any fatalities or LT. The remaining HDS cases presented as hepatocellular injury, predominantly in middle-aged women, and, more frequently, led to death or transplantation, compared to injury from medications (13% vs. 3%; P bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes (death and transplantation). (Hepatology 2014;60:1399-1408). © 2014 by the American Association for the Study of Liver Diseases.

  11. Sex Differences in Placental Mitochondrial Function Associated with Ozone-Induced Fetal Growth Restriction

    Science.gov (United States)

    Fetal growth restriction is a major underlying cause of infant mortality worldwide. Despite knowledge of risk factors for adverse pregnancy outcomes, the mechanisms that drive compromised growth during pregnancy have not been well established. Placental maladaptation, particularl...

  12. Choline-Deficient-Diet-Induced Fatty Liver Is a Metastasis-Resistant Microenvironment.

    Science.gov (United States)

    Nakamura, Miki; Suetsugu, Atsushi; Hasegawa, Kosuke; Matsumoto, Takuro; Aoki, Hitomi; Kunisada, Takahiro; Shimizu, Masahito; Saji, Shigetoyo; Moriwaki, Hisataka; Hoffman, Robert M

    2017-07-01

    Fatty liver disease is increasing in the developed and developing world. Liver metastasis from malignant lymphoma in the fatty liver is poorly understood. In a previous report, we developed color-coded imaging of the tumor microenvironment (TME) of the murine EL4-RFP malignant lymphoma during metastasis, including the lung. In the present report, we investigated the potential and microenvironment of the fatty liver induced by a choline-deficient diet as a metastatic site in this mouse lymphoma model. C57BL/6-GFP transgenic mice were fed with a choline-deficient diet in order to establish a fatty liver model. EL4-RFP cells were injected in the spleen of normal mice and fatty-liver mice. Metastases in mice with fatty liver or normal liver were imaged with the Olympus SZX7 microscope and the Olympus FV1000 confocal microscope. Metastases of EL4-RFP were observed in the liver, ascites and bone marrow. Primary tumors were imaged in the spleen at the injection site. The fewest metastases were observed in the fatty liver. In addition, the fewest cancer-associated fibroblasts (CAFs) were observed in the fatty liver. The relative metastatic resistance of the fatty liver may be due to the reduced number of CAFs in the fatty livers. The mechanism of the effect of the choline-deficient diet is discussed. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  13. Non-invasive monitoring of carcinogenesis in N-nitrosodiethylamine induced liver cancer

    Energy Technology Data Exchange (ETDEWEB)

    Park, Ju Hui; Kang, Joo Hyun; Lee, Yong Jin; Lee, Tae Sup; Kim, Kwang Il; Cheon, Gi Jeong; Choi, Chang Woon; Lim, Sang Moo [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Park, Young Seo [Kyungwon University, Seongnam (Korea, Republic of)

    2010-10-15

    Molecular imaging based on reporter gene expression allows tissue-specific events or processes to be measured using the bioluminescence imaging (BLI) reporter gene expression vector controlled by specific enhancer/promoters. Alpha-fetoprotein (AFP), which is a tumor marker, is a serum glycoprotein that is expressed normally by fetal liver and yolk-sac cells, as well as in trace amounts in the fetal gastrointestinal tract. The serum concentration of AFP decreases rapidly after birth and its expression is repressed in adults. Approximately 80% of HCC patients show an increase in the AFP level. Therefore, AFP has been used for many years as a diagnostic and prognostic serum marker for HCC and transgenic system for AFP was proposed as a valuable tool for elucidation of mechanism of transcriptional regulation during liver development and hepatocarcinogenesis. In this study, firefly luciferase (fLuc) expressing transgenic mice controlled by the AFP enhancer/ promoter (enh/promoter) were produced to screen for the development of AFP-producing liver cancer. These models are expected to be useful for monitoring agents or drugs that modulate the AFP level as well as for measuring the specific signaling events important for liver cancer development

  14. Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury.

    Science.gov (United States)

    Addante, Annalisa; Roncero, Cesáreo; Almalé, Laura; Lazcanoiturburu, Nerea; García-Álvaro, María; Fernández, Margarita; Sanz, Julián; Hammad, Seddik; Nwosu, Zeribe C; Lee, Se-Jin; Fabregat, Isabel; Dooley, Steven; Ten Dijke, Peter; Herrera, Blanca; Sánchez, Aránzazu

    2018-05-11

    Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride-induced chronic injury. We have now addressed the role of BMP9 in 3,5 diethoxicarbonyl-1,4 dihydrocollidine (DDC)-induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion. WT and BMP9KO mice were submitted to DDC diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT-qPCR and western blot. BMP9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA approaches were used to identify the receptors mediating BMP9 effects. Deletion of BMP9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP9 results in overactivation of PI3K/AKT, ERK-MAPKs and c-Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC feeding. Importantly, BMP9 directly targets oval cells, it activates SMAD1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor-Like Kinase 2 (ALK2) type I receptor. We identify BMP9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP9 as an attractive therapeutic target for chronic liver diseases. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Differential effects of experimental and cold-induced hyperthyroidism on factors inducing rat liver oxidative damage

    OpenAIRE

    Venditti, Paola; Pamplona Gras, Reinald; Ayala, Victoria; Rosa, R. de; Caldarone, G.; Di Meo, S.

    2006-01-01

    Thyroid hormone-induced increase in metabolic rates is often associated with increased oxidative stress. The aim of the present study was to investigate the contribution of iodothyronines to liver oxidative stress in the functional hyperthyroidism elicited by cold, using as models cold-exposed and 3,5,3'-triiodothyronine (T-3)- or thyroxine (T-4)-treated rats. The hyperthyroid state was always associated with increases in both oxidative capacity and oxidative damage of the tissue. The most ex...

  16. Sugammadex antagonism of rocuronium-induced neuromuscular blockade in patients with liver cirrhosis undergoing liver resection: a randomized controlled study.

    Science.gov (United States)

    Abdulatif, Mohamed; Lotfy, Maha; Mousa, Mahmoud; Afifi, Mohamed H; Yassen, Khaled

    2018-02-05

    This randomized controlled study compared the recovery times of sugammadex and neostigmine as antagonists of moderate rocuroniuminduced neuromuscular block in patients with liver cirrhosis and controls undergoing liver resection. The study enrolled 27 adult patients with Child class "A" liver cirrhosis and 28 patients with normal liver functions. Normal patients and patients with liver cirrhosis were randomized according to the type of antagonist (sugammadex 2mg/kg or neostigmine 50μg/kg). The primary outcome was the time from antagonist administration to a trainoffour (TOF) ratio of 0.9 using mechanosensor neuromuscular transmission module. The durations of the intubating and topup doses of rocuronium, the length of stay in the postanesthesia care unit (PACU), and the incidence of postoperative re curarization were recorded. The durations of the intubating and topup doses of rocuronium were prolonged in patients with liver cirrhosis than controls. The times to a TOF ratio of 0.9 were 3.1 (1.0) and 2.6 (1.0) min after sugammadex administration in patients with liver cirrhosis and controls, respectively, p=1.00. The corresponding times after neostigmine administration were longer than sugammadex 14.5 (3.6) and 15.7 (3.6) min, respectively, psugammadex compared to neostigmine. We did not encounter postoperative recurarization after sugammadex or neostigmine. Sugammadex rapidly antagonize moderate residual rocuronium induced neuromuscular block in patients with Child class "A" liver cirrhosis undergoing liver resection. Sugammadex antagonism is associated with 80% reduction in the time to adequate neuromuscular recovery compared to neostigmine.

  17. Ethanol extract from portulaca oleracea L. attenuated acetaminophen-induced mice liver injury

    Science.gov (United States)

    Liu, Xue-Feng; Zheng, Cheng-Gang; Shi, Hong-Guang; Tang, Gu-Sheng; Wang, Wan-Yin; Zhou, Juan; Dong, Li-Wei

    2015-01-01

    Acetaminophen-induced liver injury represents the most frequent cause of drug-induced liver failure in the world. Portulaca oleracea L., a widely distributed weed, has been used as a folk medicine in many countries. Previously, we reported that the ethanol extracts of Portulaca oleracea L. (PO) exhibited significant anti-hypoxic activity. In the present study, we investigated the role of PO on acetaminophen (APAP) induced hepatotoxicity. The results demonstrated that PO was an effective anti-oxidative agent, which could, to some extent, reverse APAP-induced hepatotoxicity by regulating the reactive oxygen species (ROS) in the liver of mice. At the same time, PO treatment significantly decreased mice serum levels of IL-6 and TNFα and their mRNA expression in liver tissue IL-α and TNFα play an important role during APAP-induced liver injury. Furthermore, PO inhibited APAP and TNFα-induced activation of JNK, whose activation play an important effect during APAP induced liver injury. These findings suggested that administration of PO may be an effective strategy to prevent or treat liver injury induced by APAP. PMID:25901199

  18. Quercetin prevents pyrrolizidine alkaloid clivorine-induced liver injury in mice by elevating body defense capacity.

    Directory of Open Access Journals (Sweden)

    Lili Ji

    Full Text Available Quercetin is a plant-derived flavonoid that is widely distributed in nature. The present study is designed to analyze the underlying mechanism in the protection of quercetin against pyrrolizidine alkaloid clivorine-induced acute liver injury in vivo. Serum transaminases, total bilirubin analysis, and liver histological evaluation demonstrated the protection of quercetin against clivorine-induced liver injury. Terminal dUTP nick end-labeling assay demonstrated that quercetin reduced the increased amount of liver apoptotic cells induced by clivorine. Western-blot analysis of caspase-3 showed that quercetin inhibited the cleaved activation of caspase-3 induced by clivorine. Results also showed that quercetin reduced the increase in liver glutathione and lipid peroxidative product malondialdehyde induced by clivorine. Quercetin reduced the enhanced liver immunohistochemical staining for 4-hydroxynonenal induced by clivorine. Results of the Mouse Stress and Toxicity PathwayFinder RT2 Profiler PCR Array demonstrated that the expression of genes related with oxidative or metabolic stress and heat shock was obviously altered after quercetin treatment. Some of the alterations were confirmed by real-time PCR. Our results demonstrated that quercetin prevents clivorine-induced acute liver injury in vivo by inhibiting apoptotic cell death and ameliorating oxidative stress injury. This protection may be caused by the elevation of the body defense capacity induced by quercetin.

  19. Quercetin Prevents Pyrrolizidine Alkaloid Clivorine-Induced Liver Injury in Mice by Elevating Body Defense Capacity

    Science.gov (United States)

    Ji, Lili; Ma, Yibo; Wang, Zaiyong; Cai, Zhunxiu; Pang, Chun; Wang, Zhengtao

    2014-01-01

    Quercetin is a plant-derived flavonoid that is widely distributed in nature. The present study is designed to analyze the underlying mechanism in the protection of quercetin against pyrrolizidine alkaloid clivorine-induced acute liver injury in vivo. Serum transaminases, total bilirubin analysis, and liver histological evaluation demonstrated the protection of quercetin against clivorine-induced liver injury. Terminal dUTP nick end-labeling assay demonstrated that quercetin reduced the increased amount of liver apoptotic cells induced by clivorine. Western-blot analysis of caspase-3 showed that quercetin inhibited the cleaved activation of caspase-3 induced by clivorine. Results also showed that quercetin reduced the increase in liver glutathione and lipid peroxidative product malondialdehyde induced by clivorine. Quercetin reduced the enhanced liver immunohistochemical staining for 4-hydroxynonenal induced by clivorine. Results of the Mouse Stress and Toxicity PathwayFinder RT2 Profiler PCR Array demonstrated that the expression of genes related with oxidative or metabolic stress and heat shock was obviously altered after quercetin treatment. Some of the alterations were confirmed by real-time PCR. Our results demonstrated that quercetin prevents clivorine-induced acute liver injury in vivo by inhibiting apoptotic cell death and ameliorating oxidative stress injury. This protection may be caused by the elevation of the body defense capacity induced by quercetin. PMID:24905073

  20. Autoradiography in fetal golden hamsters treated with tritiated diethylnitrosamine

    International Nuclear Information System (INIS)

    Reznik-Schueller, H.M.; Hague, B.F. Jr.

    1981-01-01

    Tritiated diethylnitrosamine was administered to female Syrian golden hamsters on each of the last 4 days (days 12-15) of pregnancy. The distribution of bound radioactivity was monitored by light microscopic autoradiography of fetal tracheas and livers, the placentas, and the maternal livers. In the trachea, the fetal target organ, bound radioactivity was restricted to the respiratory epithelium, where diethylnitrosamine-induced tracheal tumors arise. Mucous cells and nonciliated stem cells were identified as the principal sites of binding; other cell types within the tracheal epithelium contained only small amounts of bound radioactivity. The level of binding observed in the fetal trachea increased steadily from day 12 to day 15, which correlated well with the levels of differentiation of this tissue during this period. This observation also agrees with the previously reported observation that tumor incidence increases from 40 to 95% in Syrian golden hamsters between days 12 and 15

  1. Maternal Diet during Pregnancy Induces Gene Expression and DNA Methylation Changes in Fetal Tissues in Sheep.

    Science.gov (United States)

    Lan, Xianyong; Cretney, Evan C; Kropp, Jenna; Khateeb, Karam; Berg, Mary A; Peñagaricano, Francisco; Magness, Ronald; Radunz, Amy E; Khatib, Hasan

    2013-01-01

    Studies in rats and mice have established that maternal nutrition induces epigenetic modifications, sometimes permanently, that alter gene expression in the fetus, which in turn leads to phenotypic changes. However, limited data is available on the influence of maternal diet on epigenetic modifications and gene expression in sheep. Therefore, the objectives of this study were to investigate the impact of different maternal dietary energy sources on the expression of imprinted genes in fetuses in sheep. Ewes were naturally bred to a single sire and from days 67 ± 3 of gestation until necropsy (days 130 ± 1), they were fed one of three diets of alfalfa haylage (HY; fiber), corn (CN; starch), or dried corn distiller's grains (DG; fiber plus protein plus fat). A total of 26 fetuses were removed from the dams and longissimus dorsi, semitendinosus, perirenal adipose depot, and subcutaneous adipose depot tissues were collected for expression and DNA methylation analyses. Expression analysis of nine imprinted genes and three DNA methyltransferase (DNMTs) genes showed significant effects of the different maternal diets on the expression of these genes. The methylation levels of CpG islands of both IGF2R and H19 were higher in HY and DG than CN fetuses in both males and females. This result is consistent with the low amino acid content of the CN diet, a source of methyl group donors, compared to HY and DG diets. Thus, results of this study provide evidence of association between maternal nutrition during pregnancy and transcriptomic and epigenomic alterations of imprinted genes and DNMTs in the fetal tissues.

  2. Maternal diet during pregnancy induces gene expression and DNA methylation changes in fetal tissues in sheep

    Directory of Open Access Journals (Sweden)

    Xianyong eLan

    2013-04-01

    Full Text Available Studies in rats and mice have established that maternal nutrition induces epigenetic modifications, sometimes permanently, that alter gene expression in the fetus, which in turn leads to phenotypic changes. However, limited data is available on the influence of maternal diet on epigenetic modifications and gene expression in sheep. Therefore, the objectives of this study were to investigate the impact of different maternal dietary energy sources on the expression of imprinted genes in fetuses in sheep. Ewes were naturally bred to a single sire and from d 67 ± 3 of gestation until necropsy (d 130 ± 1, they were fed one of three diets of alfalfa haylage (HY; fiber, corn (CN; starch, or dried corn distiller’s grains (DG; fiber plus protein plus fat. A total of 26 fetuses were removed from the dams and longissimus dorsi, semitendinosus, perirenal adipose depot, and subcutaneous adipose depot tissues were collected for expression and DNA methylation analyses. Expression analysis of nine imprinted genes and three DNA methylatransferase (DNMTs genes showed significant effects of the different maternal diets on the expression of these genes. The methylation levels of CpG islands of both IGF2R and H19 were higher in HY and DG than CN fetuses in both males and females. This result is consistent with the low amino acid content of the CN diet, a source of methyl group donors, compared to HY and DG diets. Thus, results of this study provide evidence of association between maternal nutrition during pregnancy and transcriptomic and epigenomic alterations of imprinted genes and DNMTs in the fetal tissues.

  3. Generation and characterization of induced pluripotent stem cells from guinea pig fetal fibroblasts

    Science.gov (United States)

    Wu, Yuehong; Li, Ouyang; He, Chengwen; Li, Yong; Li, Min; Liu, Xiaoming; Wang, Yujiong; He, Yulong

    2017-01-01

    Induced pluripotent stem cells (iPS) represent an important tool to develop disease-modeling assays, drug testing assays and cell-based replacement therapies. The application of iPS in these fields requires the development of suitable animal models. Of the suitable species, guinea pigs are particularly important and offer significant advantages. Successful iPS generation has been accomplished in a number of species; however, it has not been reported in the guinea pig. The present study successfully generated iPS from guinea pigs (giPS) using single polycistronic virus transduction with mouse octamer-binding transcription factor 4 (Oct4), sex determining region Y-box 2 (Sox2), Kruppel-like factor 4 and c-Myc. The giPS cell lines were cultured in media containing leukemia inhibitory factor and guinea pig fibroblast cells were used as feeder cells. These cultures were expanded under feeder-free culture conditions using ESGRO Complete Plus Clonal Grade medium containing 15% fetal bovine serum on gelatin-coated dishes. The resultant cells had a normal karyotype, exhibited alkaline phosphatase activity and expressed the pluripotency markers Oct4, Sox2 and Nanog. The cells differentiated in vivo to form teratomas that contained all three germ layers of the tissue cells. The generation of giPS may facilitate future studies investigating the mechanisms underlying innate immunity, particularly for tuberculosis. These experiments provide proof of principle that iPS technology may be adapted to use the guinea pig as a model of human diseases. PMID:28393187

  4. Rapamycin inhibits BMP-7-induced osteogenic and lipogenic marker expressions in fetal rat calvarial cells.

    Science.gov (United States)

    Yeh, Lee-Chuan C; Ma, Xiuye; Ford, Jeffery J; Adamo, Martin L; Lee, John C

    2013-08-01

    Bone morphogenetic proteins (BMPs) promote osteoblast differentiation and bone formation in vitro and in vivo. BMPs canonically signal through Smad transcription factors, but BMPs may activate signaling pathways traditionally stimulated by growth factor tyrosine kinase receptors. Of these, the mTOR pathway has received considerable attention because BMPs activate P70S6K, a downstream effector of mTOR, suggesting that BMP-induced osteogenesis is mediated by mTOR activation. However, contradictory effects of the mTOR inhibitor rapamycin (RAPA) on bone formation have been reported. Since bone formation is thought to be inversely related to lipid accumulation and mTOR is also important for lipid synthesis, we postulated that BMP-7 may stimulate lipogenic enzyme expression in a RAPA-sensitive mechanism. To test this hypothesis, we determined the effects of RAPA on BMP-7-stimulated expression of osteogenic and lipogenic markers in cultured fetal rat calvarial cells. Our study showed that BMP-7 promoted the expression of osteogenic and lipogenic markers. The effect of BMP-7 on osteogenic markers was greater in magnitude than on lipogenic markers and was temporally more sustained. RAPA inhibited basal and BMP-7-stimulated osteogenic and lipogenic marker expression and bone nodule mineralization. The acetyl CoA carboxylase inhibitor TOFA stimulated the expression of osteoblast differentiation markers, whereas palmitate suppressed their expression. We speculate that the BMP-7-stimulated adipogenesis is part of the normal anabolic response to BMPs, but that inappropriate activation of the lipid biosynthetic pathway by mTOR could have deleterious effects on bone formation and could explain paradoxical effects of RAPA to promote bone formation. Copyright © 2013 Wiley Periodicals, Inc.

  5. Generation and characterization of induced pluripotent stem cells from guinea pig fetal fibroblasts.

    Science.gov (United States)

    Wu, Yuehong; Li, Ouyang; He, Chengwen; Li, Yong; Li, Min; Liu, Xiaoming Liu; Wang, Yujiong; He, Yulong

    2017-06-01

    Induced pluripotent stem cells (iPS) represent an important tool to develop disease‑modeling assays, drug testing assays and cell‑based replacement therapies. The application of iPS in these fields requires the development of suitable animal models. Of the suitable species, guinea pigs are particularly important and offer significant advantages. Successful iPS generation has been accomplished in a number of species; however, it has not been reported in the guinea pig. The present study successfully generated iPS from guinea pigs (giPS) using single polycistronic virus transduction with mouse octamer‑binding transcription factor 4 (Oct4), sex determining region Y‑box 2 (Sox2), Kruppel‑like factor 4 and c‑Myc. The giPS cell lines were cultured in media containing leukemia inhibitory factor and guinea pig fibroblast cells were used as feeder cells. These cultures were expanded under feeder‑free culture conditions using ESGRO Complete Plus Clonal Grade medium containing 15% fetal bovine serum on gelatin‑coated dishes. The resultant cells had a normal karyotype, exhibited alkaline phosphatase activity and expressed the pluripotency markers Oct4, Sox2 and Nanog. The cells differentiated in vivo to form teratomas that contained all three germ layers of the tissue cells. The generation of giPS may facilitate future studies investigating the mechanisms underlying innate immunity, particularly for tuberculosis. These experiments provide proof of principle that iPS technology may be adapted to use the guinea pig as a model of human diseases.

  6. Inflammatory-induced hibernation in the fetus: priming of fetal sheep metabolism correlates with developmental brain injury.

    Directory of Open Access Journals (Sweden)

    Matthias Keller

    Full Text Available Prenatal inflammation is considered an important factor contributing to preterm birth and neonatal mortality and morbidity. The impact of prenatal inflammation on fetal bioenergetic status and the correlation of specific metabolites to inflammatory-induced developmental brain injury are unknown. We used a global metabolomics approach to examine plasma metabolites differentially regulated by intrauterine inflammation. Preterm-equivalent sheep fetuses were randomized to i.v. bolus infusion of either saline-vehicle or LPS. Blood samples were collected at baseline 2 h, 6 h and daily up to 10 days for metabolite quantification. Animals were killed at 10 days after LPS injection, and brain injury was assessed by histopathology. We detected both acute and delayed effects of LPS on fetal metabolism, with a long-term down-regulation of fetal energy metabolism. Within the first 3 days after LPS, 121 metabolites were up-regulated or down-regulated. A transient phase (4-6 days, in which metabolite levels recovered to baseline, was followed by a second phase marked by an opposing down-regulation of energy metabolites, increased pO(2 and increased markers of inflammation and ADMA. The characteristics of the metabolite response to LPS in these two phases, defined as 2 h to 2 days and at 6-9 days, respectively, were strongly correlated with white and grey matter volumes at 10 days recovery. Based on these results we propose a novel concept of inflammatory-induced hibernation of the fetus. Inflammatory priming of fetal metabolism correlated with measures of brain injury, suggesting potential for future biomarker research and the identification of therapeutic targets.

  7. Human Precision-Cut Liver Slices as an ex Vivo Model to Study Idiosyncratic Drug-Induced Liver Injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge M.; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, M.T.; Groothuis, Geny M. M.

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Because of the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict

  8. Human precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Westra, Inge; Starokozhko, Viktoriia; Dragovic, Sanja; Merema, Maja; Groothuis, Genoveva

    2013-01-01

    Idiosyncratic drug-induced liver injury (IDILI) is a major problem during drug development and has caused drug withdrawal and black-box warnings. Due to the low concordance of the hepatotoxicity of drugs in animals and humans, robust screening methods using human tissue are needed to predict and to

  9. Anabolic steroid-induced cardiomyopathy underlying acute liver failure in a young bodybuilder.

    Science.gov (United States)

    Bispo, Miguel; Valente, Ana; Maldonado, Rosário; Palma, Rui; Glória, Helena; Nóbrega, João; Alexandrino, Paula

    2009-06-21

    Heart failure may lead to subclinical circulatory disturbances and remain an unrecognized cause of ischemic liver injury. We present the case of a previously healthy 40-year-old bodybuilder, referred to our Intensive-Care Unit of Hepatology for treatment of severe acute liver failure, with the suspicion of toxic hepatitis associated with anabolic steroid abuse. Despite the absence of symptoms and signs of congestive heart failure at admission, an anabolic steroid-induced dilated cardiomyopathy with a large thrombus in both ventricles was found to be the underlying cause of the liver injury. Treatment for the initially unrecognized heart failure rapidly restored liver function to normal. To our knowledge, this is the first reported case of severe acute liver failure due to an unrecognized anabolic steroid-induced cardiomyopathy. Awareness of this unique presentation will allow for prompt treatment of this potentially fatal cause of liver failure.

  10. Tocilizumab-Induced Acute Liver Injury in Adult Onset Still’s Disease

    Directory of Open Access Journals (Sweden)

    Michael Drepper

    2013-01-01

    Full Text Available Background. Tocilizumab, a monoclonal humanized anti-IL-6 receptor antibody, is used in treatment of refractory adult onset Still’s disease (AOSD. Mild to moderate liver enzyme elevation is a well-known side effect, but severe liver injury has only been reported in 3 cases in the literature. Case. A young female suffering from corticoid and methotrexate refractory AOSD was treated by tocilizumab. After 19 months of consecutive treatment, she developed acute severe liver injury. Liver biopsy showed extensive hepatocellular necrosis with ballooned hepatocytes, highly suggestive of drug-induced liver injury. No other relevant drug exposure beside tocilizumab was recorded. She recovered totally after treatment discontinuation and an initial 3-day course of intravenous N-acetylcysteine with normalization of liver function tests after 6 weeks. Conclusion. Acute severe hepatitis can be associated with tocilizumab as documented in this case. Careful monitoring of liver function tests is warranted during tocilizumab treatment.

  11. Apoptosis Induced in The Brain and Liver of Fetuses And Placenta of Irradiated Pregnant Rats Treated With Antacid Containing Aluminum

    International Nuclear Information System (INIS)

    Ramadan, F.L.; Madkour, N.K.

    2012-01-01

    Aluminum (Al) is widely used in antacid medicine which frequently used by pregnant women. It is of great importance to increase the knowledge about its harmful effects on the fetuses. The present study clarified that administration of antacid containing Al and/or exposure to gamma radiation induced maternal and fetal detrimental impact. Pregnant albino rats were administered antacid containing Al on the gestational days 5th, 7th, 9th, 11th, 13th, 15th and 17th at a dose of 4.5 mg/g and exposed to whole body fractionated gamma radiation (2 Gy) at a dose of 0.5 Gy for 4 times on gestational days 6th, 8th, 10th and 12th of pregnancy. Morphological, biochemical and molecular changes were studied. The investigation was carried out one day prior to parturition (the 20th day of gestation). Antacid containing Al and/or radiation induced growth retardation, intrauterine death, malformations and embryonic resorption. The extent of lipid peroxidase formation as well as glutathione content in the brain and liver tissues of rat fetuses and placenta of pregnant rats were used as sensitive parameters to evaluate tissues damage. Antacid containing Al and/or radiation treatment resulted in decreased total protein content in the maternal placenta tissue. Moreover, the elevation in the lipid peroxidase (malondialdehyde; MDA) was accompanied with decline in the glutathione content (GSH) in the brain and liver tissues of rat fetuses. The activity of a key enzyme of apoptosis namely the caspase-3 was analyzed, which its activation represent a point of no return in apoptosis induction. Apoptosis was confirmed by another important hallmark of programmed cell death such as the DNA fragmentation. Treatment with antacid containing Al and/or gamma irradiation significantly increased caspase-3 activity and DNA fragmentation in maternal placental tissue and fetal brain and liver tissues as compared to control animals. In conclusion, the present investigation showed that the deleterious

  12. Immunohistochemical study of macrophage migration inhibitory factor in rat liver fibrosis induced by thioacetamide

    OpenAIRE

    Y Hori; S Sato; J Yamate; M Kurasaki

    2009-01-01

    Macrophage migration inhibitory factor (MIF) is a molecule known to regulate macrophage accumulation at sites of inflammation. To elucidate the role of MIF in progression of liver fibrosis, the immunohistochemical localization of MIF and macrophages in the liver were examined. Male Wistar rats received thioacetamide (TA) injections (200 mg/kg, i.p.) for 1 or 6 weeks. In biochemical and histological tests, it was confirmed that liver fibrosis was induced. In immunohistochemical analyses, the e...

  13. Drug-induced liver injury associated with HIV medications.

    Science.gov (United States)

    Jain, Mamta K

    2007-08-01

    Antiretroviral therapy (ART) for HIV infection frequently has been associated with elevated liver enzyme levels. Determining the cause of elevated liver enzyme levels in patients who have HIV is difficult because ART usually consists of three different drugs, patients may be taking additional hepatotoxic medications and patients who have HIV often suffer from other liver diseases. Several agents, however, are recognized as having noteworthy and specific patterns of toxicity. This article reviews the different HIV drug classes, incidence of elevated liver enzyme values by class and by individual drug, risk factors, specific toxicities, and possible mechanisms of injury.

  14. Biophysical model for thorotrast-induced liver cancers

    International Nuclear Information System (INIS)

    Noesterer, M; Hofmann, W.; Andreev, S.G.

    1996-01-01

    In Germany between 1930 and 1950, an estimated 10,000 to 20,000 patients received Thorostrast injections, mostly for angiographic examinations. About 59% of the intravascularly injected Thorotrast was retained by the liver. Based on a mean injected volume of 25 ml and an average exposure time of about 40 years, Thorotrast patients received a mean liver dose of about 9.5 Gy. As a consequence, about 20% of the 2,326 Thorotrast patients examined in the German Thorotrast Study died of liver tumors, while only 2 cases of primary liver tumors were observed in the 1,890 control patients

  15. Sulfur Amino Acids in Diet-induced Fatty Liver: A New Perspective Based on Recent Findings

    Directory of Open Access Journals (Sweden)

    John I. Toohey

    2014-06-01

    Full Text Available The relationship of sulfur amino acids to diet-induced fatty liver was established 80 years ago, with cystine promoting the condition and methionine preventing it. This relationship has renewed importance today because diet-induced fatty liver is relevant to the current epidemics of obesity, non-alcoholic fatty liver disease, metabolic syndrome, and type 2 diabetes. Two recent papers provide the first evidence linking sulfane sulfur to diet-induced fatty liver opening a new perspective on the problem. This review summarizes the early data on sulfur amino acids in fatty liver and correlates that data with current knowledge of sulfur metabolism. Evidence is reviewed showing that the lipotropic effect of methionine may be mediated by sulfane sulfur and that the hepatosteatogenic effect of cystine may be related to the removal of sulfane sulfur by cysteine catabolites. Possible preventive and therapeutic strategies are discussed.

  16. Progesterone promotes maternal–fetal tolerance by reducing human maternal T‐cell polyfunctionality and inducing a specific cytokine profile

    Science.gov (United States)

    Eldershaw, Suzy A.; Inman, Charlotte F.; Coomarasamy, Aravinthan; Moss, Paul A. H.; Kilby, Mark D.

    2015-01-01

    Progesterone is a steroid hormone essential for the maintenance of human pregnancy, and its actions are thought to include promoting maternal immune tolerance of the semiallogenic fetus. We report that exposure of maternal T cells to progesterone at physiological doses induced a unique skewing of the cytokine production profile of CD4+ and CD8+ T cells, with reductions not only in potentially deleterious IFN‐γ and TNF‐α production but also in IL‐10 and IL‐5. Conversely, production of IL‐4 was increased. Maternal T cells also became less polyfunctional, focussing cytokine production toward profiles including IL‐4. This was accompanied by reduced T‐cell proliferation. Using fetal and viral antigen‐specific CD8+ T‐cell clones, we confirmed that this as a direct, nonantigen‐specific effect. Yet human T cells lacked conventional nuclear progesterone receptors, implicating a membrane progesterone receptor. CD4+ and CD8+ T cells responded to progesterone in a dose‐dependent manner, with subtle effects at concentrations comparable to those in maternal blood, but profound effects at concentrations similar to those at the maternal–fetal interface. This characterization of how progesterone modulates T‐cell function is important in understanding the normal biology of pregnancy and informing the rational use of progesterone therapy in pregnancies at risk of fetal loss. PMID:26249148

  17. Progesterone promotes maternal-fetal tolerance by reducing human maternal T-cell polyfunctionality and inducing a specific cytokine profile.

    Science.gov (United States)

    Lissauer, David; Eldershaw, Suzy A; Inman, Charlotte F; Coomarasamy, Aravinthan; Moss, Paul A H; Kilby, Mark D

    2015-10-01

    Progesterone is a steroid hormone essential for the maintenance of human pregnancy, and its actions are thought to include promoting maternal immune tolerance of the semiallogenic fetus. We report that exposure of maternal T cells to progesterone at physiological doses induced a unique skewing of the cytokine production profile of CD4(+) and CD8(+) T cells, with reductions not only in potentially deleterious IFN-γ and TNF-α production but also in IL-10 and IL-5. Conversely, production of IL-4 was increased. Maternal T cells also became less polyfunctional, focussing cytokine production toward profiles including IL-4. This was accompanied by reduced T-cell proliferation. Using fetal and viral antigen-specific CD8(+) T-cell clones, we confirmed that this as a direct, nonantigen-specific effect. Yet human T cells lacked conventional nuclear progesterone receptors, implicating a membrane progesterone receptor. CD4(+) and CD8(+) T cells responded to progesterone in a dose-dependent manner, with subtle effects at concentrations comparable to those in maternal blood, but profound effects at concentrations similar to those at the maternal-fetal interface. This characterization of how progesterone modulates T-cell function is important in understanding the normal biology of pregnancy and informing the rational use of progesterone therapy in pregnancies at risk of fetal loss. © 2015 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Human fetal anatomy: MR imaging.

    Science.gov (United States)

    Weinreb, J C; Lowe, T; Cohen, J M; Kutler, M

    1985-12-01

    Twenty-four pregnant women carrying 26 fetuses (two sets of twins) were imaged with magnetic resonance (MR) imaging at 0.35 T following sonographic evaluation. Each study was retrospectively evaluated to determine which of 33 normal fetal structures were visible on the images and which imaging parameters were most useful for depicting fetal anatomy. Fetal motion degraded fetal images in all but two cases, both with oligohydramnios and in the third trimester of gestation. Nevertheless, many fetal structures were identifiable, particularly in the third trimester. Visualization of fetal anatomy improved with intravenous maternal sedation in five cases. Relatively T1-weighted images occasionally offered the advantage of less image degradation owing to fetal motion and improved contrast between different fetal structures. More T2 weighting was believed to be advantageous in one case for outlining the fetal head and in one case for delineation of the brain. In many cases, structures were similarly identifiable (though with different signal intensities) regardless of the parameters selected. The authors conclude that MR imaging of many fetal structures is currently unsatisfactory and is probably of limited value, particularly in the first and second trimesters. However, the relative frequency and detail with which the fetal head and liver can be depicted indicate that these may be areas for further investigation, and the potential utility of imaging fetal fat warrants further investigation.

  19. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    International Nuclear Information System (INIS)

    Zhang, Da-Gang; Zhang, Cheng; Wang, Jun-Xian; Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua; Lu, Yan; Tao, Li; Wang, Jian-Qing; Chen, Xi; Xu, De-Xiang

    2017-01-01

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl 4 )-induced acute liver injury. Mice were intraperitoneally injected with CCl 4 (0.15 ml/kg). In CCl 4 + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl 4 . As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl 4 -induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl 4 -induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl 4 -induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl 4 -induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl 4 -induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl 4 -induced acute liver injury. These results suggest that OCA protects against CCl 4 -induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl 4 -induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl 4 -induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

  20. Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Da-Gang [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Zhang, Cheng [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Wang, Jun-Xian [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua [Department of Toxicology, Anhui Medical University, Hefei 230032 (China); Lu, Yan; Tao, Li; Wang, Jian-Qing [Second Affiliated Hospital, Anhui Medical University, Hefei 230601 (China); Chen, Xi [First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China); Xu, De-Xiang, E-mail: xudex@126.com [Department of Toxicology, Anhui Medical University, Hefei 230032 (China)

    2017-01-01

    The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-induced hepatic pro-inflammatory gene Tnf-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB p65 and p50 subunits during CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

  1. Glucocorticoid-Induced Fetal Programming Alters the Functional Complement of Angiotensin Receptors Subtypes within the Kidney

    OpenAIRE

    Gwathmey, TanYa M.; Shaltout, Hossam A.; Rose, James C.; Diz, Debra I.; Chappell, Mark C.

    2011-01-01

    We examined the impact of fetal programming on the functional responses of renal angiotensin receptors. Fetal sheep were exposed in utero to betamethasone (BMX; 0.17 mg/kg) or control (CON) at 80–81 days gestation with full term delivery. Renal nuclear and plasma membrane fractions were isolated from 1.0–1.5 year old sheep for receptor binding and fluorescence detection of reactive oxygen species (ROS) or nitric oxide (NO). Mean arterial blood pressure and blood pressure variability were sign...

  2. Liver sinusoidal endothelial cells induce immunosuppressive IL-10-producing Th1 cells via the Notch pathway

    NARCIS (Netherlands)

    Neumann, Katrin; Rudolph, Christine; Neumann, Christian; Janke, Marko; Amsen, Derk; Scheffold, Alexander

    2015-01-01

    Under homeostasis, liver sinusoidal endothelial cells (LSECs) shift intrahepatic T-cell responses towards tolerance. However, the role of LSECs in the regulation of T-cell-induced liver inflammation is less clear. Here, we studied the capacity of LSECs to modulate pro-inflammatory Th1-cell

  3. Obeticholic acid protects mice against lipopolysaccharide-induced liver injury and inflammation.

    Science.gov (United States)

    Xiong, Xi; Ren, Yuqian; Cui, Yun; Li, Rui; Wang, Chunxia; Zhang, Yucai

    2017-12-01

    Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury. Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease.

    Directory of Open Access Journals (Sweden)

    Omar A Mesarwi

    Full Text Available Obstructive sleep apnea (OSA is associated with the progression of non-alcoholic fatty liver disease (NAFLD to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing α subunit of hypoxia inducible factor-1 (HIF-1, a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis.Wild-type mice and mice with hepatocyte-specific HIF-1α knockout (Hif1a-/-hep were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2 or normoxia (16% O2 for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking.Wild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 μg collagen/mg liver tissue, versus 1.23 μg collagen/mg liver tissue, p = 0.03, which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia.Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver

  5. An Overview on the Proposed Mechanisms of Antithyroid Drugs-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2015-03-01

    Full Text Available Drug-induced liver injury (DILI is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs.

  6. Mitochondrial DNA Hypomethylation Is a Biomarker Associated with Induced Senescence in Human Fetal Heart Mesenchymal Stem Cells

    Directory of Open Access Journals (Sweden)

    Dehai Yu

    2017-01-01

    Full Text Available Background. Fetal heart can regenerate to restore its normal anatomy and function in response to injury, but this regenerative capacity is lost within the first week of postnatal life. Although the specific molecular mechanisms remain to be defined, it is presumed that aging of cardiac stem or progenitor cells may contribute to the loss of regenerative potential. Methods. To study this aging-related dysfunction, we cultured mesenchymal stem cells (MSCs from human fetal heart tissues. Senescence was induced by exposing cells to chronic oxidative stress/low serum. Mitochondrial DNA methylation was examined during the period of senescence. Results. Senescent MSCs exhibited flattened and enlarged morphology and were positive for the senescence-associated beta-galactosidase (SA-β-Gal. By scanning the entire mitochondrial genome, we found that four CpG islands were hypomethylated in close association with senescence in MSCs. The mitochondrial COX1 gene, which encodes the main subunit of the cytochrome c oxidase complex and contains the differentially methylated CpG island 4, was upregulated in MSCs in parallel with the onset of senescence. Knockdown of DNA methyltransferases (DNMT1, DNMT3a, and DNMT3B also upregulated COX1 expression and induced cellular senescence in MSCs. Conclusions. This study demonstrates that mitochondrial CpG hypomethylation may serve as a critical biomarker associated with cellular senescence induced by chronic oxidative stress.

  7. The Effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on Alcohol-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Yu-Jie Zhang

    2016-09-01

    Full Text Available Previous studies have shown that fruits have different effects on alcohol metabolism and alcohol-induced liver injury. The present work selected three fruits and aimed at studying the effects of Syzygium samarangense, Passiflora edulis and Solanum muricatum on alcohol-induced liver injury in mice. The animals were treated daily with alcohol and fruit juices for fifteen days. Chronic treatment with alcohol increased the levels of aspartate transaminase (AST, alanine transaminase (ALT, total bilirubin (TBIL, triglyceride (TG, malondialdehyde (MDA, and decreased total protein (TP. Histopathological evaluation also showed that ethanol induced extensive fat droplets in hepatocyte cytoplasm. Syzygium samarangense and Passiflora edulis normalized various biochemical parameters. Solanum muricatum increased the level of ALT and induced infiltration of inflammatory cells in the liver. These results strongly suggest that treatment with Syzygium samarangense and Passiflora edulis could protect liver from the injury of alcohol, while Solanum muricatum could aggravate the damage.

  8. Preventive effect of zinc on nickel-induced oxidative liver injury in rats

    African Journals Online (AJOL)

    MIDOU

    2013-12-18

    Dec 18, 2013 ... induced oxidative liver injury and lipid peroxidation probably due to its antioxidant proprieties. ... enzyme in every enzyme classification (Coyle et al.,. 2002). Others .... control group had a regular histological structure with a.

  9. Liver

    International Nuclear Information System (INIS)

    Bernardino, M.E.; Sones, P.J. Jr.; Barton Price, R.; Berkman, W.A.

    1984-01-01

    Evaluation of the liver for focal lesions is extremely important because the liver is one of the most common sites for metastatic disease. Most patients with metastatic deposits to the liver have a survival rate of about 6 months. Thus, metastatic disease to the liver has an extremely grave prognosis. In the past patients with hepatic lesions had no therapeutic recourse. However, with recent aggressive surgical advances (such as partial hepatectomies) and hepatic artery embolization, survival of patients with hepatic metastases has increased. Thus it is important for noninvasive imaging not only to detect lesions early in their course, but also to give their true hepatic involvement and the extent of the neoplastic process elsewhere in the body. Recent advances in imaging have been rapidly changing over the past 5 years. These changes have been more rapid in computed tomography (CT) and ultrasound than in radionuclide imaging. Thus, the question addressed in this chapter is: What is the relationship of hepatic ultrasound to the other current diagnostic modalities in detecting metastatic liver disease and other focal liver lesions? Also, what is its possible future relationship to nuclear magnetic resonance?

  10. Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal sheep.

    Science.gov (United States)

    Lie, Shervi; Morrison, Janna L; Williams-Wyss, Olivia; Suter, Catherine M; Humphreys, David T; Ozanne, Susan E; Zhang, Song; MacLaughlin, Severence M; Kleemann, David O; Walker, Simon K; Roberts, Claire T; McMillen, I Caroline

    2014-05-01

    This study aimed to determine whether exposure of the oocyte and/or embryo to maternal undernutrition results in the later programming of insulin action in the liver and factors regulating gluconeogenesis. To do this, we collect livers from singleton and twin fetal sheep that were exposed to periconceptional (PCUN; -60 to 7 days) or preimplantation (PIUN; 0-7 days) undernutrition at 136-138 days of gestation (term = 150 days). The mRNA and protein abundance of insulin signaling and gluconeogenic factors were then quantified using qRT-PCR and Western blotting, respectively, and global microRNA expression was quantified using deep sequencing methodology. We found that hepatic PEPCK-C mRNA (P < 0.01) and protein abundance and the protein abundance of IRS-1 (P < 0.01), p110β (P < 0.05), PTEN (P < 0.05), CREB (P < 0.01), and pCREB (Ser(133); P < 0.05) were decreased in the PCUN and PIUN singletons. In contrast, hepatic protein abundance of IRS-1 (P < 0.01), p85 (P < 0.01), p110β (P < 0.001), PTEN (P < 0.01), Akt2 (P < 0.01), p-Akt (Ser(473); P < 0.01), and p-FOXO-1 (Thr24) (P < 0.01) was increased in twins. There was a decrease in PEPCK-C mRNA (P < 0.01) but, paradoxically, an increase in PEPCK-C protein (P < 0.001) in twins. Both PCUN and PIUN altered the hepatic expression of 23 specific microRNAs. We propose that the differential impact of maternal undernutrition in the presence of one or two embryos on mRNAs and proteins involved in the insulin signaling and gluconeogenesis is explained by changes in the expression of a suite of specific candidate microRNAs.

  11. Nicotine-induced retardation of chondrogenesis through down-regulation of IGF-1 signaling pathway to inhibit matrix synthesis of growth plate chondrocytes in fetal rats

    International Nuclear Information System (INIS)

    Deng, Yu; Cao, Hong; Cu, Fenglong; Xu, Dan; Lei, Youying; Tan, Yang; Magdalou, Jacques; Wang, Hui; Chen, Liaobin

    2013-01-01

    Previous studies have confirmed that maternal tobacco smoking causes intrauterine growth retardation (IUGR) and skeletal growth retardation. Among a multitude of chemicals associated with cigarette smoking, nicotine is one of the leading candidates for causing low birth weights. However, the possible mechanism of delayed chondrogenesis by prenatal nicotine exposure remains unclear. We investigated the effects of nicotine on fetal growth plate chondrocytes in vivo and in vitro. Rats were given 2.0 mg/kg·d of nicotine subcutaneously from gestational days 11 to 20. Prenatal nicotine exposure increased the levels of fetal blood corticosterone and resulted in fetal skeletal growth retardation. Moreover, nicotine exposure induced the inhibition of matrix synthesis and down-regulation of insulin-like growth factor 1 (IGF-1) signaling in fetal growth plates. The effects of nicotine on growth plates were studied in vitro by exposing fetal growth plate chondrocytes to 0, 1, 10, or 100 μM of nicotine for 10 days. Nicotine inhibited matrix synthesis and down-regulated IGF-1 signaling in chondrocytes in a concentration-dependent manner. These results suggest that prenatal nicotine exposure induces delayed chondrogenesis and that the mechanism may involve the down-regulation of IGF-1 signaling and the inhibition of matrix synthesis by growth plate chondrocytes. The present study aids in the characterization of delayed chondrogenesis caused by prenatal nicotine exposure, which might suggest a candidate mechanism for intrauterine origins of osteoporosis and osteoarthritis. - Highlights: ► Prenatal nicotine-exposure could induce delayed chondrogenesis in fetal rats. ► Nicotine inhibits matrix synthesis of fetal growth plate chondrocytes. ► Nicotine inhibits IGF-1 signaling pathway in fetal growth plate chondrocytes

  12. Nicotine-induced retardation of chondrogenesis through down-regulation of IGF-1 signaling pathway to inhibit matrix synthesis of growth plate chondrocytes in fetal rats

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Yu; Cao, Hong; Cu, Fenglong [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Xu, Dan [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China); Lei, Youying [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Tan, Yang [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Magdalou, Jacques [UMR 7561 CNRS-Nancy Université, Faculté de Médicine, Vandoeuvre-lès-Nancy (France); Wang, Hui [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China); Chen, Liaobin, E-mail: lbchen@whu.edu.cn [Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China)

    2013-05-15

    Previous studies have confirmed that maternal tobacco smoking causes intrauterine growth retardation (IUGR) and skeletal growth retardation. Among a multitude of chemicals associated with cigarette smoking, nicotine is one of the leading candidates for causing low birth weights. However, the possible mechanism of delayed chondrogenesis by prenatal nicotine exposure remains unclear. We investigated the effects of nicotine on fetal growth plate chondrocytes in vivo and in vitro. Rats were given 2.0 mg/kg·d of nicotine subcutaneously from gestational days 11 to 20. Prenatal nicotine exposure increased the levels of fetal blood corticosterone and resulted in fetal skeletal growth retardation. Moreover, nicotine exposure induced the inhibition of matrix synthesis and down-regulation of insulin-like growth factor 1 (IGF-1) signaling in fetal growth plates. The effects of nicotine on growth plates were studied in vitro by exposing fetal growth plate chondrocytes to 0, 1, 10, or 100 μM of nicotine for 10 days. Nicotine inhibited matrix synthesis and down-regulated IGF-1 signaling in chondrocytes in a concentration-dependent manner. These results suggest that prenatal nicotine exposure induces delayed chondrogenesis and that the mechanism may involve the down-regulation of IGF-1 signaling and the inhibition of matrix synthesis by growth plate chondrocytes. The present study aids in the characterization of delayed chondrogenesis caused by prenatal nicotine exposure, which might suggest a candidate mechanism for intrauterine origins of osteoporosis and osteoarthritis. - Highlights: ► Prenatal nicotine-exposure could induce delayed chondrogenesis in fetal rats. ► Nicotine inhibits matrix synthesis of fetal growth plate chondrocytes. ► Nicotine inhibits IGF-1 signaling pathway in fetal growth plate chondrocytes.

  13. Arsenic induces apoptosis in mouse liver is mitochondria dependent and is abrogated by N-acetylcysteine

    International Nuclear Information System (INIS)

    Santra, Amal; Chowdhury, Abhijit; Ghatak, Subhadip; Biswas, Ayan; Dhali, Gopal Krishna

    2007-01-01

    Arsenicosis, caused by arsenic contamination of drinking water supplies, is a major public health problem in India and Bangladesh. Chronic liver disease, often with portal hypertension occurs in chronic arsenicosis, contributes to the morbidity and mortality. The early cellular events that initiate liver cell injury due to arsenicosis have not been studied. Our aim was to identify the possible mechanisms related to arsenic-induced liver injury in mice. Liver injury was induced in mice by arsenic treatment. The liver was used for mitochondrial oxidative stress, mitochondrial permeability transition (MPT). Evidence of apoptosis was sought by TUNEL test, caspase assay and histology. Pretreatment with N-acetyl-L-cysteine (NAC) was done to modulate hepatic GSH level. Arsenic treatment in mice caused liver injury associated with increased oxidative stress in liver mitochondria and alteration of MPT. Altered MPT facilitated cytochrome c release in the cytosol, activation of caspase 9 and caspase 3 activities and apoptotic cell death. Pretreatment of NAC to arsenic-treated mice abrogated all these alteration suggesting a glutathione (GSH)-dependent mechanism. Oxidative stress in mitochondria and inappropriate MPT are important in the pathogenesis of arsenic induced apoptotic liver cell injury. The phenomenon is GSH dependent and supplementation of NAC might have beneficial effects

  14. Hepatoprotective effects of setarud against carbon tetrachloride-induced liver injury in rats.

    Science.gov (United States)

    Khorshid, Hamid Reza Khorram; Azonov, Jahan A; Novitsky, Yury A; Farzamfar, Bardia; Shahhosseiny, Mohammad Hassan

    2008-01-01

    To assess the hepatoprotective activity of a new herbal drug "setarud" in experimental liver fibrosis, 48 male Wistar rats were divided into four groups: controls, carbon tetrachloride (CCl4) group, and two treatment groups that received CCl4 and setarud at doses of 0.02 or 0.04 g/Kg/day for 30 days. Body weight gain, biochemical liver tests, bile flow rate and composition, and changes in liver morphology in the four groups were studied. CCl4 administration led to morphological and biochemical evidence of liver injury as compared to untreated controls. Setarud administration led to significant protection against CCl4-induced changes in body weight gain, liver morphology, bile flow and concentration. It was also associated with significantly lower serum liver enzyme levels (pliver disease are warranted.

  15. Biochemical and radio-immunological studies on HCV-induced liver fibrosis

    International Nuclear Information System (INIS)

    Abdel-Mageed, M.E.A.

    2010-01-01

    Hepatitis C virus infection is now becoming a common health problem in Egypt. Liver biopsy is the gold standard for this diagnosis. However, liver biopsy is invasive and is associated with complications with chronic hepatitis C patients. There is a clinical need for noninvasive measurement of liver fibrosis. Noninvasive bio markers such as Collagen III was identified in serum samples of patients with HCV induced liver fibrosis at 70 kDa using SDS-PAGE and western blot, measured by ELISA and purified using electro elution . Hyaluronic acid also can be used to differentiate between liver fibrosis patients and healthy individuals using radioimmunoassay .we have developed noninvasive diagnosis that can be applied to patients who either have contraindications or refuse liver biopsy for the management of their HCV infection.

  16. Differential effects of experimental and cold-induced hyperthyroidism on factors inducing rat liver oxidative damage.

    Science.gov (United States)

    Venditti, P; Pamplona, R; Ayala, V; De Rosa, R; Caldarone, G; Di Meo, S

    2006-03-01

    Thyroid hormone-induced increase in metabolic rates is often associated with increased oxidative stress. The aim of the present study was to investigate the contribution of iodothyronines to liver oxidative stress in the functional hyperthyroidism elicited by cold, using as models cold-exposed and 3,5,3'-triiodothyronine (T3)- or thyroxine (T4)-treated rats. The hyperthyroid state was always associated with increases in both oxidative capacity and oxidative damage of the tissue. The most extensive damage to lipids and proteins was found in T3-treated and cold-exposed rats, respectively. Increase in oxygen reactive species released by mitochondria and microsomes was found to contribute to tissue oxidative damage, whereas the determination of single antioxidants did not provide information about the possible contribution of a reduced effectiveness of the antioxidant defence system. Indeed, liver oxidative damage in hyperthyroid rats was scarcely related to levels of the liposoluble antioxidants and activities of antioxidant enzymes. Conversely, other biochemical changes, such as the degree of fatty acid unsaturation and hemoprotein content, appeared to predispose hepatic tissue to oxidative damage associated with oxidative challenge elicited by hyperthyroid state. As a whole, our results confirm the idea that T3 plays a key role in metabolic changes and oxidative damage found in cold liver. However, only data concerning changes in glutathione peroxidase activity and mitochondrial protein content favour the idea that dissimilarities in effects of cold exposure and T3 treatment could depend on differences in serum levels of T4.

  17. In Vitro Large Scale Production of Human Mature Red Blood Cells from Hematopoietic Stem Cells by Coculturing with Human Fetal Liver Stromal Cells

    Directory of Open Access Journals (Sweden)

    Jiafei Xi

    2013-01-01

    Full Text Available In vitro models of human erythropoiesis are useful in studying the mechanisms of erythroid differentiation in normal and pathological conditions. Here we describe an erythroid liquid culture system starting from cord blood derived hematopoietic stem cells (HSCs. HSCs were cultured for more than 50 days in erythroid differentiation conditions and resulted in a more than 109-fold expansion within 50 days under optimal conditions. Homogeneous erythroid cells were characterized by cell morphology, flow cytometry, and hematopoietic colony assays. Furthermore, terminal erythroid maturation was improved by cosculturing with human fetal liver stromal cells. Cocultured erythroid cells underwent multiple maturation events, including decrease in size, increase in glycophorin A expression, and nuclear condensation. This process resulted in extrusion of the pycnotic nuclei in up to 80% of the cells. Importantly, they possessed the capacity to express the adult definitive β-globin chain upon further maturation. We also show that the oxygen equilibrium curves of the cord blood-differentiated red blood cells (RBCs are comparable to normal RBCs. The large number and purity of erythroid cells and RBCs produced from cord blood make this method useful for fundamental research in erythroid development, and they also provide a basis for future production of available RBCs for transfusion.

  18. Identification of Novel Translational Urinary Biomarkers for Acetaminophen-Induced Acute Liver Injury Using Proteomic Profiling in Mice

    NARCIS (Netherlands)

    van Swelm, Rachel P. L.; Laarakkers, Coby M. M.; van der Kuur, Ellen C.; Morava-Kozicz, Eva; Wevers, Ron A.; Augustijn, Kevin D.; Touw, Daan J.; Sandel, Maro H.; Masereeuw, Rosalinde; Russel, Frans G. M.

    2012-01-01

    Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced

  19. Hepatoprotective Effect of Citral on Acetaminophen-Induced Liver Toxicity in Mice

    Directory of Open Access Journals (Sweden)

    Nancy Sayuri Uchida

    2017-01-01

    Full Text Available High doses of acetaminophen (APAP lead to acute liver damage. In this study, we evaluated the effects of citral in a murine model of hepatotoxicity induced by APAP. The liver function markers alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, and gamma-glutamyl transferase (γGT were determined to evaluate the hepatoprotective effects of citral. The livers were used to determine myeloperoxidase (MPO activity and nitric oxide (NO production and in histological analysis. The effect of citral on leukocyte migration and antioxidant activity was evaluated in vitro. Citral pretreatment decreased significantly the levels of ALT, AST, ALP, and γGT, MPO activity, and NO production. The histopathological analysis showed an improvement of hepatic lesions in mice after citral pretreatment. Citral inhibited neutrophil migration and exhibited antioxidant activity. Our results suggest that citral protects the liver against liver toxicity induced by APAP.

  20. Risks of herbalism: a case report of Mexican poppy (Argemone mexicana L induced liver toxicity

    Directory of Open Access Journals (Sweden)

    Carlos Alfredo Meléndez González

    2013-08-01

    Full Text Available The increasing consumption of alternative medicines has lead to a greater awareness about the deleterious effects and interactions that these products can induce. Consequently, medical literature reports liver toxicity from Aloe, Camellia sinensis (green tea, Rhammus purshianus, Aesculus hippocastanum (buckeye and Valeriana officinalis (valerian, among others. This article reports a female patient who twice consumed Mexican poppy (Argemone mexicana L with a one-year interval between ingestions. Both times she developed diarrhea, jaundice and general malaise with impaired liver function tests. Other causes of liver disease were ruled out. Questionnaires were used to assess the possibility of drug-induced liver damage. Clinical information was collected from the patient’s medical record and the literature on the subject was reviewed. We conclude that, at least in this case, the most likely cause of liver toxicity was Argemone mexicana L consumption.

  1. Saccharomyces boulardii Administration Changes Gut Microbiota and Attenuates D-Galactosamine-Induced Liver Injury.

    Science.gov (United States)

    Yu, Lei; Zhao, Xue-Ke; Cheng, Ming-Liang; Yang, Guo-Zhen; Wang, Bi; Liu, Hua-Juan; Hu, Ya-Xin; Zhu, Li-Li; Zhang, Shuai; Xiao, Zi-Wen; Liu, Yong-Mei; Zhang, Bao-Fang; Mu, Mao

    2017-05-02

    Growing evidence has shown that gut microbiome is a key factor involved in liver health. Therefore, gut microbiota modulation with probiotic bacteria, such as Saccharomyces boulardii, constitutes a promising therapy for hepatosis. In this study, we aimed to investigate the protective effects of S. boulardii on D-Galactosamine-induced liver injury in mice. Liver function test and histopathological analysis both suggested that the liver injury can be effectively attenuated by S. boulardii administration. In the meantime, S. boulardii induced dramatic changes in the gut microbial composition. At the phylum level, we found that S. boulardii significantly increased in the relative abundance of Bacteroidetes, and decreased the relative abundance of Firmicutes and Proteobacteria, which may explain the hepatic protective effects of S. boulardii. Taken together, our results demonstrated that S. boulardii administration could change the gut microbiota in mice and alleviate acute liver failure, indicating a potential protective and therapeutic role of S. boulardii.

  2. Chronic Uridine Administration Induces Fatty Liver and Pre-Diabetic Conditions in Mice.

    Directory of Open Access Journals (Sweden)

    Yasuyo Urasaki

    Full Text Available Uridine is a pyrimidine nucleoside that exerts restorative functions in tissues under stress. Short-term co-administration of uridine with multiple unrelated drugs prevents drug-induced liver lipid accumulation. Uridine has the ability to modulate liver metabolism; however, the precise mechanism has not been delineated. In this study, long-term effects of uridine on liver metabolism were examined in both HepG2 cell cultures and C57BL/6J mice. We report that uridine administration was associated with O-GlcNAc modification of FOXO1, increased gluconeogenesis, reduced insulin signaling activity, and reduced expression of a liver-specific fatty acid binding protein FABP1. Long-term uridine feeding induced systemic glucose intolerance and severe liver lipid accumulation in mice. Our findings suggest that the therapeutic potentials of uridine should be designed for short-term acute administration.

  3. Development and validation of a dynamic outcome prediction model for paracetamol-induced acute liver failure

    DEFF Research Database (Denmark)

    Bernal, William; Wang, Yanzhong; Maggs, James

    2016-01-01

    : The models developed here show very good discrimination and calibration, confirmed in independent datasets, and suggest that many patients undergoing transplantation based on existing criteria might have survived with medical management alone. The role and indications for emergency liver transplantation......BACKGROUND: Early, accurate prediction of survival is central to management of patients with paracetamol-induced acute liver failure to identify those needing emergency liver transplantation. Current prognostic tools are confounded by recent improvements in outcome independent of emergency liver...... transplantation, and constrained by static binary outcome prediction. We aimed to develop a simple prognostic tool to reflect current outcomes and generate a dynamic updated estimation of risk of death. METHODS: Patients with paracetamol-induced acute liver failure managed at intensive care units in the UK...

  4. Fetal MRI; Fetales MRT

    Energy Technology Data Exchange (ETDEWEB)

    Blondin, D. [Inst. fuer Diagn. Radiologie, Uniklinikum Duesseldorf (Germany); Turowski, B. [Inst. fuer Diagn. Radiologie, Neuroradiologie, Uniklinikum Duesseldorf (Germany); Schaper, J. [Inst. fuer Diagn. Radiologie, Kinderradiologie, Uniklinikum Duesseldorf (Germany)

    2007-02-15

    Ultrasonography is the method of choice for prenatal malformation screening, but it does not always provide sufficient information for correct diagnosis or adequate abnormality evaluation. Fetal MRI is increasingly being used to complete sonographic findings. It was initially used for evaluation of cerebral abnormalities but is increasingly being applied to other fetal areas. In vivo investigation of fetal brain maturation has been enhanced by MRI. An adequate analysis of fetal chest and abdomen can be achieved with fast T2-, T1-weighted and diffusion-weighted imaging (DWI). The advantages include the great field of view and the excellent soft tissue contrast. This allows correct diagnosis of congenital diaphragmatic hernia and evaluation of the consequences on pulmonary growth. Other pulmonary malformations, such as cystic adenomatoid malformation, sequestration and brochogenic cysts, can also be easily identified. Renal position can be quickly determined using DWI sequences and renal agenesia can be easily diagnosed with only one sequence. Prenatal MRI is virtually as effective as postnatal examination, dispenses with transport of a potentially very ill newborn, and provides logistic advantages. Therefore, prenatal MRI is useful for adequate postnatal treatment of newborns with malformations. (orig.)

  5. Genotoxicity and fetal abnormality in streptozotocin-induced diabetic rats exposed to cigarette smoke prior to and during pregnancy.

    Science.gov (United States)

    Damasceno, D C; Volpato, G T; Sinzato, Y K; Lima, P H O; Souza, M S S; Iessi, I L; Kiss, A C I; Takaku, M; Rudge, M V C; Calderon, I M P

    2011-10-01

    Maternal hyperglycemia during early pregnancy is associated with increased risk of abnormalities in the offspring. Malformation rates among the offspring of diabetic mothers are 2-5-fold higher than that of the normal population, and congenital malformations are the major cause of mortality and morbidity in the offspring of diabetic mothers. Metabolic changes, such as hyperglycemia and the metabolites obtained from cigarettes both increase the production of reactive oxygen species (ROS) in the embryo or fetus, causing DNA damage. To evaluate the maternal and fetal genotoxicity, and to assess the incidence of fetal anomaly in diabetic female rats exposed to cigarette smoke at different stages of pregnancy in rats. Diabetes was induced by streptozotocin administration and cigarette smoke exposure was produced by a mechanical smoking device that generated mainstream smoke that was delivered into a chamber. Female Wistar rats were randomly assigned to: non-diabetic (ND) and diabetic (D) groups exposed to filtered air; a diabetic group exposed to cigarette smoke prior to and during pregnancy (DS) and a diabetic group only exposed to cigarette smoke prior to pregnancy (DSPP). On pregnancy day 21, blood samples were obtained for DNA damage analysis and fetuses were collected for congenital anomaly assessment. Statistical significance was set at p<0.05 for all analysis. Exposure of diabetic rats to tobacco smoke prior to pregnancy increased fetal DNA damage, but failed to induce teratogenicity. Thus, these results reinforce the importance for women to avoid exposure to cigarette smoke long before they become pregnant. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York.

  6. Does heart rate variability reflect the systemic inflammatory response in a fetal sheep model of lipopolysaccharide-induced sepsis?

    International Nuclear Information System (INIS)

    Durosier, Lucien D; Cao, Mingju; Frasch, Martin G; Herry, Christophe L; Seely, Andrew J E; Cortes, Marina; Burns, Patrick; Desrochers, André; Fecteau, Gilles

    2015-01-01

    Fetal inflammatory response occurs during chorioamnionitis, a frequent and often subclinical inflammation associated with increased risk for brain injury and life-lasting neurologic deficits. No means of early detection exist. We hypothesized that systemic fetal inflammation without septic shock will be reflected in alterations of fetal heart rate (FHR) variability (fHRV) distinguishing baseline versus inflammatory response states.In chronically instrumented near-term fetal sheep (n = 24), we induced an inflammatory response with lipopolysaccharide (LPS) injected intravenously (n = 14). Ten additional fetuses served as controls. We measured fetal plasma inflammatory cytokine IL-6 at baseline, 1, 3, 6, 24 and 48 h. 44 fHRV measures were determined continuously every 5 min using continuous individualized multi-organ variability analysis (CIMVA). CIMVA creates an fHRV measures matrix across five signal-analytical domains, thus describing complementary properties of fHRV. Using principal component analysis (PCA), a widely used technique for dimensionality reduction, we derived and quantitatively compared the CIMVA fHRV PCA signatures of inflammatory response in LPS and control groups.In the LPS group, IL-6 peaked at 3 h. In parallel, PCA-derived fHRV composite measures revealed a significant difference between LPS and control group at different time points. For the LPS group, a sharp increase compared to baseline levels was observed between 3 h and 6 h, and then abating to baseline levels, thus tracking closely the IL-6 inflammatory profile. This pattern was not observed in the control group. We also show that a preselection of fHRV measures prior to the PCA can potentially increase the difference between LPS and control groups, as early as 1 h post LPS injection.We propose a fHRV composite measure that correlates well with levels of inflammation and tracks well its temporal profile. Our results highlight the potential role of HRV to study and monitor the

  7. Role and mechanisms of autophagy in acetaminophen-induced liver injury.

    Science.gov (United States)

    Chao, Xiaojuan; Wang, Hua; Jaeschke, Hartmut; Ding, Wen-Xing

    2018-04-23

    Acetaminophen (APAP) overdose is the most frequent cause of acute liver failure in the USA and many other countries. Although the metabolism and pathogenesis of APAP has been extensively investigated for decades, the mechanisms by which APAP induces liver injury are incompletely known, which hampers the development of effective therapeutic approaches to tackle this important clinical problem. Autophagy is a highly conserved intracellular degradation pathway, which aims at recycling cellular components and damaged organelles in response to adverse environmental conditions and stresses as a survival mechanism. There is accumulating evidence indicating that autophagy is activated in response to APAP overdose in specific liver zone areas, and pharmacological activation of autophagy protects against APAP-induced liver injury. Increasing evidence also suggests that hepatic autophagy is impaired in nonalcoholic fatty livers (NAFLD), and NAFLD patients are more susceptible to APAP-induced liver injury. Here, we summarized the current progress on the role and mechanisms of autophagy in protecting against APAP-induced liver injury. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Distinct cellular responses differentiating alcohol- and hepatitis C virus-induced liver cirrhosis

    Directory of Open Access Journals (Sweden)

    Boix Loreto

    2006-11-01

    Full Text Available Abstract Background Little is known at the molecular level concerning the differences and/or similarities between alcohol and hepatitis C virus induced liver disease. Global transcriptional profiling using oligonucleotide microarrays was therefore performed on liver biopsies from patients with cirrhosis caused by either chronic alcohol consumption or chronic hepatitis C virus (HCV. Results Global gene expression patterns varied significantly depending upon etiology of liver disease, with a greater number of differentially regulated genes seen in HCV-infected patients. Many of the gene expression changes specifically observed in HCV-infected cirrhotic livers were expectedly associated with activation of the innate antiviral immune response. We also compared severity (CTP class of cirrhosis for each etiology and identified gene expression patterns that differentiated ethanol-induced cirrhosis by class. CTP class A ethanol-cirrhotic livers showed unique expression patterns for genes implicated in the inflammatory response, including those related to macrophage activation and migration, as well as lipid metabolism and oxidative stress genes. Conclusion Stages of liver cirrhosis could be differentiated based on gene expression patterns in ethanol-induced, but not HCV-induced, disease. In addition to genes specifically regulating the innate antiviral immune response, mechanisms responsible for differentiating chronic liver damage due to HCV or ethanol may be closely related to regulation of lipid metabolism and to effects of macrophage activation on deposition of extracellular matrix components.

  9. Effects of thyroid dysfunction-induced liver oxidative

    African Journals Online (AJOL)

    Unicornis

    were randomly divided into four groups of six each: the first group served as a ... significant increase in plasmatic activities of AST, ALT, ALP, LDH, and liver malondialdehyde level. ...... cope with MD toxicity, more attention is needed to limit its.

  10. Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver

    Directory of Open Access Journals (Sweden)

    Patricia Rivera

    2017-10-01

    Full Text Available Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory N-acyl ethanolamide (NAE-peroxisome proliferators activated receptor alpha (PPARα system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP, a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5–5–10–20 mM and time-course (2–6–24 h study in human HepG2 cells showed a biphasic response, with a decreased PPARα expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (PPARα, NAPE-PLD, and FAAH, including the NAEs oleoyl ethanolamide (OEA and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg. The gene expression levels of Pparα and Faah were decreased after 6 h of treatment and, after 24 h, the gene expression levels of Nape-pld and Faah, as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (Cyp2e1, Caspase3, αSma, Tnfα, and Mcp1-related alterations observed after repeated APAP administration were aggravated in the liver of Pparα-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver

  11. Effect of adoptive transfer or depletion of regulatory T cells on triptolide-induced liver injury

    Directory of Open Access Journals (Sweden)

    Xinzhi eWang

    2016-04-01

    Full Text Available ObjectiveThe aim of this study is to clarify the role of regulatory T cell (Treg in triptolide (TP-induced hepatotoxicity. MethodsFemale C57BL/6 mice received either adoptive transfer of Tregs or depletion of Tregs, then underwent TP administration and were sacrificed 24 hours after TP administration. Liver injury was determined according to ALT and AST levels in serum and histopathological change in liver tissue. Hepatic frequencies of Treg cells and the mRNA expression levles of transcription factor FoxP3 and RORγt, IL-10, SOCS and Notch/Notch ligand were investigated.ResultsDuring TP-induced liver injury, hepatic Treg and IL-10 decreased, while Th17 cell transcription factor RORγt, SOCS signaling and Notch signaling increased, accompanied with liver inflammation. Adoptive transfer of Tregs ameliorated the severity of TP-induced liver injury, accompanied with increased levels of hepatic Treg and IL-10. Adoptive transfer of Tregs remarkably inhibited the expression of RORγt, SOCS3, Notch1 and Notch3. On the contrary, depletion of Treg cells in TP-administered mice resulted in a notable increase of RORγt, SOCS1, SOCS3 and Notch3, while the Treg and IL-10 of liver decreased. Consistent with the exacerbation of liver injury, higher serum levels of ALT and AST were detected in Treg-depleted mice. ConclusionsThese results showed that adoptive transfer or depletion of Tregs attenuated or aggravated TP-induced liver injury, suggesting that Tregs could play important roles in the progression of liver injury. SOCS proteins and Notch signaling affected Tregs, which may contribute to the pathogenesis of TP-induced hepatotoxicity.

  12. Glucocorticoid-induced fetal programming alters the functional complement of angiotensin receptor subtypes within the kidney.

    Science.gov (United States)

    Gwathmey, TanYa M; Shaltout, Hossam A; Rose, James C; Diz, Debra I; Chappell, Mark C

    2011-03-01

    We examined the impact of fetal programming on the functional responses of renal angiotensin receptors. Fetal sheep were exposed in utero to betamethasone (BMX; 0.17 mg/kg) or control (CON) at 80 to 81 days gestation with full-term delivery. Renal nuclear and plasma membrane fractions were isolated from sheep age 1.0 to 1.5 years for receptor binding and fluorescence detection of reactive oxygen species (ROS) or nitric oxide (NO). Mean arterial blood pressure and blood pressure variability were significantly higher in the BMX-exposed adult offspring versus CON sheep. The proportion of nuclear AT(1) receptors sensitive to losartan was 2-fold higher (67 ± 6% vs 27 ± 9%; Psheep (16 ± 3% vs 6 ± 4%; Pfetal programming.

  13. Lyman NTCP model analysis of radiation-induced liver disease in hypofractionated conformal radiotherapy for primary liver carcinoma

    International Nuclear Information System (INIS)

    Xu Zhiyong; Zhu Yi; Zhao Jiaodong; Fu Xiaolong; Jiang Guoliang; Liang Shixiong; Zhu Xiaodong

    2006-01-01

    Objective: To identify the factors associated with radiation-induced liver disease (RILD) and to describe the probability of RILD using the Lyman normal tissue complication(NTCP) model for primary liver carcinoma(PLC) treated with hypofractionated conformal therapy (CRT). Methods: A total of 109 PLC patients treated with hypofractionated CRT were prospectively followed according to the Child-Pugh classification for liver cirrhosis, 93 patients in class A and 16 in class B. The mean dose of radiation to the isocenter was (53.5±5.5) Gy, fractions of (4.8±0.5) Gy, with interfraction interval of 48 hours and irradiation 3 times per week. Maximal likelihood analysis yielded the best estimates of parameters of the Lyman NTCP model for all patients; Child-Pugh A and Child-Pugh B patients, respectively. Results: Of all the patients, 17 developed RILD (17/109), 8 in Child-Pugh A (8/93) and 9 in Child-Pugh B (9/16). By multivariate analysis, only the Child-Pugh Grade of liver cirrhosis was the independent factor (P=0.000) associated with the developing of BILD. The best estimates of the NTCP parameters for all 109 patients were n=1.1, m=0.35 and TD 50 (1)=38.5 Gy. The n, m, TD 50 (1) estimated from patients with Child-Pugh A was 1.1, 0.28, 40.5 Gy, respectively, compared with 0.7, 0.43, 23 Gy respectively, for patients with Child-Pugh B. Conclusions: Primary liver cancer patients who possess Child-Pugh B cirrhosis would present a significantly greater susceptibility to RILD after hypofractionated CRT than patients with Child-Pugh A cirrhosis. The predominant risk factor for developing RILD is the severity of hepatic cirrhosis in the liver of PLC patients. (authors)

  14. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    Energy Technology Data Exchange (ETDEWEB)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsuneyama, Koichi [Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930‐0194 (Japan); Endo, Shinya [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsukui, Tohru [Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350‐1241 (Japan); Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan)

    2012-10-01

    Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

  15. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    International Nuclear Information System (INIS)

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori; Tsuneyama, Koichi; Endo, Shinya; Tsukui, Tohru; Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-01-01

    Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

  16. Fetal echocardiography

    International Nuclear Information System (INIS)

    Chaubal, Nitin G.; Chaubal, Jyoti

    2009-01-01

    USG performed with a high-end machine, using a good cine-loop facility is extremely helpful in the diagnosis of fetal cardiac anomalies. In fetal echocardiography, the four-chamber view and the outflow-tract view are used to diagnose cardiac anomalies. The most important objective during a targeted anomaly scan is to identify those cases that need a dedicated fetal echocardiogram. Associated truncal and chromosomal anomalies need to be identified. This review shows how fetal echocardiography, apart from identifying structural defects in the fetal heart, can be used to look at rhythm abnormalities and other functional aspects of the fetal heart

  17. Nebivolol and chrysin protect the liver against ischemia/reperfusion-induced injury in rats

    Directory of Open Access Journals (Sweden)

    Sayed M. Mizar

    2015-03-01

    Full Text Available Oxidative stress plays a key role in the pathogenesis of hepatic ischemia/reperfusion (I/R-induced injury, one of the leading causes of liver damage post-surgical intervention, trauma and transplantation. This study aimed to evaluate the protective effect of nebivolol and chrysin against I/R-induced liver injury via their vasodilator and antioxidant effects, respectively. Adult male Wister rats received nebivolol (5 mg/kg and/or chrysin (25 mg/kg by oral gavage daily for one week then subjected to ischemia via clamping the portal triad for 30 min then reperfusion for 30 min. Liver function enzymes, alanine transaminase (ALT and aspartate transaminase (AST, as well as hepatic Myeloperoxidase (MPO, total nitrate (NOx, glutathione (GSH and liver malondialdehyde (MDA were measured at the end of the experiment. Liver tissue damage was examined by histopathology. In addition, the expression levels of nitric oxide synthase (NOS subtypes, endothelial (eNOS and inducible (iNOS in liver samples were assessed by Western blotting and confirmed by immunohistochemical analysis. Both chrysin and nebivolol significantly counteracted I/R-induced oxidative stress and tissue damage biomarkers. The combination of these agents caused additive liver protective effect against I/R-induced damage via the up regulation of nitric oxide expression and the suppression of oxidative stress. Chrysin and nebivolol combination showed a promising protective effect against I/R-induced liver injury, at least in part, via decreasing oxidative stress and increasing nitric oxide levels.

  18. Liver Status Assessment by Spectrally and Time Resolved IR Detection of Drug Induced Breath Gas Changes

    Directory of Open Access Journals (Sweden)

    Tom Rubin

    2016-05-01

    Full Text Available The actual metabolic capacity of the liver is crucial for disease identification, liver therapy, and liver tumor resection. By combining induced drug metabolism and high sensitivity IR spectroscopy of exhaled air, we provide a method for quantitative liver assessment at bedside within 20 to 60 min. Fast administration of 13C-labelled methacetin induces a fast response of liver metabolism and is tracked in real-time by the increase of 13CO2 in exhaled air. The 13CO2 concentration increase in exhaled air allows the determination of the metabolic liver capacity (LiMAx-test. Fluctuations in CO2 concentration, pressure and temperature are minimized by special gas handling, and tracking of several spectrally resolved CO2 absorption bands with a quantum cascade laser. Absorption measurement of different 12CO2 and 13CO2 rotation-vibration transitions in the same time window allows for multiple referencing and reduction of systematic errors. This FLIP (Fast liver investigation package setup is being successfully used to plan operations and determine the liver status of patients.

  19. Effects of Fatty Liver Induced by Excess Orotic Acid on B-Group Vitamin Concentrations of Liver, Blood, and Urine in Rats.

    Science.gov (United States)

    Shibata, Katsumi; Morita, Nobuya; Kawamura, Tomoyo; Tsuji, Ai; Fukuwatari, Tsutomu

    2015-01-01

    Fatty liver is caused when rats are given orotic acid of the pyrimidine base in large quantities. The lack of B-group vitamins suppresses the biosynthesis of fatty acids. We investigated how orotic acid-induced fatty liver affects the concentrations of liver, blood, and urine B-group vitamins in rats. The vitamin B6 and B12 concentrations of liver, blood, and urine were not affected by orotic acid-induced fatty liver. Vitamin B2 was measured only in the urine, but was unchanged. The liver, blood, and urine concentrations of niacin and its metabolites fell dramatically. Niacin and its metabolites in the liver, blood, and urine were affected as expected. Although the concentrations of vitamin B1, pantothenic acid, folate, and biotin in liver and blood were decreased by orotic acid-induced fatty liver, these urinary excretion amounts showed a specific pattern toward increase. Generally, as for the typical urinary excretion of B-group vitamins, these are excreted when the body is saturated. However, the ability to sustain vitamin B1, pantothenic acid, folate, and biotin decreased in fatty liver, which is hypothesized as a specific phenomenon. This metabolic response might occur to prevent an abnormally increased biosynthesis of fatty acids by orotic acid.

  20. Increased expression of PPARγ in high fat diet-induced liver steatosis in mice

    International Nuclear Information System (INIS)

    Inoue, Mitsutaka; Ohtake, Takaaki; Motomura, Wataru; Takahashi, Nobuhiko; Hosoki, Yayoi; Miyoshi, Shigeki; Suzuki, Yasuaki; Saito, Hiroyuki; Kohgo, Yutaka; Okumura, Toshikatsu

    2005-01-01

    The present study was performed to examine a hypothesis that peroxisome proliferator-activated receptor γ (PPARγ) is implicated in high fat diet-induced liver steatosis. Mice were fed with control or high fat diet containing approximately 10% or 80% cholesterol, respectively. Macroscopic and microscopic findings demonstrated that lipid accumulation in the liver was observed as early as 2 weeks after high fat diet and that high fat diet for 12 weeks developed a fatty liver phenotype, establishing a novel model of diet-induced liver steatosis. Gene profiling with microarray and real-time PCR studies demonstrated that among genes involved in lipid metabolism, adipogenesis-related genes, PPARγ and its targeted gene, CD36 mRNA expression was specifically up-regulated in the liver by high fat diet for 2 weeks. Immunohistochemical study revealed that PPARγ protein expression is increased in the nuclei of hepatocytes by high fat diet. It was also shown that protein expression of cAMP response element-binding protein (CREB), an upstream molecule of PPARγ, in the liver was drastically suppressed by high fat diet. All these results suggest for the first time that the CREB-PPARγ signaling pathway may be involved in the high fat diet-induced liver steatosis

  1. Sirolimus influence on hepatectomy-induced liver regeneration in rats

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    Edimar Leandro Toderke

    Full Text Available OBJECTIVE: To evaluate the influence of sirolimus on liver regeneration triggered by resection of 70% of the liver of adult rats. METHODS: we used 40 Wistar rats randomly divided into two groups (study and control, each group was divided into two equal subgroups according to the day of death (24 hours and seven days. Sirolimus was administered at a dose of 1mg/kg in the study group and the control group was given 1 ml of saline. The solutions were administered daily since three days before hepatectomy till the rats death to removal of the regenerated liver, conducted in 24 hours or 7 days after hepatectomy. Liver regeneration was measured by the KWON formula, by thenumber of mitotic figures (hematoxylin-eosin staining and by the immunohistochemical markers PCNA and Ki-67. RESULTS: there was a statistically significant difference between the 24h and the 7d groups. When comparing the study and control groups in the same period, there was a statistically significant variation only for Ki-67, in which there were increased numbers of hepatocytes in cell multiplication in the 7d study group compared with the 7d control group (p = 0.04. CONCLUSION: there was no negative influence of sirolimus in liver regeneration and there was a positive partial effect at immunohistochemistry with Ki-67.

  2. Expression of miRNA-122 Induced by Liver Toxicants in Zebrafish

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    Hyun-Sik Nam

    2016-01-01

    Full Text Available MicroRNA-122 (miRNA-122, also known as liver-specific miRNA, has recently been shown to be a potent biomarker in response to liver injury in mammals. The objective of this study was to examine its expression in response to toxicant treatment and acute liver damage, using the zebrafish system as an alternative model organism. For the hepatotoxicity assay, larval zebrafish were arrayed in 24-well plates. Adult zebrafish were also tested and arrayed in 200 mL cages. Animals were exposed to liver toxicants (tamoxifen or acetaminophen at various doses, and miRNA-122 expression levels were analyzed using qRT-PCR in dissected liver, brain, heart, and intestine, separately. Our results showed no significant changes in miRNA-122 expression level in tamoxifen-treated larvae; however, miRNA-122 expression was highly induced in tamoxifen-treated adults in a tissue-specific manner. In addition, we observed a histological change in adult liver (0.5 μM and cell death in larval liver (5 μM at different doses of tamoxifen. These results indicated that miRNA-122 may be utilized as a liver-specific biomarker for acute liver toxicity in zebrafish.

  3. The inverse relationship between bladder and liver in 4-aminobiphenyl-induced DNA damage

    Science.gov (United States)

    Stablewski, Aimee B.; Vouros, Paul; Zhang, Yuesheng

    2015-01-01

    Bladder cancer risk is significantly higher in men than in women. 4-Aminobiphenyl (ABP) is a major human bladder carcinogen from tobacco smoke and other sources. In mice, male bladder is more susceptible to ABP-induced carcinogenesis than female bladder, but ABP is more carcinogenic in the livers of female mice than of male mice. Here, we show that castration causes male mice to acquire female phenotype regarding susceptibility of bladder and liver to ABP. However, spaying has little impact on organ susceptibility to ABP. Liver UDP-glucuronosyltransferases (UGTs) are believed to protect liver against but sensitize bladder to ABP, as glucuronidation of ABP and its metabolites generally reduces their toxicity and promotes their elimination via urine, but the metabolites are labile in urine, delivering carcinogenic species to the bladder. Indeed, liver expression of ABP-metabolizing human UGT1A3 transgene in mice increases bladder susceptibility to ABP. However, ABP-specific liver UGT activity is significantly higher in wild-type female mice than in their male counterparts, and castration also significantly increases ABP-specific UGT activity in the liver. Taken together, our data suggest that androgen increases bladder susceptibility to ABP via liver, likely by modulating an ABP-metabolizing liver enzyme, but exclude UGT as an important mediator. PMID:25596734

  4. Assessment of Both Maternal and Fetal Ghrelin and Resistin Levels in Pregnancy Induced Hypertension

    International Nuclear Information System (INIS)

    Khattab, N.F.; El-Nashar, N.A.; Marei, E.S.

    2010-01-01

    Pregnancy-induced hypertension (PIH) is mainly a vascular disease, probably caused by an imbalance between vasodilator and vasoconstrictor agents that results in generalized vasospasm and poor perfusion in many organs including the placenta. The current study was carried out on 55 women, fourty were pregnant and delivered by Elective Cesarean Section, 20 of them were normal healthy pregnant women with uncomplicated term singleton gestation and twenty with PIH. Fifteen were healthy non pregnant women (24-33 years old) served as control group. Active total serum ghrelin (pg/ml) and serum resistin (ng/ml) were measured using ELISA kits. At 25 weeks of gestational age, a highly significant decrease in ghrelin levels in the pregnant groups was detected compared to the non-pregnant group (p<0.0001). Comparing serum ghrelin levels between both pregnant groups showed that it was significantly higher in PIH pregnant women (p<0.05). However, serum resistin showed significant increase in pregnant women compared to the non pregnant. At time of delivery, ghrelin was found to be significantly higher in PIH patients (47.41±8.55 pg/ml) than in normal pregnant women (36.74±6.74 pg/ml). However no significant change was found in serum ghrelin and resistin concentrations in the umbilical cord blood between the previous 2 groups. A significant increase in the umbilical cord blood of ghrelin (41.82±6.30 pg/ml) was detected compared to maternal ghrelin (36.74±6.74 pg/ml) in normal pregnant women (p<0.05), but not in PIH pregnant women. However, a significant increase was detected in the umbilical cord blood of resistin in both normal and PIH pregnant groups compared to their corresponding maternal blood (p< 0.05). In normal pregnant women, serum ghrelin concentration was negatively correlated with both the systolic and diastolic blood pressure (systolic: p<0.05, diastolic: p<0.05). Furthermore, serum ghrelin concentration was also negatively correlated with the systolic blood

  5. Human herpesvirus 6A induces apoptosis of primary human fetal astrocytes via both caspase-dependent and -independent pathways

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    Gu Bin

    2011-12-01

    Full Text Available Abstract Background Human herpesvirus 6 (HHV-6 is a T-lymphtropic and neurotropic virus that can infect various types of cells. Sequential studies reported that apoptosis of glia and neurons induced by HHV-6 might act a potential trigger for some central nervous system (CNS diseases. HHV-6 is involved in the pathogenesis of encephalitis, multiple sclerosis (MS and fatigue syndrome. However, the mechanisms responsible for the apoptosis of infected CNS cells induced by HHV-6 are poorly understood. In this study, we investigated the cell death processes of primary human fetal astrocytes (PHFAs during productive HHV-6A infection and the underlying mechanisms. Results HHV-6A can cause productive infection in primary human fetal astrocytes. Annexin V-PI staining and electron microscopic analysis indicated that HHV-6A was an inducer of apoptosis. The cell death was associated with activation of caspase-3 and cleavage of poly (ADP-ribose polymerase (PARP, which is known to be an important substrate for activated caspase-3. Caspase-8 and -9 were also significantly activated in HHV-6A-infected cells. Moreover, HHV-6A infection led to Bax up-regulation and Bcl-2 down-regulation. HHV-6A infection increased the release of Smac/Diablo, AIF and cytochrome c from mitochondria to cytosol, which induced apoptosis via the caspase-dependent and -independent pathways. In addition, we also found that anti-apoptotic factors such as IAPs and NF-κB decreased in HHV-6A infected PHFAs. Conclusion This is the first demonstration of caspase-dependent and -independent apoptosis in HHV-6A-infected glial cells. These findings would be helpful in understanding the mechanisms of CNS diseases caused by HHV-6.

  6. The Hepatoprotection Provided by Taurine and Glycine against Antineoplastic Drugs Induced Liver Injury in an Ex Vivo Model of Normothermic Recirculating Isolated Perfused Rat Liver

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    Reza Heidari

    2016-03-01

    Full Text Available Taurine (2-aminoethane sulfonic acid is a non-protein amino acid found in high concentration in different tissues. Glycine (Amino acetic acid is the simplest amino acid incorporated in the structure of proteins. Several investigations indicate the hepatoprotective properties of these amino acids. On the other hand, antineoplastic agents-induced serum transaminase elevation and liver injury is a clinical complication. The current investigation was designed to screen the possible hepatoprotective properties of taurine and glycine against antineoplastic drugs-induced hepatic injury in an ex vivo model of isolated perfused rat liver. Rat liver was perfused with different concentration (10 μM, 100 μM and 1000 μM of antineoplastic drugs (Mitoxantrone, Cyclophosphamide, Cisplatin, 5 Fluorouracil, Doxorubicin and Dacarbazine via portal vein. Taurine and glycine were administered to drug-treated livers and liver perfusate samples were collected for biochemical measurements (ALT, LDH, AST, and K+. Markers of oxidative stress (reactive oxygen species formation, lipid peroxidation, total antioxidant capacity and glutathione were also assessed in liver tissue. Antineoplastic drugs caused significant pathological changes in perfusate biochemistry. Furthermore, markers of oxidative stress were significantly elevated in drug treated livers. It was found that taurine (5 and 10 mM and glycine (5 and 10 mM administration significantly mitigated the biomarkers of liver injury and attenuated drug induced oxidative stress. Our data indicate that taurine and glycine supplementation might help as potential therapeutic options to encounter anticancer drugs-induced liver injury.

  7. Cadmium-induced neural tube defects and fetal growth restriction: Association with disturbance of placental folate transport

    International Nuclear Information System (INIS)

    Zhang, Gui-Bin; Wang, Hua; Hu, Jun; Guo, Min-Yin; Wang, Ying; Zhou, Yan; Yu, Zhen; Fu, Lin; Chen, Yuan-Hua; Xu, De-Xiang

    2016-01-01

    Previous studies found that maternal Cd exposure on gestational day (GD)9 caused forelimb ectrodactyly and tail deformity, the characteristic malformations. The aim of the present study was to investigate whether maternal Cd exposure on GD8 induces fetal neural tube defects (NTDs). Pregnant mice were intraperitoneally injected with CdCl 2 (2.5 or 5.0 mg/kg) on GD8. Neither forelimb ectrodactyly nor tail deformity was observed in mice injected with CdCl 2 on GD8. Instead, maternal Cd exposure on GD8 resulted in the incidence of NTDs. Moreover, maternal Cd exposure on GD8 resulted in fetal growth restriction. In addition, maternal Cd exposure on GD8 reduced placental weight and diameter. The internal space of maternal and fetal blood vessels in the labyrinth layer was decreased in the placentas of mice treated with CdCl 2 . Additional experiment showed that placental PCFT protein and mRNA, a critical folate transporter, was persistently decreased when dams were injected with CdCl 2 on GD8. Correspondingly, embryonic folate content was markedly decreased in mice injected with CdCl 2 on GD8, whereas Cd had little effect on folate content in maternal serum. Taken together, these results suggest that maternal Cd exposure during organogenesis disturbs transport of folate from maternal circulation to the fetuses through down-regulating placental folate transporters. - Highlights: • Maternal Cd exposure during organogenesis causes NTDs and FGR. • Maternal Cd exposure during organogenesis impairs placental development. • Cd disturbs transport of folate by down-regulating placental folate transporters.

  8. Cadmium-induced neural tube defects and fetal growth restriction: Association with disturbance of placental folate transport

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Gui-Bin; Wang, Hua, E-mail: wanghuadev@126.com; Hu, Jun; Guo, Min-Yin; Wang, Ying; Zhou, Yan; Yu, Zhen; Fu, Lin; Chen, Yuan-Hua; Xu, De-Xiang, E-mail: xudex@126.com

    2016-09-01

    Previous studies found that maternal Cd exposure on gestational day (GD)9 caused forelimb ectrodactyly and tail deformity, the characteristic malformations. The aim of the present study was to investigate whether maternal Cd exposure on GD8 induces fetal neural tube defects (NTDs). Pregnant mice were intraperitoneally injected with CdCl{sub 2} (2.5 or 5.0 mg/kg) on GD8. Neither forelimb ectrodactyly nor tail deformity was observed in mice injected with CdCl{sub 2} on GD8. Instead, maternal Cd exposure on GD8 resulted in the incidence of NTDs. Moreover, maternal Cd exposure on GD8 resulted in fetal growth restriction. In addition, maternal Cd exposure on GD8 reduced placental weight and diameter. The internal space of maternal and fetal blood vessels in the labyrinth layer was decreased in the placentas of mice treated with CdCl{sub 2}. Additional experiment showed that placental PCFT protein and mRNA, a critical folate transporter, was persistently decreased when dams were injected with CdCl{sub 2} on GD8. Correspondingly, embryonic folate content was markedly decreased in mice injected with CdCl{sub 2} on GD8, whereas Cd had little effect on folate content in maternal serum. Taken together, these results suggest that maternal Cd exposure during organogenesis disturbs transport of folate from maternal circulation to the fetuses through down-regulating placental folate transporters. - Highlights: • Maternal Cd exposure during organogenesis causes NTDs and FGR. • Maternal Cd exposure during organogenesis impairs placental development. • Cd disturbs transport of folate by down-regulating placental folate transporters.

  9. Hepatocurative potential of sesquiterpene lactones of Taraxacum officinale on carbon tetrachloride induced liver toxicity in mice.

    Science.gov (United States)

    Mahesh, A; Jeyachandran, R; Cindrella, L; Thangadurai, D; Veerapur, V P; Muralidhara Rao, D

    2010-06-01

    The hepatocurative potential of ethanolic extract (ETO) and sesquiterpene lactones enriched fraction (SL) of Taraxacum officinale roots was evaluated against carbon tetrachloride (CCl 4 ) induced hepatotoxicity in mice. The diagnostic markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and total bilirubin contents were significantly elevated, whereas significant reduction in the level of reduced glutathione (GSH) and enhanced hepatic lipid peroxidation, liver weight and liver protein were observed in CCl 4 induced hepatotoxicity in mice. Post-treatment with ETO and SL significantly protected the hepatotoxicity as evident from the lower levels of hepatic enzyme markers, such as serum transaminase (ALT, AST), ALP and total bilirubin. Further, significant reduction in the liver weight and liver protein in drug-treated hepatotoxic mice and also reduced oxidative stress by increasing reduced glutathione content and decreasing lipid peroxidation level has been noticed. The histopathological evaluation of the liver also revealed that ETO and SL reduced the incidence of liver lesions induced by CCl 4 . The results indicate that sesquiterpene lactones have a protective effect against acute hepatotoxicity induced by the administration of CCl 4 in mice. Furthermore, observed activity of SL may be due to the synergistic action of two sesquiterpene lactones identified from enriched ethyl acetate fraction by HPLC method.

  10. Drug-induced liver toxicity and prevention by herbal antioxidants: an overview

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    Divya eSingh

    2016-01-01

    Full Text Available The liver is the center for drug and xenobiotic metabolism, which is influenced most with medication/xenobiotic-mediated toxic activity. Drug-induced hepatotoxicity is common and its actual frequency is hard to determine due to underreporting, difficulties in detection or diagnosis, and incomplete observation of exposure. The death rate is high, up to about 10% for medication instigated liver danger. Endorsed medications (counting acetaminophen represented >50% of instances of intense liver failure in a study from the Acute Liver Failure Study Group (ALFSG of the patients admitted in 17 US healing facilities. Albeit different studies are accessible uncovering the mechanistic aspects of medication prompted hepatotoxicity, we are in the dilemma about the virtual story. The expanding prevalence and effectiveness of Ayurveda and herbal products in the treatment of various disorders led the investigators to look into their potential in countering drug-induced liver toxicity. Several plant products have been reported to date to mitigate the drug-induced toxicity. The dietary nature and less side reactions of the herbs provide them an extra edge over other candidates of supplementary medication. In this paper, we have discussed on the mechanism involved in drug-induced liver toxicity and the potential of herbal antioxidants as supplementary medication.

  11. Arsenic induced apoptosis in rat liver following repeated 60 days exposure

    International Nuclear Information System (INIS)

    Bashir, Somia; Sharma, Yukti; Irshad, M.; Nag, T.C.; Tiwari, Monica; Kabra, M.; Dogra, T.D.

    2006-01-01

    Background: Accumulation of the wide spread environmental toxin arsenic in liver results in hepatotoxcity. Exposure to arsenite and other arsenicals has been previously shown to induce apoptosis in certain tumor cell lines at low (1-3 μM) concentration. Aim: The present study was focused to elucidate the role of free radicals in arsenic toxicity and to investigate the nature of in vivo sodium arsenite induced cell death in liver. Methods: Male wistar rats were exposed to arsenite at three different doses of 0.05, 2.5 and 5 mg/l for 60 days. Oxidative stress in liver was measured by estimating pro-oxidant and antioxidant activity in liver. Histopathological examination of liver was carried out by light and transmission electron microscopy. Analysis of DNA fragmentation by gel electrophoresis was used to identify apoptosis after the exposure. Terminal deoxy-nucleotidyl transferase mediated dUTP Nick end-labeling (TUNEL) assay was used to qualify and quantify apoptosis. Results: A significant increase in cytochrome-P450 and lipid peroxidation accompanied with a significant alteration in the activity of many of the antioxidants was observed, all suggestive of arsenic induced oxidative stress. Histopathological examination under light and transmission electron microscope suggested a combination of ongoing necrosis and apoptosis. DNA-TUNEL showed an increase in apoptotic cells in liver. Agarose gel electrophoresis of DNA of hepatocytes resulted in a characteristic ladder pattern. Conclusion: Chronic arsenic administration induces a specific pattern of apoptosis called post-mitotic apoptosis

  12. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

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    Yannam, Govardhana Rao [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Han, Bing [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi' an Jiaotong University, Xi' an, Shaanxi (China); Setoyama, Kentaro [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamamoto, Toshiyuki [Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska (United States); Ito, Ryotaro; Brooks, Jenna M. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Guzman-Lepe, Jorge [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Galambos, Csaba [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Fong, Jason V. [Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); Deutsch, Melvin; Quader, Mubina A. [Department of Radiation Oncology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); Yamanouchi, Kosho [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York (United States); Kabarriti, Rafi; Mehta, Keyur [Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York (United States); Soto-Gutierrez, Alejandro [Department of Pathology, Children' s Hospital of Pittsburgh, Pittsburgh, Pennsylvania (United States); McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania (United States); and others

    2014-02-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury.

  13. Hepatoprotective Effect of Essential Oils from Hyptis crenata in Sepsis-Induced Liver Dysfunction.

    Science.gov (United States)

    Lima, Glauber Cruz; Vasconcelos, Yuri de Abreu Gomes; de Santana Souza, Marilia Trindade; Oliveira, Alan Santos; Bomfim, Rangel Rodrigues; de Albuquerque Júnior, Ricardo Luiz Cavalcanti; Camargo, Enilton Aparecido; Portella, Viviane Gomes; Coelho-de-Souza, Andrelina Noronha; Diniz, Lúcio Ricardo Leite

    2018-02-28

    No specific therapeutics are available for the treatment of sepsis-induced liver dysfunction, a clinical complication strongly associated with the high mortality rate of septic patients. This study investigated the effect of the essential oil of Hyptis crenata (EOHc), a lamiaceae plant used to treat liver disturbances in Brazilian folk medicine, on liver function during early sepsis. Sepsis was induced by the cecal ligation and puncture (CLP) model. Rats were divided into four groups: Sham, Sham+EOHc, CLP, and CLP+EOHc. EOHc (300 mg/kg) was orally administered 12 and 24 h after surgery. The animals were sacrificed for blood collection and liver tissue samples 48 h after surgery. Hepatic function was evaluated by measuring serum bilirubin, alkaline phosphatase (ALP), aspartate aminotransferase, and alanine aminotransferase (ALT) levels. The levels of malondialdehyde and the activity of superoxide dismutase, catalase, and GSH peroxidase (GSH-Px) were measured for assessment of oxidative stress. Liver morphology was analyzed by hematoxylin and eosin staining. EOHc normalized serum ALP, ALT, and bilirubin levels and inhibited morphological changes. In addition, we observed that EOHc inhibited elevation in hepatic lipid peroxidation and reduction of the glutathione peroxidase activity induced by sepsis. Our data show that EOHc plays a protective effect against liver injury induced by sepsis.

  14. A Nonhuman Primate Model of Human Radiation-Induced Venocclusive Liver Disease and Hepatocyte Injury

    International Nuclear Information System (INIS)

    Yannam, Govardhana Rao; Han, Bing; Setoyama, Kentaro; Yamamoto, Toshiyuki; Ito, Ryotaro; Brooks, Jenna M.; Guzman-Lepe, Jorge; Galambos, Csaba; Fong, Jason V.; Deutsch, Melvin; Quader, Mubina A.; Yamanouchi, Kosho; Kabarriti, Rafi; Mehta, Keyur; Soto-Gutierrez, Alejandro

    2014-01-01

    Background: Human liver has an unusual sensitivity to radiation that limits its use in cancer therapy or in preconditioning for hepatocyte transplantation. Because the characteristic veno-occlusive lesions of radiation-induced liver disease do not occur in rodents, there has been no experimental model to investigate the limits of safe radiation therapy or explore the pathogenesis of hepatic veno-occlusive disease. Methods and Materials: We performed a dose-escalation study in a primate, the cynomolgus monkey, using hypofractionated stereotactic body radiotherapy in 13 animals. Results: At doses ≥40 Gy, animals developed a systemic syndrome resembling human radiation-induced liver disease, consisting of decreased albumin, elevated alkaline phosphatase, loss of appetite, ascites, and normal bilirubin. Higher radiation doses were lethal, causing severe disease that required euthanasia approximately 10 weeks after radiation. Even at lower doses in which radiation-induced liver disease was mild or nonexistent, latent and significant injury to hepatocytes was demonstrated by asialoglycoprotein-mediated functional imaging. These monkeys developed hepatic failure with encephalopathy when they received parenteral nutrition containing high concentrations of glucose. Histologically, livers showed central obstruction via an unusual intimal swelling that progressed to central fibrosis. Conclusions: The cynomolgus monkey, as the first animal model of human veno-occlusive radiation-induced liver disease, provides a resource for characterizing the early changes and pathogenesis of venocclusion, for establishing nonlethal therapeutic dosages, and for examining experimental therapies to minimize radiation injury

  15. Protective effect of bile acid derivatives in phalloidin-induced rat liver toxicity

    International Nuclear Information System (INIS)

    Herraez, Elisa; Macias, Rocio I.R.; Vazquez-Tato, Jose; Hierro, Carlos; Monte, Maria J.; Marin, Jose J.G.

    2009-01-01

    Phalloidin causes severe liver damage characterized by marked cholestasis, which is due in part to irreversible polymerization of actin filaments. Liver uptake of this toxin through the transporter OATP1B1 is inhibited by the bile acid derivative BALU-1, which does not inhibit the sodium-dependent bile acid transporter NTCP. The aim of the present study was to investigate whether BALU-1 prevents liver uptake of phalloidin without impairing endogenous bile acid handling and hence may have protective effects against the hepatotoxicity induced by this toxin. In anaesthetized rats, i.v. administration of BALU-1 increased bile flow more than taurocholic acid (TCA). Phalloidin administration decreased basal (- 60%) and TCA-stimulated bile flow (- 55%) without impairing bile acid output. Phalloidin-induced cholestasis was accompanied by liver necrosis, nephrotoxicity and haematuria. In BALU-1-treated animals, phalloidin-induced cholestasis was partially prevented. Moreover haematuria was not observed, which was consistent with histological evidences of BALU-1-prevented injury of liver and kidney tissue. HPLC-MS/MS analysis revealed that BALU-1 was secreted in bile mainly in non-conjugated form, although a small proportion ( TCA > DHCA > UDCA. In conclusion, BALU-1 is able to protect against phalloidin-induced hepatotoxicity, probably due to an inhibition of the liver uptake and an enhanced biliary secretion of this toxin.

  16. Total Flavonoids from Mimosa Pudica Protects Carbon Tetrachloride -Induced Acute Liver Injury in Mice

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    Zhen-qin QIU

    2015-03-01

    Full Text Available Objective: To observe the protective effect of total flavonoids from Mimosa pudica on carbon tetrachloride (CCl4-induced acute liver injury in mice. Methods: CCl4-induced acute liver injury model in mice was established. The activity of ALT and AST, the content of serum albumin (Alb and total antioxidant capacity (T-AOC were determined. The content of malondiadehyde (MDA was measured and the activity of superoxide dismutase (SOD was determined. The histopathological changes of liver were observed.Results: Compared with CCl4 modle group, each dose group of total flavonouida from Mimosa pudica couldreduced the activity of ALT and AST in mice obviously (P<0.01, indicating they had remarkably protective effect on CCl4-induced acute liver injury in mice. high and middle dose groups of total flavonouida from Mimosa pudica couldincrease the content of Alb in mice (P<0.01. Each dose group of total flavonouida from Mimosa pudica could enhance the level of T-AOC (P<0.01. each dose group of total flavonouida from Mimosa pudica could lower the content of liver homogenate MDA but enhance the activity of SOD in a dose-depended manner (P<0.01. Conclusion: Total flavones from Mimosa Pudica have obvious protective effect on CCl4-induced acute liver injury in mice.

  17. Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

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    Tobias Eggert

    Full Text Available Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL, while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

  18. Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

    Science.gov (United States)

    Eggert, Tobias; Medina-Echeverz, José; Kapanadze, Tamar; Kruhlak, Michael J; Korangy, Firouzeh; Greten, Tim F

    2014-01-01

    Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

  19. Human Chorionic Gonadotropin Has Anti-Inflammatory Effects at the Maternal-Fetal Interface and Prevents Endotoxin-Induced Preterm Birth, but Causes Dystocia and Fetal Compromise in Mice1

    Science.gov (United States)

    Furcron, Amy-Eunice; Romero, Roberto; Mial, Tara N.; Balancio, Amapola; Panaitescu, Bogdan; Hassan, Sonia S.; Sahi, Aashna; Nord, Claire; Gomez-Lopez, Nardhy

    2016-01-01

    Human chorionic gonadotropin (hCG) is implicated in the maintenance of uterine quiescence by down-regulating myometrial gap junctions during pregnancy, and it was considered as a strategy to prevent preterm birth after the occurrence of preterm labor. However, the effect of hCG on innate and adaptive immune cells implicated in parturition is poorly understood. Herein, we investigated the immune effects of hCG at the maternal-fetal interface during late gestation, and whether this hormone can safely prevent endotoxin-induced preterm birth. Using immunophenotyping, we demonstrated that hCG has immune effects at the maternal-fetal interface (decidual tissues) by: 1) increasing the proportion of regulatory T cells; 2) reducing the proportion of macrophages and neutrophils; 3) inducing an M1 → M2 macrophage polarization; and 4) increasing the proportion of T helper 17 cells. Next, ELISAs were used to determine whether the local immune changes were associated with systemic concentrations of progesterone, estradiol, and/or cytokines (IFNgamma, IL1beta, IL2, IL4, IL5, IL6, IL10, IL12p70, KC/GRO, and TNFalpha). Plasma concentrations of IL1beta, but not progesterone, estradiol, or any other cytokine, were increased following hCG administration. Pretreatment with hCG prevented endotoxin-induced preterm birth by 44%, proving the effectiveness of this hormone as an anti-inflammatory agent. However, hCG administration alone caused dystocia and fetal compromise, as proven by Doppler ultrasound. These results provide insight into the mechanisms whereby hCG induces an anti-inflammatory microenvironment at the maternal-fetal interface during late gestation, and demonstrate its effectiveness in preventing preterm labor/birth. However, the deleterious effects of this hormone on mothers and fetuses warrant caution. PMID:27146032

  20. Fetal echocardiography

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/007340.htm Fetal echocardiography To use the sharing features on this page, please enable JavaScript. Fetal echocardiography is a test that uses sound waves ( ultrasound ) ...

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

    Directory of Open Access Journals (Sweden)

    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.

  2. Radiation-induced liver lesions in beagle dogs

    International Nuclear Information System (INIS)

    Hahn, F.F.; Muggenburg, B.A.; Boecker, B.B.

    1994-01-01

    The risk for liver disease from internally deposited beta-emitting radionuclides is unknown because there are no human populations exposed to hepatotropic beta-emitting radionuclides available for study. In this report, we discuss the hepatic lesion in dogs exposed to a beta-emitting radionuclide, 144 CeCl 3 , and held for their life spans

  3. Fetal exposure to herpesviruses may be associated with pregnancy-induced hypertensive disorders and preterm birth in a Caucasian population.

    Science.gov (United States)

    Gibson, C S; Goldwater, P N; MacLennan, A H; Haan, E A; Priest, K; Dekker, G A

    2008-03-01

    To investigate the role of fetal viral infection in the development of a range of adverse pregnancy outcomes (APOs), including pregnancy-induced hypertensive disorders (PIHD), antepartum haemorrhage (APH), birthweight PTBs, the risk of developing PIHD was increased in the presence of DNA from Herpes PCR group B viruses (OR 3.57, 95% CI 1.10-11.70), CMV (OR 3.89, 95% CI 1.67-9.06), any herpesvirus (OR 5.70, 95% CI 1.85-17.57) and any virus (OR 5.17, 95% CI 1.68-15.94). The presence of CMV was associated with PTB (OR 1.61, 95% CI 1.14-2.27). No significant association was observed between SGA or APH and exposure to viral infection. Fetal exposure to herpesvirus infection was associated with PIHD for both term and PTBs in this exploratory study. Exposure to CMV may also be associated with PTB. These findings need confirmation in future studies.

  4. Caspase 3 activity in isolated fetal rat lung fibroblasts and rat periodontal ligament fibroblasts: cigarette smoke-induced alterations

    Directory of Open Access Journals (Sweden)

    James Elliot Scott

    2016-03-01

    Full Text Available Background Cigarette smoking is the leading cause of preventable death in the world. It has been implicated in the pathogenesis of pulmonary, oral and systemic diseases. Smoking during pregnancy is clearly a risk factor for the developing fetus and may be a major cause of infant mortality. Moreover, the oral cavity is the first site of exposure to cigarette smoke and may be a possible source for the spread of toxins to other organs of the body. Fibroblasts in general are morphologically heterogeneous connective tissue cells with diverse functions. Apoptosis or programmed cell death is a crucial process during embryogenesis and for the maintenance of homeostasis throughout life. Deregulation of apoptosis has been implicated in abnormal lung development in the fetus and disease progression in adults. Caspases, are proteases which belong to the family of cysteine aspartic acid proteases and are the key components for the downstream amplification of intra-cellular apoptotic signals. Of the 14 caspases known, caspase-3 is the key executioner of apoptosis. Fetal rat lung fibroblasts but not PDL viability is reduced by exposure to CSE. In addition Caspase 3 activity is elevated after CSE exposure in fetal lung fibroblasts but not in PDLs. Expression of caspase 3 is induced in CSE exposed lung fibroblasts but not in PDLs. Caspase 3 was localized to the cytoplasm in both cell types.

  5. Bupivacaine drug-induced liver injury: a case series and brief review of the literature.

    Science.gov (United States)

    Chintamaneni, Preethi; Stevenson, Heather L; Malik, Shahid M

    2016-08-01

    Bupivacaine is an established and efficacious anesthetic that has become increasingly popular in postoperative pain management. However, there is limited literature regarding the potential for bupivacaine-induced delayed liver toxicity. Describe cholestasis as a potential adverse reaction of bupivacaine infusion into a surgical wound. Retrospective review of patients' medical records. We report the cases of 3 patients with new onset of cholestatic injury after receiving bupivacaine infusion for postoperative herniorrhaphy pain management. All patients had negative serologic workups for other causes of liver injury. All patients achieved eventual resolution of their liver injury. Bupivacaine-induced liver injury should be on the differential of individuals presenting with jaundice and cholestasis within a month of infusion via a surgically placed catheter of this commonly used anesthetic. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Liver fibrosis in mice induced by carbon tetrachloride and its reversion by luteolin

    International Nuclear Information System (INIS)

    Domitrovic, Robert; Jakovac, Hrvoje; Tomac, Jelena; Sain, Ivana

    2009-01-01

    Hepatic fibrosis is effusive wound healing process in which excessive connective tissue builds up in the liver. Because specific treatments to stop progressive fibrosis of the liver are not available, we have investigated the effects of luteolin on carbon tetrachloride (CCl 4 )-induced hepatic fibrosis. Male Balb/C mice were treated with CCl 4 (0.4 ml/kg) intraperitoneally (i.p.), twice a week for 6 weeks. Luteolin was administered i.p. once daily for next 2 weeks, in doses of 10, 25, and 50 mg/kg of body weight. The CCl 4 control group has been observed for spontaneous reversion of fibrosis. CCl 4 -intoxication increased serum aminotransferase and alkaline phosphatase levels and disturbed hepatic antioxidative status. Most of these parameters were spontaneously normalized in the CCl 4 control group, although the progression of liver fibrosis was observed histologically. Luteolin treatment has increased hepatic matrix metalloproteinase-9 levels and metallothionein (MT) I/II expression, eliminated fibrinous deposits and restored architecture of the liver in a dose-dependent manner. Concomitantly, the expression of glial fibrillary acidic protein and α-smooth muscle actin indicated deactivation of hepatic stellate cells. Our results suggest the therapeutic effects of luteolin on CCl 4 -induced liver fibrosis by promoting extracellular matrix degradation in the fibrotic liver tissue and the strong enhancement of hepatic regenerative capability, with MTs as a critical mediator of liver regeneration.

  7. PROTECTIVE EFFECTS OF HYPOTHALAMIC BETA-ENDORPHIN NEURONS AGAINST ALCOHOL-INDUCED LIVER INJURIES AND LIVER CANCERS IN RAT ANIMAL MODELS

    Science.gov (United States)

    Murugan, Sengottuvelan; Boyadjieva, Nadka; Sarkar, Dipak K.

    2014-01-01

    Background Recently, retrograde tracing has provided evidence for an influence of hypothalamic β-endorphin (BEP) neurons on the liver, but functions of these neurons are not known. We evaluated the effect of BEP neuronal activation on alcohol-induced liver injury and hepatocellular cancer. Methods Male rats received either BEP neuron transplants or control transplants in the hypothalamus and randomly assigned to feeding alcohol-containing liquid diet or control liquid diet for 8 weeks or to treatment of a carcinogen diethylnitrosamine (DEN). Liver tissues of these animals were analyzed histochemically and biochemically for tissue injuries or cancer. Results Alcohol-feeding increased liver weight and induced several histopathological changes such as prominent microvesicular steatosis and hepatic fibrosis. Alcohol feeding also increased protein levels of triglyceride, hepatic stellate cell activation factors and catecholamines in the liver and endotoxin levels in the plasma. However, these effects of alcohol on the liver were reduced in animals with BEP neuron transplants. BEP neuron transplants also suppressed carcinogen-induced liver histopathologies such as extensive fibrosis, large focus of inflammatory infiltration, hepatocelluar carcinoma, collagen deposition, numbers of preneoplastic foci, levels of hepatic stellate cell activation factors and catecholamines, as well as inflammatory milieu and the levels of NK cell cytotoxic factors in the liver. Conclusion These findings are the first evidence for a role of hypothalamic BEP neurons in influencing liver functions. Additionally, the data identify that BEP neuron transplantation prevents hepatocellular injury and hepatocellular carcinoma formation possibly via influencing the immune function. PMID:25581653

  8. Enhanced protective activity of nano formulated andrographolide against arsenic induced liver damage.

    Science.gov (United States)

    Das, Sujata; Pradhan, Goutam Kumar; Das, Subhadip; Nath, Debjani; Das Saha, Krishna

    2015-12-05

    Chronic exposure to arsenic over a period of time induces toxicity, primarily in liver but gradually in all systems of the body. Andrographolide (AG), a major diterpene lactone of Andrographis paniculata, shows a wide array of physiological functions including hepatoprotection. Therapeutic applications of AG are however seriously constrained because of its insolubility, poor bioavailability, and short plasma half-life. Nanoparticulation of AG is a possible solution to these problems. In the present study we investigated the effectiveness of polylactide co-glycolide (PLGA) nanocapsulated andrographolide (NA) against arsenic induced liver damage in mice. NA of average diameter 65.8 nm and encapsulation efficiency of 64% were prepared. Sodium arsenite at a dose of 40 mg/L supplied via drinking water in mice significantly raised the serum level of liver function markers such as AST, ALT, and ALP, and caused arsenic deposition in liver and ROS generation, though it did not show any lethality up to 30 days of exposure. However, even liver toxicity was not observed when mice were given AG and NA orally at doses up to 100 mg/kg bwt and 20 mg/kg bwt respectively on alternate days for one month. Treatment of non-toxic doses of AG or NA on alternate days along with arsenic significantly decreased the arsenic induced elevation of the serum level of ALT, AST and ALP, and arsenic deposition in liver. AG and NA increased the level of hepatic antioxidant enzymes such as superoxide dismutase (SOD), and catalase (CAT), and the level of reduced glutathione (GSH). Also, the ROS level was lowered in mice exposed to arsenic but treated with AG or NA. Protective efficiency of NA is about five times more than that of AG. Administration of NA to arsenic-treated mice caused signs of improvement in liver tissue architecture. In conclusion, the results of this study suggest that NA could be beneficial against arsenic-induced liver toxicity. Copyright © 2015 Elsevier Ireland Ltd. All rights

  9. Immunohistochemical Analysis of Platelet Extract Effects on Liver Injury Induced by CCl4 in Male Rats

    OpenAIRE

    Zahra Hesami; Maryam Ayatollahi; Bita Geramizadeh; Akram Jamshidzadeh; Akbar Vahdati

    2016-01-01

    Backgrounds & objectives: Liver damage results in a large accumulation of external cellular matrix that affects the function of this important body organ in a long term and finally stops its function completely. The growth factors existing in platelet extract are more cost-effective, available, and stable than recombinant ones. To determine whether the platelet extract effects on histological changes in liver injury induced by carbon tetrachloride (CCl4), we used immunohistochemical analysis ...

  10. Potential Effect of Bacopa monnieri on Nitrobenzene Induced Liver Damage in Rats.

    Science.gov (United States)

    Menon, B Rajalakshmy; Rathi, M A; Thirumoorthi, L; Gopalakrishnan, V K

    2010-10-01

    The study was designed to evaluate the hepatoprotective activity of ethanolic extract of Bacopa monnieri in acute experimental liver injury induced by Nitrobenzene in rats. The extract at the dose of 200 mg/kg body weight was administered orally once every day for 10 days. The increased serum marker enzymes, Aspartate transaminase, Alanine transaminase and alkaline phosphatase were restored towards normalization significantly by the extract. Significant increase in SOD, CAT and GPx was observed in extract treated liver injured experimental rats. Histopathological examination of the liver tissues supported the hepatoprotection. It is concluded that the ethanolic extract of Bacopa monieri plant possess good hepatoprotective activity.

  11. Drug-Induced Liver Injury Associated with Complementary and Alternative Medicines

    Science.gov (United States)

    Takahashi, Koji; Kanda, Tatsuo; Yasui, Shin; Haga, Yuki; Kumagai, Junichiro; Sasaki, Reina; Wu, Shuang; Nakamoto, Shingo; Nakamura, Masato; Arai, Makoto; Yokosuka, Osamu

    2016-01-01

    A 24-year-old man was admitted due to acute hepatitis with unknown etiology. After his condition and laboratory data gradually improved with conservative therapy, he was discharged 1 month later. Two months after his discharge, however, liver dysfunction reappeared. After his mother accidentally revealed that he took complementary and alternative medicine, discontinuation of the therapy caused his condition to improve. Finally, he was diagnosed with a recurrent drug-induced liver injury associated with Japanese complementary and alternative medicine. It is important to take the medical history in detail and consider complementary and alternative medicine as a cause of liver disease. PMID:28100990

  12. Hepatic overproduction of 13-HODE due to ALOX15 upregulation contributes to alcohol-induced liver injury in mice

    OpenAIRE

    Zhang, Wenliang; Zhong, Wei; Sun, Qian; Sun, Xinguo; Zhou, Zhanxiang

    2017-01-01

    Chronic alcohol feeding causes lipid accumulation and apoptosis in the liver. This study investigated the role of bioactive lipid metabolites in alcohol-induced liver damage and tested the potential of targeting arachidonate 15-lipoxygenase (ALOX15) in treating alcoholic liver disease (ALD). Results showed that chronic alcohol exposure induced hepatocyte apoptosis in association with increased hepatic 13-HODE. Exposure of 13-HODE to Hepa-1c1c7 cells induced oxidative stress, ER stress and apo...

  13. Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction

    Energy Technology Data Exchange (ETDEWEB)

    Massey, Veronica L. [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Stocke, Kendall S. [Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Schmidt, Robin H.; Tan, Min [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Ajami, Nadim [Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX (United States); Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX (United States); Neal, Rachel E. [Department of Environmental and Occupational Health Sciences, School of Public Health, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Petrosino, Joseph F. [Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX (United States); Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, TX (United States); Barve, Shirish [Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States); Arteel, Gavin E., E-mail: gavin.arteel@louisville.edu [Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States)

    2015-05-01

    Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9 ppm as sodium arsenite) for 10 weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects. - Highlights: • Arsenic (As) enhances liver damage caused by a high-fat (HFD) diet in mice. • Oligofructose protects against As-enhanced liver damage caused by HFD. • As causes dysbiosis in the GI tract and exacerbates the dysbiosis caused by HFD. • OFC prevents the dysbiosis caused by HFD and As, increasing commensal bacteria.

  14. Oligofructose protects against arsenic-induced liver injury in a model of environment/obesity interaction

    International Nuclear Information System (INIS)

    Massey, Veronica L.; Stocke, Kendall S.; Schmidt, Robin H.; Tan, Min; Ajami, Nadim; Neal, Rachel E.; Petrosino, Joseph F.; Barve, Shirish; Arteel, Gavin E.

    2015-01-01

    Arsenic (As) tops the ATSDR list of hazardous environmental chemicals and is known to cause liver injury. Although the concentrations of As found in the US water supply are generally too low to directly damage the liver, subhepatotoxic doses of As sensitize the liver to experimental NAFLD. It is now suspected that GI microbiome dysbiosis plays an important role in development of NALFD. Importantly, arsenic has also been shown to alter the microbiome. The purpose of the current study was to test the hypothesis that the prebiotic oligofructose (OFC) protects against enhanced liver injury caused by As in experimental NAFLD. Male C57Bl6/J mice were fed low fat diet (LFD), high fat diet (HFD), or HFD containing oligofructose (OFC) during concomitant exposure to either tap water or As-containing water (4.9 ppm as sodium arsenite) for 10 weeks. HFD significantly increased body mass and caused fatty liver injury, as characterized by an increased liver weight-to-body weight ratio, histologic changes and transaminases. As observed previously, As enhanced HFD-induced liver damage, which was characterized by enhanced inflammation. OFC supplementation protected against the enhanced liver damage caused by As in the presence of HFD. Interestingly, arsenic, HFD and OFC all caused unique changes to the gut flora. These data support previous findings that low concentrations of As enhance liver damage caused by high fat diet. Furthermore, these results indicate that these effects of arsenic may be mediated, at least in part, by GI tract dysbiosis and that prebiotic supplementation may confer significant protective effects. - Highlights: • Arsenic (As) enhances liver damage caused by a high-fat (HFD) diet in mice. • Oligofructose protects against As-enhanced liver damage caused by HFD. • As causes dysbiosis in the GI tract and exacerbates the dysbiosis caused by HFD. • OFC prevents the dysbiosis caused by HFD and As, increasing commensal bacteria

  15. Potential and Challenges of Induced Pluripotent Stem Cells in Liver Diseases Treatment

    Directory of Open Access Journals (Sweden)

    Yue Yu

    2014-09-01

    Full Text Available Tens of millions of patients are affected by liver disease worldwide. Many of these patients can benefit from cell therapy involving living metabolically active cells, either by treatment of their liver disease, or by prevention of their disease phenotype. Cell therapies, including hepatocyte transplantation and bioartificial liver (BAL devices, have been proposed as therapeutic alternatives to the shortage of transplantable livers. Both BAL and hepatocyte transplantation are cellular therapies that avoid use of a whole liver. Hepatocytes are also widely used in drug screening and liver disease modelling. However, the demand for human hepatocytes, heavily outweighs their availability by conventional means. Induced pluripotent stem cells (iPSCs technology brings together the potential benefits of embryonic stem cells (ESCs (i.e., self-renewal, pluripotency and addresses the major ethical and scientific concerns of ESCs: embryo destruction and immune-incompatibility. It has been shown that hepatocyte-like cells (HLCs can be generated from iPSCs. Furthermore, human iPSCs (hiPSCs can provide an unlimited source of human hepatocytes and hold great promise for applications in regenerative medicine, drug screening and liver diseases modelling. Despite steady progress, there are still several major obstacles that need to be overcome before iPSCs will reach the bedside. This review will focus on the current state of efforts to derive hiPSCs for potential use in modelling and treatment of liver disease.

  16. Zinc supplementation suppresses the progression of bile duct ligation-induced liver fibrosis in mice.

    Science.gov (United States)

    Shi, Fang; Sheng, Qin; Xu, Xinhua; Huang, Wenli; Kang, Y James

    2015-09-01

    Metallothionein (MT) gene therapy leads to resolution of liver fibrosis in mouse model, in which the activation of collagenases is involved in the regression of liver fibrosis. MT plays a critical role in zinc sequestration in the liver suggesting its therapeutic effect would be mediated by zinc. The present study was undertaken to test the hypothesis that zinc supplementation suppresses liver fibrosis. Male Kunming mice subjected to bile duct ligation (BDL) resulted in liver fibrosis as assessed by increased α-smooth muscle actin (α-SMA) and collagen I production/deposition in the liver. Zinc supplementation was introduced 4 weeks after BDL surgery via intragastric administration once daily for 2 weeks resulting in a significant reduction in the collagen deposition in the liver and an increase in the survival rate. Furthermore, zinc suppressed gene expression of α-SMA and collagen I and enhanced the capacity of collagen degradation, as determined by the increased activity of total collagenases and elevated mRNA and protein levels of MMP13. Therefore, the results demonstrate that zinc supplementation suppresses BDL-induced liver fibrosis through both inhibiting collagen production and enhancing collagen degradation. © 2014 by the Society for Experimental Biology and Medicine.

  17. Resveratrol, a Natural Antioxidant, Has a Protective Effect on Liver Injury Induced by Inorganic Arsenic Exposure

    Directory of Open Access Journals (Sweden)

    Zhigang Zhang

    2014-01-01

    Full Text Available Resveratrol (Rev can ameliorate cytotoxic chemotherapy-induced toxicity and oxidative stress. Arsenic trioxide (As2O3 is a known cytotoxic environmental toxicant and a potent chemotherapeutic agent. However, the mechanisms by which resveratrol protects the liver against the cytotoxic effects of As2O3 are not known. Therefore, in the present study we investigated the mechanisms involved in the action of resveratrol using a cat model in which hepatotoxicity was induced by means of As2O3 treatment. We found that pretreatment with resveratrol, administered using a clinically comparable dose regimen, reversed changes in As2O3-induced morphological and liver parameters and resulted in a significant improvement in hepatic function. Resveratrol treatment also improved the activities of antioxidant enzymes and attenuated As2O3-induced increases in reactive oxygen species and malondialdehyde production. In addition, resveratrol attenuated the As2O3-induced reduction in the ratio of reduced glutathione to oxidized glutathione and the retention of arsenic in liver tissue. These findings provide a better understanding of the mechanisms whereby resveratrol modulates As2O3-induced changes in liver function and tissue morphology. They also provide a stronger rationale for the clinical utilization of resveratrol for the reduction of As2O3-induced hepatotoxicity.

  18. Curcumin Attenuates N-Nitrosodiethylamine-Induced Liver Injury in Mice by Utilizing the Method of Metabonomics.

    Science.gov (United States)

    Qiu, Peiyu; Sun, Jiachen; Man, Shuli; Yang, He; Ma, Long; Yu, Peng; Gao, Wenyuan

    2017-03-08

    N-Nitrosodiethylamine (DEN) exists as a food additive in cheddar cheese, processed meats, beer, water, and so forth. It is a potent hepatocarcinogen in animals and humans. Curcumin as a natural dietary compound decreased DEN-induced hepatocarcinogenesis in this research. According to the histopathological examination of liver tissues and biomarker detection in serum and livers, it was demonstrated that curcumin attenuated DEN-induced hepatocarcinogenesis through parts of regulating the oxidant stress enzymes (T-SOD and CAT), liver function (ALT and AST) and LDHA, AFP level, and COX-2/PGE2 pathway. Furthermore, curcumin attenuated metabolic disorders via increasing concentration of glucose and fructose, and decreasing levels of glycine and proline, and mRNA expression of GLUT1, PKM and FASN. Docking study indicated that curcumin presented strong affinity with key metabolism enzymes such as GLUT1, PKM, FASN and LDHA. There were a number of amino acid residues involved in curcumin-targeting enzymes of hydrogen bonds and hydrophobic interactions. All in all, curcumin exhibited a potent liver protective agent inhibiting chemically induced liver injury through suppressing liver cellular metabolism in the prospective application.

  19. Pulmonary Hypoplasia Caused by Fetal Ascites in Congenital Cytomegalovirus Infection Despite Fetal Therapy

    Directory of Open Access Journals (Sweden)

    Kazumichi Fujioka

    2017-11-01

    Full Text Available We report two cases of pulmonary hypoplasia due to fetal ascites in symptomatic congenital cytomegalovirus (CMV infections despite fetal therapy. The patients died soon after birth. The pathogenesis of pulmonary hypoplasia in our cases might be thoracic compression due to massive fetal ascites as a result of liver insufficiency. Despite aggressive fetal treatment, including multiple immunoglobulin administration, which was supposed to diminish the pathogenic effects of CMV either by neutralization or immunomodulatory effects, the fetal ascites was uncontrollable. To prevent development of pulmonary hypoplasia in symptomatic congenital CMV infections, further fetal intervention to reduce ascites should be considered.

  20. Fetal effects of epidermal growth factor deficiency induced in rats by autoantibodies against epidermal growth factor

    DEFF Research Database (Denmark)

    Raaberg, Lasse; Nexø, Ebba; Jørgensen, P E

    1995-01-01

    , the amount of surfactant protein-A was decreased, suggesting a delayed lung maturation. The offspring of EGF-immunized rats had dry and wrinkled skin. The skin was thin and the hair follicles were immature. This suggests a role for EGF in the growth and development of the skin. The liver/body weight ratio...

  1. PHTHALATE ESTER-INDUCED MALFORMATIONS ARE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND STEROID HORMONE PRODUCTION IN THE FETAL RAT TESTIS DURING SEXUAL DIFFERENTIATION

    Science.gov (United States)

    Phthalate ester-induced gubernacular ligament lesions are associated with reduced Insl3 gene expression in the fetal rat testis during sexual differentiation.Vickie S Wilson, Christy Lambright, Johnathan Furr, Joseph Ostby, Carmen Wood, Gary Held, L.Earl Gray Jr.U.S. EPA,...

  2. Turmeric Extract Rescues Ethanol-Induced Developmental Defect in the Zebrafish Model for Fetal Alcohol Spectrum Disorder (FASD).

    Science.gov (United States)

    Muralidharan, Pooja; Connors, Craig T; Mohammed, Arooj S; Sarmah, Swapnalee; Marrs, Kathleen; Marrs, James A; Chism, Grady W

    2017-09-01

    Prenatal ethanol exposure causes the most frequent preventable birth disorder, fetal alcohol spectrum disorder (FASD). The effect of turmeric extracts in rescuing an ethanol-induced developmental defect using zebrafish as a model was determined. Ethanol-induced oxidative stress is one of the major mechanisms underlying FASD. We hypothesize that antioxidant inducing properties of turmeric may alleviate ethanol-induced defects. Curcuminoid content of the turmeric powder extract (5 mg/mL turmeric in ethanol) was determined by UPLC and found to contain Curcumin (124.1 ± 0.2 μg/mL), Desmethoxycurcumin (43.4 ± 0.1 μg/mL), and Bisdemethoxycurcumin (36.6 ± 0.1 μg/mL). Zebrafish embryos were treated with 100 mM (0.6% v/v) ethanol during gastrulation through organogenesis (2 to 48 h postfertilization (hpf)) and supplemented with turmeric extract to obtain total curcuminoid concentrations of 0, 1.16, 1.72, or 2.32 μM. Turmeric supplementation showed significant rescue of the body length at 72 hpf compared to ethanol-treated embryos. The mechanism underlying the rescue remains to be determined. © 2017 Institute of Food Technologists®.

  3. Mouse precision-cut liver slices as an ex vivo model to study idiosyncratic drug-induced liver injury.

    Science.gov (United States)

    Hadi, Mackenzie; Chen, Yixi; Starokozhko, Viktoriia; Merema, Marjolijn T; Groothuis, Geny M M

    2012-09-17

    Idiosyncratic drug-induced liver injury (IDILI) has been the top reason for withdrawing drugs from the market or for black box warnings. IDILI may arise from the interaction of a drug's reactive metabolite with a mild inflammation that renders the liver more sensitive to injury resulting in increased toxicity (inflammatory stress hypothesis). Aiming to develop a robust ex vivo screening method to study inflammatory stress-related IDILI mechanisms and to find biomarkers that can detect or predict IDILI, mouse precision-cut liver slices (mPCLS) were coincubated for 24 h with IDILI-related drugs and lipopolysaccharide. Lipopolysaccharide exacerbated ketoconazole (15 μM) and clozapine (45 μM) toxicity but not their non-IDILI-related comparators, voriconazole (1500 μM) and olanzapine (45 μM). However, the other IDILI-related drugs tested [diclofenac (200 μM), carbamazepine (400 μM), and troglitazone (30 μM)] did not cause synergistic toxicity with lipopolysaccharide after 24 h of incubation. Lipopolysaccharide further decreased the reduced glutathione levels caused by ketoconazole or clozapine in mPCLS after 24 h of incubation, which was not the case for the other drugs. Lipopolysaccharide significantly increased nitric oxide (NO), cytokine, and chemokine release into the mPCLS media, while the treatment with the drugs alone did not cause any substantial change. All seven drugs drastically reduced lipopolysaccharide-induced NO production. Interestingly, only ketoconazole and clozapine increased the lipopolysaccharide-induced granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) release. Pilot experiments showed that diclofenac and troglitazone, but not carbamazepine, demonstrated synergistic toxicity with lipopolysaccharide after a longer incubation of 48 h in mPCLS. In conclusion, we have developed an ex vivo model to detect inflammatory stress-related liver toxicity and identified ketoconazole, clozapine

  4. Maresin 1, a Proresolving Lipid Mediator, Mitigates Carbon Tetrachloride-Induced Liver Injury in Mice

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    Ruidong Li

    2016-01-01

    Full Text Available Maresin 1 (MaR 1 was recently reported to have protective properties in several different animal models of acute inflammation by inhibiting inflammatory response. However, its function in acute liver injury is still unknown. To address this question, we induced liver injury in BALB/c mice with intraperitoneal injection of carbon tetrachloride with or without treatment of MaR 1. Our data showed that MaR 1 attenuated hepatic injury, oxidative stress, and lipid peroxidation induced by carbon tetrachloride, as evidenced by increased thiobarbituric acid reactive substances and reactive oxygen species levels were inhibited by treatment of MaR 1. Furthermore, MaR 1 increased activities of antioxidative mediators in carbon tetrachloride-treated mice liver. MaR 1 decreased indices of inflammatory mediators such as tumor necrosis factor-α, interleukin-6, interleukin-1β, monocyte chemotactic protein 1, myeloperoxidase, cyclooxygenase-2, and inducible nitric oxide synthase. Administration of MaR 1 inhibited activation of nuclear factor kappa B (NF-κb and mitogen-activated protein kinases (MAPKs in the liver of CCl4 treated mice. In conclusion, these results suggested the antioxidative, anti-inflammatory properties of MaR 1 in CCl4 induced liver injury. The possible mechanism is partly implicated in its abilities to inhibit ROS generation and activation of NF-κb and MAPK pathway.

  5. T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury.

    Science.gov (United States)

    Wuillemin, Natascha; Terracciano, Luigi; Beltraminelli, Helmut; Schlapbach, Christoph; Fontana, Stefano; Krähenbühl, Stephan; Pichler, Werner J; Yerly, Daniel

    2014-06-01

    Drug-induced liver injury is a major safety issue. It can cause severe disease and is a common cause of the withdrawal of drugs from the pharmaceutical market. Recent studies have identified the HLA-B(∗)57:01 allele as a risk factor for floxacillin (FLUX)-induced liver injury and have suggested a role for cytotoxic CD8(+) T cells in the pathomechanism of liver injury caused by FLUX. This study aimed to confirm the importance of FLUX-reacting cytotoxic lymphocytes in the pathomechanism of liver injury and to dissect the involved mechanisms of cytotoxicity. IHC staining of a liver biopsy from a patient with FLUX-induced liver injury revealed periportal inflammation and the infiltration of cytotoxic CD3(+) CD8(+) lymphocytes into the liver. The infiltration of cytotoxic lymphocytes into the liver of a patient with FLUX-induced liver injury demonstrates the importance of FLUX-reacting T cells in the underlying pathomechanism. Cytotoxicity of FLUX-reacting T cells from 10 HLA-B(∗)57:01(+) healthy donors toward autologous target cells and HLA-B(∗)57:01-transduced hepatocytes was analyzed in vitro. Cytotoxicity of FLUX-reacting T cells was concentration dependent and required concentrations in the range of peak serum levels after FLUX administration. Killing of target cells was mediated by different cytotoxic mechanisms. Our findings emphasize the role of the adaptive immune system and especially of activated drug-reacting T cells in human leukocyte antigen-associated, drug-induced liver injury. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  6. Alloxan-Induced Diabetes Causes Morphological and Ultrastructural Changes in Rat Liver that Resemble the Natural History of Chronic Fatty Liver Disease in Humans

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    Amanda Natália Lucchesi

    2015-01-01

    Full Text Available Purpose. This study evaluated the long-term effects of alloxan-induced diabetes in rat liver. Methods. Thirty nondiabetic control rats (NC and 30 untreated diabetic (UD rats were divided into three subgroups sacrificed after 6, 14, or 26 weeks. Clinical and laboratory parameters were assessed. Fresh liver weight and its relationship with body weight were obtained, and liver tissue was analyzed. Results. UD rats showed sustained hyperglycemia, high glycosylated hemoglobin, and low plasma insulin. High serum levels of AST and ALT were observed in UD rats after 2 weeks, but only ALT remained elevated throughout the experiment. Fresh liver weight was equal between NC and UD rats, but the fresh liver weight/body weight ratio was significantly higher in UD rats after 14 and 26 weeks. UD rats showed liver morphological changes characterized by hepatic sinusoidal enlargement and micro- and macrovesicular hepatocyte fatty degeneration with progressive liver structure loss, steatohepatitis, and periportal fibrosis. Ultrastructural changes of hepatocytes, such as a decrease in the number of intracytoplasmic organelles and degeneration of mitochondria, rough endoplasmic reticulum, and nuclei, were also observed. Conclusion. Alloxan-induced diabetes triggered liver morphological and ultrastructural changes that closely resembled human disease, ranging from steatosis to steatohepatitis and liver fibrosis.

  7. The relationship between radiation-induced apoptosis and the expression of cytokines in the rat's liver

    International Nuclear Information System (INIS)

    An, Eun Joo; Lee, Kyung Ja; Rhee, Chung Sik

    2000-01-01

    To determine the role of cytokines in the apoptosis of rat's liver following irradiation. Sprague-Dawley rats were irradiated to entire body with a single dose of 8 Gy. The rats were divided into 5 groups according to the sacrifice day after irradiation. The liver and blood after 1, 3, 5, 7, and 14 days irradiation were sampled for evaluation of mechanism of apoptosis and role of cytokine in relation to radiation-induced tissue damage. The study was composed of microscopic evaluation of liver tissue, in situ detection method for apoptosis, immunohistochemical stain of IL-1, IL-4, IL-6 and TNF, bioassay and radioimmunoassay of IL-6 in liver tissue and blood. Radiation-induced liver damage was noted from first day of radiation, and most severe parenchymal damage associated with infiltration of chronic inflammatory cells was seen in the groups of 5 days after radiation. A number of apoptosis were observed 1 day after radiation on both light microscope and in situ method. Afterwards, the number of apoptosis was gradually diminished. On immunohistochemical study, IL-1 and TNF were expressed 1, 3 days after radiation, but not expressed after that. IL-4 was not expressed in the entire groups. IL-6 was expressed with strong positivity in 1, 3 days after radiation. Bioassay and RIA of IL-6 in liver tissue and blood showed the highest value in 1 day after radiation, and the value is diminished after then. Apoptosis seemed to be the important mechanism of radiation-induced liver damage, and is possibly induced by the release of cytokines, such as IL-1, IL-6, TNF in view the simultaneously increased appearance of apoptosis and cytokines

  8. Involvement of immune-related factors in diclofenac-induced acute liver injury in mice

    International Nuclear Information System (INIS)

    Yano, Azusa; Higuchi, Satonori; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-01-01

    Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. However, the underlying mechanism of DILI is little known. It is difficult to predict DILI in humans due to the lack of experimental animal models. Diclofenac, a non-steroidal anti-inflammatory drug rarely causes severe liver injury in human, but there is some evidence for immunoallergic idiosyncratic reactions. In this study, the mechanism of diclofenac-induced liver injury in mice was investigated. First, we established the dosing condition for liver injury in normal mice. Plasma ALT and AST levels were significantly increased in diclofenac-administered (80 mg/kg, i.p.) mice in a dose- and time-dependent manner. Among several interleukins (ILs) and chemokines, mRNA expression of helper T (Th) 17 cell-mediated factors, such as retinoid orphan receptor (ROR)-γt, and signal transducers and activators of transcription factor (STAT) 3 in the liver, and the plasma IL-17 level were significantly increased. Neutralization of IL-17 tended to suppress the hepatotoxicity of diclofenac, suggesting that IL-17 was partly involved. Gadolinium chloride (GdCl 3 ) administration demonstrated that Kupffer cells are not likely to be involved in diclofenac hepatotoxicity. Hepatic expressions of IL-1β mRNA and plasma IL-1β were significantly increased soon after the diclofenac administration. Then, the results of an in vivo neutralization study of IL-1β suggested that IL-1β was involved early in the time of pathogenesis of the diclofenac-induced liver injury. In conclusion, we firstly developed a diclofenac-induced acute liver injury model in normal mice, and the involvement of IL-17 and IL-1β was clarified.

  9. Involvement of immune-related factors in diclofenac-induced acute liver injury in mice.

    Science.gov (United States)

    Yano, Azusa; Higuchi, Satonori; Tsuneyama, Koichi; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2012-03-11

    Drug-induced liver injury (DILI) is a major safety concern in drug development and clinical drug therapy. However, the underlying mechanism of DILI is little known. It is difficult to predict DILI in humans due to the lack of experimental animal models. Diclofenac, a non-steroidal anti-inflammatory drug rarely causes severe liver injury in human, but there is some evidence for immunoallergic idiosyncratic reactions. In this study, the mechanism of diclofenac-induced liver injury in mice was investigated. First, we established the dosing condition for liver injury in normal mice. Plasma ALT and AST levels were significantly increased in diclofenac-administered (80 mg/kg, i.p.) mice in a dose- and time-dependent manner. Among several interleukins (ILs) and chemokines, mRNA expression of helper T (Th) 17 cell-mediated factors, such as retinoid orphan receptor (ROR)-γt, and signal transducers and activators of transcription factor (STAT) 3 in the liver, and the plasma IL-17 level were significantly increased. Neutralization of IL-17 tended to suppress the hepatotoxicity of diclofenac, suggesting that IL-17 was partly involved. Gadolinium chloride (GdCl₃) administration demonstrated that Kupffer cells are not likely to be involved in diclofenac hepatotoxicity. Hepatic expressions of IL-1β mRNA and plasma IL-1β were significantly increased soon after the diclofenac administration. Then, the results of an in vivo neutralization study of IL-1β suggested that IL-1β was involved early in the time of pathogenesis of the diclofenac-induced liver injury. In conclusion, we firstly developed a diclofenac-induced acute liver injury model in normal mice, and the involvement of IL-17 and IL-1β was clarified. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  10. Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease.

    Science.gov (United States)

    Lee, Yun-Hee; Kim, Sou Hyun; Kim, Sang-Nam; Kwon, Hyun-Jung; Kim, Jeong-Dong; Oh, Ji Youn; Jung, Young-Suk

    2016-07-26

    Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease.

  11. Restoration of dioxin-induced damage to fetal steroidogenesis and gonadotropin formation by maternal co-treatment with α-lipoic acid.

    Directory of Open Access Journals (Sweden)

    Takayuki Koga

    Full Text Available 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, an endocrine disruptor, causes reproductive and developmental toxic effects in pups following maternal exposure in a number of animal models. Our previous studies have demonstrated that TCDD imprints sexual immaturity by suppressing the expression of fetal pituitary gonadotropins, the regulators of gonadal steroidogenesis. In the present study, we discovered that all TCDD-produced damage to fetal production of pituitary gonadotropins as well as testicular steroidogenesis can be repaired by co-treating pregnant rats with α-lipoic acid (LA, an obligate co-factor for intermediary metabolism including energy production. While LA also acts as an anti-oxidant, other anti-oxidants; i.e., ascorbic acid, butylated hydroxyanisole and edaravone, failed to exhibit any beneficial effects. Neither wasting syndrome nor CYP1A1 induction in the fetal brain caused through the activation of aryl hydrocarbon receptor (AhR could be attenuated by LA. These lines of evidence suggest that oxidative stress makes only a minor contribution to the TCDD-induced disorder of fetal steroidogenesis, and LA has a restorative effect by targeting on mechanism(s other than AhR activation. Following a metabolomic analysis, it was found that TCDD caused a more marked change in the hypothalamus, a pituitary regulator, than in the pituitary itself. Although the components of the tricarboxylic acid cycle and the ATP content of the fetal hypothalamus were significantly changed by TCDD, all these changes were again rectified by exogenous LA. We also provided evidence that the fetal hypothalamic content of endogenous LA is significantly reduced following maternal exposure to TCDD. Thus, the data obtained strongly suggest that TCDD reduces the expression of fetal pituitary gonadotropins to imprint sexual immaturity or disturb development by suppressing the level of LA, one of the key players serving energy production.

  12. Fasting-induced liver GADD45β restrains hepatic fatty acid uptake and improves metabolic health.

    Science.gov (United States)

    Fuhrmeister, Jessica; Zota, Annika; Sijmonsma, Tjeerd P; Seibert, Oksana; Cıngır, Şahika; Schmidt, Kathrin; Vallon, Nicola; de Guia, Roldan M; Niopek, Katharina; Berriel Diaz, Mauricio; Maida, Adriano; Blüher, Matthias; Okun, Jürgen G; Herzig, Stephan; Rose, Adam J

    2016-06-01

    Recent studies have demonstrated that repeated short-term nutrient withdrawal (i.e. fasting) has pleiotropic actions to promote organismal health and longevity. Despite this, the molecular physiological mechanisms by which fasting is protective against metabolic disease are largely unknown. Here, we show that, metabolic control, particularly systemic and liver lipid metabolism, is aberrantly regulated in the fasted state in mouse models of metabolic dysfunction. Liver transcript assays between lean/healthy and obese/diabetic mice in fasted and fed states uncovered "growth arrest and DNA damage-inducible" GADD45β as a dysregulated gene transcript during fasting in several models of metabolic dysfunction including ageing, obesity/pre-diabetes and type 2 diabetes, in both mice and humans. Using whole-body knockout mice as well as liver/hepatocyte-specific gain- and loss-of-function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity-driven hyperglycaemia. In summary, fasting stress-induced GADD45β represents a liver-specific molecular event promoting adaptive metabolic function. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

  13. Preventive effect of halofuginone on concanavalin A-induced liver fibrosis.

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    Jie Liang

    Full Text Available Halofuginone (HF is an active component of extracts derived from the plant alkaloid febrifugine and has shown therapeutic promise in animal models of fibrotic disease. Our main objectives were to clarify the suppressive effect of HF on concanavalin A (ConA-induced liver fibrosis. ConA injection into the tail vein caused a great increase in the serum aspartate aminotransferase (AST and alanine aminotransferase (ALT levels, while orally administration of HF significantly decreased the levels of the transaminases. In addition, the levels of hyaluronic acid (HA, procollagen III (PCIII and TGF-β1 in the serum and collagen I, α-SMA, tissue inhibitors of metalloproteinase 2 (TIMP2 and Smad3 in the liver tissue were significantly lowered with the treatment of HF. Histological examination also demonstrated that HF significantly reduced the severity of liver fibrosis. Since ConA-induced liver fibrosis is caused by the repeated activation of T cells, immunomodulatory substances might be responsible for the suppressive effect of HF. We found that the production of nuclear factor (NF-kB in the serum was increased in ConA-treated group, while decreased significantly with the treatment of HF. The changes of inflammatory cytokines tumor necrosis factor (TNF-α, IL-6 and IL-1β in the serum followed the same rhythm. All together, our findings indicate that orally administration HF (10ppm would attenuate the liver fibrosis by suppressing the synthesis of collagen I and inflammation-mediated liver injury.

  14. Protection from radiation induced changes in liver and serum transaminase of whole body gamma irradiated rats

    International Nuclear Information System (INIS)

    Elkashef, H.S.; Roushdy, H.M.; Saada, H.N.; Abdelsamie, M.

    1986-01-01

    Whole body gamma irradiation of rats with a dose of 5.5 Gy induced significant changes in the activity of liver and serum transaminase. The results indicated that this radiation dose caused a significant increase in the activity of serum Got and GPT on the third and seventh days after irradiation. This was followed by significant decreases on the fourteenth post-irradiation day. The activity of Got returned to is control activity, while the activity of GPT was significantly above the control on the twenty ones post-irradiation day. The activity of Got, in the liver of irradiated rats was elevated during the post-irradiation days, but on the twenty one day activity was about the normal value. The activity of liver GPT firstly decreased and then increased very much but attained the control level on the fourteenth after irradiation. The intraperitoneal injection of testosterone-vitamin E mixture 10 days before whole body gamma irradiation caused complete recovery for the activity of liver and serum Got. No indication of remarkable recovery in the case of GPT activity was recorded either in liver or in serum of irradiated rats. The applied mixture could protect against radiation induced changes in Got activity of liver and serum but could not protect or ameliorate the changes which occurred in the activity of GPT of the two tissues. 2 tab

  15. Mangosteen peel extract reduces formalin-induced liver cell death in rats

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    Afiana Rohmani

    2014-08-01

    Full Text Available Background Formalin is a xenobiotic that is now commonly used as a preservative in the food industry. The liver is an organ that has the highest metabolic capacity as compared to other organs. Mangosteen or Garcinia mangostana Linn (GML peel contains xanthones, which are a source of natural antioxidants. The purpose of this study was to evaluate the effect of mangosteen peel extract on formalin-induced liver cell mortality rate and p53 protein expression in Wistar rats. Methods Eighteen rats received formalin orally for 2 weeks, and were subsequently divided into 3 groups, consisting of the formalin-control group receiving a placebo and treatment groups 1 and 2, which were treated with mangosteen peel extract at doses of 200 and 400 mg/kgBW/day, respectively. The treatment was carried out for 1 week, and finally the rats were terminated. The differences in liver cell mortality rate and p53 protein expression were analyzed. Results One-way ANOVA analysis showed significant differences in liver cell mortality rate among the three groups (p=0.004. The liver cell mortality rate in the treatment group receiving 400 mg/kgBW/day extract was lower than that in the formalin-control group. There was no p53 expression in all groups. Conclusions Garcinia mangostana Linn peel extract reduced the mortality rate of liver cells in rats receiving oral formalin. Involvement of p53 expression in liver cell mortality in rats exposed to oral formalin is presumably negligible.

  16. Lansoprazole-induced acute lung and liver injury: a case report.

    Science.gov (United States)

    Atkins, Christopher; Maheswaran, Tina; Rushbrook, Simon; Kamath, Ajay

    2014-12-01

    A 61-year old woman was admitted with increasing dyspnea and deranged liver function tests. A chest X-ray revealed small volume lungs with reticulo-nodular shadowing. High resolution computed tomography of the chest revealed interlobular septal thickening. The patient subsequently underwent an open lung biopsy and ultrasound-guided liver biopsy, which were consistent with a hypersensitivity pneumonitis and drug-induced liver injury respectively. The patient had previously been commenced on lansoprazole 10 days before the onset of symptoms; this had been stopped at diagnosis. High dose prednisolone was commenced, and the patient went on to make a full recovery. Hypersensitivity pneumonitis is a form of interstitial lung disease that is rarely associated with lansoprazole; this is the first report of it causing an idiosyncratic reaction affecting the lung and liver simultaneously. This case demonstrates the importance of obtaining a full drug history, as early identification of the offending agent will improve outcomes.

  17. Protective effect of bicyclol on tetracycline-induced fatty liver in mice

    International Nuclear Information System (INIS)

    Yu, Hong-Yan; Wang, Bao-Lian; Zhao, Jing; Yao, Xiao-Min; Gu, Yu; Li, Yan

    2009-01-01

    Peroxisome proliferators-activated receptor α (PPARα) and oxidative stress are two important pathological factors in non-alcoholic fatty liver disease (NAFLD). Tetracycline-induced fatty liver was partly due to the disturbance of mitochondrial fatty acids β-oxidation regulated by PPARα. Bicyclol was found to protect against high fat diet-induced fatty liver through modulating PPARα and clearing reactive oxygen species (ROS). The present study was performed to further investigate the effect of bicyclol on tetracycline-induced fatty liver and related mechanism in mice. Bicyclol (75, 150, 300 mg/kg) was given orally three times in two consecutive days. Tetracycline (200 mg/kg) was injected intraperitoneally 1 h after the last administration of bicyclol. Oxidative stress, mitochondrial function, PPARα and its target genes were evaluated by biochemical and RT-PCR analysis. The activity of CYP4A was assessed by liquid chromatography/mass spectrometry (LC/MS) method. Bicyclol significantly protected against tetracycline-induced fatty liver by reducing the accumulation of hepatic lipids and elevation of serum aminotransferase. In addition, bicyclol remarkably alleviated the over-production of thiobarbituric acid-reactive substance. The reduced activity of mitochondrial respiratory chain (MRC) complexes I and IV and mitochondrial permeability transition (MPT) were also improved by bicyclol. Furthermore, bicyclol inhibited the decrease of PPARα expression and its target genes, including long-chain acyl CoA dehydrogenase (LCAD), acetyl CoA oxidase (AOX) and CYP4A at mRNA and enzyme activity level. Bicyclol protected against tetracycline-induced fatty liver mainly through modulating the disturbance of PPARα pathway and ameliorating mitochondrial function.

  18. Role of nonalcoholic fatty liver disease as risk factor for drug-induced hepatotoxicity

    Science.gov (United States)

    Massart, Julie; Begriche, Karima; Moreau, Caroline; Fromenty, Bernard

    2017-01-01

    Background Obesity is often associated with nonalcoholic fatty liver disease (NAFLD), which refers to a large spectrum of hepatic lesions including fatty liver, nonalcoholic steatohepatitis (NASH) and cirrhosis. Different investigations showed or suggested that obesity and NAFLD are able to increase the risk of hepatotoxicity of different drugs. Some of these drugs could induce more frequently an acute hepatitis in obese individuals whereas others could worsen pre-existing NAFLD. Aim The main objective of the present review was to collect the available information regarding the role of NAFLD as risk factor for drug-induced hepatotoxicity. For this purpose, we performed a data-mining analysis using different queries including drug-induced liver injury (or DILI), drug-induced hepatotoxicity, fatty liver, nonalcoholic fatty liver disease (or NAFLD), steatosis and obesity. The main data from the collected articles are reported in this review and when available, some pathophysiological hypotheses are put forward. Relevance for patients Drugs that could pose a potential risk in obese patients include compounds belonging to different pharmacological classes such as acetaminophen, halothane, methotrexate, rosiglitazone, stavudine and tamoxifen. For some of these drugs, experimental investigations in obese rodents confirmed the clinical observations and unveiled different pathophysiological mechanisms which could explain why these pharmaceuticals are particularly hepatotoxic in obesity and NAFLD. Other drugs such as pentoxifylline, phenobarbital and omeprazole might also pose a risk but more investigations are required to determine whether this risk is significant or not. Because obese people often take several drugs for the treatment of different obesity-related diseases such as type 2 diabetes, hyperlipidemia and coronary heart disease, it is urgent to identify the main pharmaceuticals that can cause acute hepatitis on a fatty liver background or induce NAFLD worsening

  19. Hepatoprotective effect of Forsythiae Fructus water extract against carbon tetrachloride-induced liver fibrosis in mice.

    Science.gov (United States)

    Zhang, Yi; Miao, Hui; Yan, Hongyu; Sheng, Yuchen; Ji, Lili

    2018-05-23

    The fruit of Forsythia suspensa (Thunb.) Vahl, named Forsythiae Fructus (Lian-Qiao), is a well-known traditional Chinese medicine (TCM) used for clearing away heat and toxic material, eliminating the mass and relieving swelling. This study aims to observe the attenuation of the water extract of Forsythiae Fructus (FSE) on carbon tetrachloride (CCl 4 )-induced hepatic fibrosis in male C57BL/6 mice. Hepatic fibrosis was induced in male C57BL/6 mice by intraperitoneal injection with 2 ml/kg CCl 4 (mixed 1: 3 in olive oil) twice a week for 4 weeks. At the same time, the mice were orally given with FSE (1, 2 g/kg) every day for 4 weeks. Serum biochemical parameters, gene and protein expression related to liver fibrosis were analyzed. The contents of forsythiaside A and forsythin in FSE were measured by high-performance liquid chromatography (HPLC). Results of serum alanine/aspartate aminotransferase (ALT/AST) activity and liver histological evaluation both showed the protection of FSE against CCl 4 -induced liver injury. Further, the anti-fibrotic effects of FSE was evidenced by the results of Masson's trichrome and Sirius red staining, liver hydroxyproline content, and serum amounts of hyaluronic acid, laminin, collagen Ⅳ and type III procollagen (PCIII). FSE also reduced the expression of α-smooth muscle actin (α-SMA) in livers from CCl 4 -injured mice. Additionally, FSE decreased the increased hepatic expression of fibroblast-specific protein 1 (FSP1) and vimentin induced by CCl 4 in mice. FSE attenuates CCl 4 -induced liver fibrosis in mice by inhibiting hepatic stellate cells (HSCs) activation, reducing hepatic extracellular matrix (ECM) disposition and reversing epithelial-mesenchymal transition (EMT). Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Hepatoprotective Effect of Opuntia robusta and Opuntia streptacantha Fruits against Acetaminophen-Induced Acute Liver Damage

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    Herson Antonio González-Ponce

    2016-10-01

    Full Text Available Acetaminophen (APAP-induced acute liver failure (ALF is a serious health problem in developed countries. N-acetyl-L-cysteine (NAC, the current therapy for APAP-induced ALF, is not always effective, and liver transplantation is often needed. Opuntia spp. fruits are an important source of nutrients and contain high levels of bioactive compounds, including antioxidants. The aim of this study was to evaluate the hepatoprotective effect of Opuntia robusta and Opuntia streptacantha extracts against APAP-induced ALF. In addition, we analyzed the antioxidant activities of these extracts. Fruit extracts (800mg/kg/day, orally were given prophylactically to male Wistar rats before intoxication with APAP (500 mg/kg, intraperitoneally. Rat hepatocyte cultures were exposed to 20mmol/LAPAP, and necrosis was assessed by LDH leakage. Opuntia robusta had significantly higher levels of antioxidants than Opuntia streptacantha. Both extracts significantly attenuated APAP-induced injury markers AST, ALT and ALP and improved liver histology. The Opuntia extracts reversed APAP-induced depletion of liver GSH and glycogen stores. In cultured hepatocytes, Opuntia extracts significantly reduced leakage of LDH and cell necrosis, both prophylactically and therapeutically. Both extracts appeared to be superior to NAC when used therapeutically. We conclude that Opuntia extracts are hepatoprotective and can be used as a nutraceutical to prevent ALF.

  1. Activation of the baboon fetal hypothalamic-pituitary-adrenocortical axis at midgestation by estrogen-induced changes in placental corticosteroid metabolism

    International Nuclear Information System (INIS)

    Pepe, G.J.; Waddell, B.J.; Albrecht, E.D.

    1990-01-01

    We have hypothesized that the change in placental cortisol (F)-cortisone (E) metabolism induced by estrogen late in gestation is important to activation of the baboon fetal hypothalamic-pituitary-adrenocortical axis, culminating in the ontogenesis of de novo F secretion by the fetal adrenal. The present study tested this hypothesis in vivo by comparing the proportion of F in the fetus derived via maternal and fetal production on day 100 (n = 7; term = day 184) and day 165 (n = 4) in untreated baboons and on day 100 in baboons (n = 9) in which 50-mg pellets of androstenedione were implanted sc in the mother in increasing numbers (i.e. two on day 70, four on day 78, six on day 86, and eight on day 94) to increase placental estrogen production. Maternal, uterine, and umbilical venous samples were collected during constant maternal infusion (120 min) of [3H]F/[14C]E, endogenous and radiolabeled F/E content was determined, and corticosteroid dynamics were quantified. The MCR and peripheral interconversion of F and E as well as the production rate of F were unaltered in the mother. However, at midgestation, androstenedione increased (P less than 0.05) estrogen by 62% and altered transuterofeto placental F-E metabolism from preferential reduction of E to preferential oxidation of F, a pattern similar to that at term. In untreated baboons, on day 100 none of the F in the fetus was due to fetal production, whereas by day 165, 49 +/- 6% was of fetal origin. In animals treated with androstenedione at midgestation, 22 +/- 4% of fetal F was derived de novo within the fetus. Thus, production of F by the fetus was negligible on day 100, increased near term in association with an increase in transplacental oxidation of F to E, and was induced at midgestation in baboons in which placental F-E metabolism was altered by an increase in estrogen production

  2. Vildagliptin Can Alleviate Endoplasmic Reticulum Stress in the Liver Induced by a High Fat Diet.

    Science.gov (United States)

    Ma, Xiaoqing; Du, Wenhua; Shao, Shanshan; Yu, Chunxiao; Zhou, Lingyan; Jing, Fei

    2018-01-01

    Purpose. We investigated whether a DDP-4 inhibitor, vildagliptin, alleviated ER stress induced by a high fat diet and improved hepatic lipid deposition. Methods. C57BL/6 mice received standard chow diet (CD), high fat diet (HFD), and HFD administered with vildagliptin (50 mg/Kg) (V-HFD). After administration for 12 weeks, serum alanine aminotransferase, glucose, cholesterol, triglyceride, and insulin levels were analyzed. Samples of liver underwent histological examination and transmission electron microscopy, real-time PCR for gene expression levels, and western blots for protein expression levels. ER stress was induced in HepG2 cells with palmitic acid and the effects of vildagliptin were investigated. Results. HFD mice showed increased liver weight/body weight (20.27%) and liver triglycerides (314.75%) compared to CD mice, but these decreased by 9.27% and 21.83%, respectively, in V-HFD mice. In the liver, HFD induced the expression of ER stress indicators significantly, which were obviously decreased by vildagliptin. In vitro, the expressions of molecular indicators of ER stress were reduced in HepG2 when vildagliptin was administered. Conclusions. Vildagliptin alleviates hepatic ER stress in a mouse high fat diet model. In HepG2 cells, vildagliptin directly reduced ER stress. Therefore, vildagliptin may be a potential agent for nonalcoholic fatty liver disease.

  3. Vildagliptin Can Alleviate Endoplasmic Reticulum Stress in the Liver Induced by a High Fat Diet

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    Xiaoqing Ma

    2018-01-01

    Full Text Available Purpose. We investigated whether a DDP-4 inhibitor, vildagliptin, alleviated ER stress induced by a high fat diet and improved hepatic lipid deposition. Methods. C57BL/6 mice received standard chow diet (CD, high fat diet (HFD, and HFD administered with vildagliptin (50 mg/Kg (V-HFD. After administration for 12 weeks, serum alanine aminotransferase, glucose, cholesterol, triglyceride, and insulin levels were analyzed. Samples of liver underwent histological examination and transmission electron microscopy, real-time PCR for gene expression levels, and western blots for protein expression levels. ER stress was induced in HepG2 cells with palmitic acid and the effects of vildagliptin were investigated. Results. HFD mice showed increased liver weight/body weight (20.27% and liver triglycerides (314.75% compared to CD mice, but these decreased by 9.27% and 21.83%, respectively, in V-HFD mice. In the liver, HFD induced the expression of ER stress indicators significantly, which were obviously decreased by vildagliptin. In vitro, the expressions of molecular indicators of ER stress were reduced in HepG2 when vildagliptin was administered. Conclusions. Vildagliptin alleviates hepatic ER stress in a mouse high fat diet model. In HepG2 cells, vildagliptin directly reduced ER stress. Therefore, vildagliptin may be a potential agent for nonalcoholic fatty liver disease.

  4. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines.

    Science.gov (United States)

    Zong, L; Yu, Q H; Du, Y X; Deng, X M

    2014-02-01

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  5. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    Energy Technology Data Exchange (ETDEWEB)

    Zong, L. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China); No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Yu, Q. H. [Second Military Medical University, Changhai Hospital, Department of Gastroenterology, Shanghai, China, Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai (China); Du, Y. X. [No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Deng, X. M. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China)

    2014-03-03

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  6. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    Directory of Open Access Journals (Sweden)

    L. Zong

    2014-03-01

    Full Text Available Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN and lipopolysaccharide (LPS in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST and alanine aminotransferase (ALT. Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  7. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    International Nuclear Information System (INIS)

    Zong, L.; Yu, Q.H.; Du, Y.X.; Deng, X.M.

    2014-01-01

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis

  8. Hepatoprotective effect of Phytosome Curcumin against paracetamol-induced liver toxicity in mice

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    Bui Thanh Tung

    2017-04-01

    Full Text Available Abstract Curcuma longa, which contains curcumin as a major constituent, has been shown many pharmacological effects, but it is limited using in clinical due to low bioavailability. In this study, we developed a phytosome curcumin formulation and evaluated the hepatoprotective effect of phytosome curcumin on paracetamol induced liver damage in mice. Phytosome curcumin (equivalent to curcumin 100 and 200 mg/kg body weight and curcumin (200 mg/kg body weight were given by gastrically and toxicity was induced by paracetamol (500 mg/kg during 7 days. On the final day animals were sacrificed and liver function markers (ALT, AST, hepatic antioxidants (SOD, CAT and GPx and lipid peroxidation in liver homogenate were estimated. Our data showed that phytosome has stronger hepatoprotective effect compared to curcumin-free. Administration of phytosome curcumin effectively suppressed paracetamol-induced liver injury evidenced by a reduction of lipid peroxidation level, and elevated enzymatic antioxidant activities of superoxide dismutase, catalase, glutathione peroxidase in mice liver tissue. Our study suggests that phytosome curcumin has strong antioxidant activity and potential hepatoprotective effects.

  9. Aging and radiation induced alternations in liver histones

    International Nuclear Information System (INIS)

    Kozurkova, M.; Misurova, E.; Kropacova, K.

    1994-01-01

    Age-related changes in histones in the liver of normal rats and in rats irradiated with 5.7 Gy gamma rays were examined. Quantitative histone changes in growing and aging rats (from 1 to 28 months of age) were found to be mild only. As they paralleled the DNA changes, the histone /DNA ratio remained stable with age. In total extracted histones there was a decrease in the H1 proportion in older groups with preceding increase in the H1 grad proportion. Thirty minutes after irradiation the amount of histones was reduced with age, probably due to an impaired extractability of histones. As the quantitative DNA changes were milder, the histone?DNA ratio decreased in aging liver after irradiation. Similar patterns of changes in proportion of the H1 fraction and H1 grad sub-fraction were observed in irradiated and nonirradiated animals in the former with an earlier onset. Irradiation, therefore, accelerated spontaneous age-related alternations. (author)

  10. Hepatoprotective Effect of Trigona spp. Bee Propolis against Carbon Tetrachloride-Induced Liver Injury in Rat

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    Rachel Amelia

    2016-06-01

    Full Text Available Background: Oxidative stress reaction can cause liver injury. This process can be prevented by antioxidant activities which can break the destructive chain caused by free radical substances in the liver. Propolis produced by Trigona spp. bee is known to have a high level of antioxidant. The aim of this study was to examine the effect of Trigona spp. bee propolis on liver histological toxicity caused by carbon tetrachloride-induced oxidative stress. Methods:This experimental study was conducted in September 2013 at the Animal Laboratory of Departement of Pharmacology and Therapy, Faculty of Medicine Universitas Padjadjaran. Twenty-four healthy male Wistar rats as objects were adapted for one week and randomly divided into 3 groups. Group I was the control negative, group II was given carbon tetrachloride on day 14, group III was given Trigona spp. bee propolis on day 1-14. On day 14, group III was injected CCl4 intraperitoneally. The quantitative data were statistically analyzed using the one way ANOVA and Tukey test with p value < 0.05. Results: Group I showed the liver contained normal cells, without significant injury of the membrane, round and complete nucleus. The average number of liver cell was 464 ± 9.59281 cells/field; group II underwent necrosis and the average of the cells was 146 ± 7.56885 cells/field; group III showed some normal liver cells, and some necrotic area with the normal liver cells average was 263 ± 14.10860 cells/field. The p-value=0.00. Conclusions: Trigona spp. bee propolis has a hepatoprotective effect against CCl4-induced liver injury histologically.

  11. JNK1 induces hedgehog signaling from stellate cells to accelerate liver regeneration in mice.

    Science.gov (United States)

    Langiewicz, Magda; Graf, Rolf; Humar, Bostjan; Clavien, Pierre A

    2018-04-27

    To improve outcomes of two-staged hepatectomies for large/multiple liver tumors, portal vein ligation (PVL) has been combined with parenchymal transection (coined ALPPS; Associated Liver Partition and Portal vein ligation for Staged hepatectomy) to greatly accelerate liver regeneration. In a novel ALPPS mouse model, we have reported paracrine Indian hedgehog (IHH) signaling from stellate cells as an early contributor to augmented regeneration. Here, we sought to identify upstream regulators of IHH. ALPPS in mice was compared against PVL and additional control surgeries. Potential IHH regulators were identified through in silico mining of transcriptomic data. JNK1 activity was reduced through SP600125 to evaluate its effects on IHH signaling. Recombinant IHH was injected after JNK diminution to substantiate their relationship during accelerated liver regeneration. Mining linked Ihh to Mapk8. JNK1 upregulation after ALPPS was validated and preceded the IHH peak. On immunofluorescence, JNK1 and IHH co-localized in ASMA-positive non-parenchymal cells. Inhibition of JNK1 prior to ALPPS surgery reduced liver weight gain to PVL levels and was accompanied by downregulation of hepatocellular proliferation and the IHH-GLI1-CCND1 axis. In JNK1-inhibited mice, recombinant IHH restored ALPPS-like acceleration of regeneration and re-elevated JNK1 activity, suggesting the presence of a positive IHH-JNK1 feedback loop. JNK1-mediated induction of IHH paracrine signaling from HSCs is essential for accelerated regeneration of parenchymal mass. The JNK1-IHH axis is a mechanism unique to ALPPS surgery and may point to therapeutic alternatives for patients with insufficient regenerative capacity. ALPPS, a novel two-staged hepatectomy, induces an unprecedented acceleration of liver regeneration to enable treatment of unresectable liver tumors. Here, we demonstrate JNK1-IHH signaling as a mechanism underlying the regenerative acceleration induced by ALPPS. Copyright © 2018 European

  12. Liver Immunology

    Science.gov (United States)

    Bogdanos, Dimitrios P.; Gao, Bin; Gershwin, M. Eric

    2014-01-01

    The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity. PMID:23720323

  13. Characterization of chemically induced liver injuries using gene co-expression modules.

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    Gregory J Tawa

    Full Text Available Liver injuries due to ingestion or exposure to chemicals and industrial toxicants pose a serious health risk that may be hard to assess due to a lack of non-invasive diagnostic tests. Mapping chemical injuries to organ-specific damage and clinical outcomes via biomarkers or biomarker panels will provide the foundation for highly specific and robust diagnostic tests. Here, we have used DrugMatrix, a toxicogenomics database containing organ-specific gene expression data matched to dose-dependent chemical exposures and adverse clinical pathology assessments in Sprague Dawley rats, to identify groups of co-expressed genes (modules specific to injury endpoints in the liver. We identified 78 such gene co-expression modules associated with 25 diverse injury endpoints categorized from clinical pathology, organ weight changes, and histopathology. Using gene expression data associated with an injury condition, we showed that these modules exhibited different patterns of activation characteristic of each injury. We further showed that specific module genes mapped to 1 known biochemical pathways associated with liver injuries and 2 clinically used diagnostic tests for liver fibrosis. As such, the gene modules have characteristics of both generalized and specific toxic response pathways. Using these results, we proposed three gene signature sets characteristic of liver fibrosis, steatosis, and general liver injury based on genes from the co-expression modules. Out of all 92 identified genes, 18 (20% genes have well-documented relationships with liver disease, whereas the rest are novel and have not previously been associated with liver disease. In conclusion, identifying gene co-expression modules associated with chemically induced liver injuries aids in generating testable hypotheses and has the potential to identify putative biomarkers of adverse health effects.

  14. Diet-induced metabolic hamster model of nonalcoholic fatty liver disease

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    Bhathena J

    2011-06-01

    Full Text Available Jasmine Bhathena, Arun Kulamarva, Christopher Martoni, Aleksandra Malgorzata Urbanska, Meenakshi Malhotra, Arghya Paul, Satya PrakashBiomedical Technology and Cell Therapy Research Laboratory, Department of Biomedical Engineering, Artificial Cells and Organs Research Centre, Faculty of Medicine, McGill University, Montreal, Québec, CanadaBackground: Obesity, hypercholesterolemia, elevated triglycerides, and type 2 diabetes are major risk factors for metabolic syndrome. Hamsters, unlike rats or mice, respond well to diet-induced obesity, increase body mass and adiposity on group housing, and increase food intake due to social confrontation-induced stress. They have a cardiovascular and hepatic system similar to that of humans, and can thus be a useful model for human pathophysiology.Methods: Experiments were planned to develop a diet-induced Bio F1B Golden Syrian hamster model of dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hamsters were fed a normal control diet, a high-fat/high-cholesterol diet, a high-fat/high-cholesterol/methionine-deficient/choline-devoid diet, and a high-fat/high-cholesterol/choline-deficient diet. Serum total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, atherogenic index, and body weight were quantified biweekly. Fat deposition in the liver was observed and assessed following lipid staining with hematoxylin and eosin and with oil red O.Results: In this study, we established a diet-induced Bio F1B Golden Syrian hamster model for studying dyslipidemia and associated nonalcoholic fatty liver disease in the metabolic syndrome. Hyperlipidemia and elevated serum glucose concentrations were induced using this diet. Atherogenic index was elevated, increasing the risk for a cardiovascular event. Histological analysis of liver specimens at the end of four weeks showed increased fat deposition in the liver of animals fed

  15. Increasing fetal ovine number per gestation alters fetal plasma clinical chemistry values.

    Science.gov (United States)

    Zywicki, Micaela; Blohowiak, Sharon E; Magness, Ronald R; Segar, Jeffrey L; Kling, Pamela J

    2016-08-01

    Intrauterine growth restriction (IUGR) is interconnected with developmental programming of lifelong pathophysiology. IUGR is seen in human multifetal pregnancies, with stepwise rises in fetal numbers interfering with placental nutrient delivery. It remains unknown whether fetal blood analyses would reflect fetal nutrition, liver, and excretory function in the last trimester of human or ovine IUGR In an ovine model, we hypothesized that fetal plasma biochemical values would reflect progressive placental, fetal liver, and fetal kidney dysfunction as the number of fetuses per gestation rose. To determine fetal plasma biochemical values in singleton, twin, triplet, and quadruplet/quintuplet ovine gestation, we investigated morphometric measures and comprehensive metabolic panels with nutritional measures, liver enzymes, and placental and fetal kidney excretory measures at gestational day (GD) 130 (90% gestation). As anticipated, placental dysfunction was supported by a stepwise fall in fetal weight, fetal plasma glucose, and triglyceride levels as fetal number per ewe rose. Fetal glucose and triglycerides were directly related to fetal weight. Plasma creatinine, reflecting fetal renal excretory function, and plasma cholesterol, reflecting placental excretory function, were inversely correlated with fetal weight. Progressive biochemical disturbances and growth restriction accompanied the rise in fetal number. Understanding the compensatory and adaptive responses of growth-restricted fetuses at the biochemical level may help explain how metabolic pathways in growth restriction can be predetermined at birth. This physiological understanding is important for clinical care and generating interventional strategies to prevent altered developmental programming in multifetal gestation. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  16. Reference intervals for putative biomarkers of drug-induced liver injury and liver regeneration in healthy human volunteers.

    Science.gov (United States)

    Francis, Ben; Clarke, Joanna I; Walker, Lauren E; Brillant, Nathalie; Jorgensen, Andrea L; Park, B Kevin; Pirmohamed, Munir; Antoine, Daniel J

    2018-05-02

    The potential of mechanistic biomarkers to improve the prediction of drug-induced liver injury (DILI) and hepatic regeneration is widely acknowledged. We sought to determine reference intervals for new biomarkers of DILI and regeneration as well as to characterize their natural variability and impact of diurnal variation. Serum samples from 200 healthy volunteers were recruited as part of a cross sectional study; of these, 50 subjects had weekly serial sampling over 3 weeks, while 24 had intensive blood sampling over a 24h period. Alanine aminotransferase (ALT), MicroRNA-122 (miR-122), high mobility group box-1 (HMGB1), total keratin-18 (FL-K18), caspase cleaved keratin-18 (cc-K18), glutamate dehydrogenase (GLDH) and colony stimulating factor-1 (CSF-1) were assessed by validated assays. Reference intervals were established for each biomarker based on the 97.5% quantile (90% CI) following the assessment of fixed effects in univariate and multivariable models (ALT 50 (41-50) U/l, miR-122 3548 (2912-4321) copies/µl, HMGB1 2.3 (2.2-2.4) ng/ml, FL-K18 475 (456-488) U/l, cc-K18 272 (256-291) U/l, GLDH 27 (26-30) U/l and CSF-1 2.4 (2.3-2.9) ng/ml). There was a small but significant intra-individual time random effect detected but no significant impact of diurnal variation was observed, with the exception of GLDH. Reference intervals for novel DILI biomarkers have been described for the first time. An upper limit of a reference range might represent the most appropriate method to utilize these data. Regulatory authorities have published letters of support encouraging further qualification of leading candidate biomarkers. These data can now be used to interpret data from exploratory clinical DILI studies and to assist their further qualification. Drug-induced liver injury (DILI) has a big impact on patient health and the development of new medicines. Unfortunately, currently used blood-based tests to assess liver injury and recovery suffer from insufficiencies. Newer blood

  17. Perfluoroalkyl acids-induced liver steatosis: Effects on genes controlling lipid homeostasis

    International Nuclear Information System (INIS)

    Das, Kaberi P.; Wood, Carmen R.; Lin, Mimi T.; Starkov, Anatoly A.; Lau, Christopher; Wallace, Kendall B.; Corton, J. Christopher; Abbott, Barbara D.

    2017-01-01

    Highlights: • Structurally diverse PFAAs induced fatty liver and increased TG accumulation in mouse. • Genes of lipid synthesis and degradation were increased after exposure to PFAAs. • PFAAs did not inhibit either mitochondrial fatty acid transport or β-oxidation directly. - Abstract: Persistent presence of perfluoroalkyl acids (PFAAs) in the environment is due to their extensive use in industrial and consumer products, and their slow decay. Biochemical tests in rodent demonstrated that these chemicals are potent modifiers of lipid metabolism and cause hepatocellular steatosis. However, the molecular mechanism of PFAAs interference with lipid metabolism remains to be elucidated. Currently, two major hypotheses are that PFAAs interfere with mitochondrial beta-oxidation of fatty acids and/or they affect the transcriptional activity of peroxisome proliferator-activated receptor α (PPARα) in liver. To determine the ability of structurally-diverse PFAAs to cause steatosis, as well as to understand the underlying molecular mechanisms, wild-type (WT) and PPARα-null mice were treated with perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), or perfluorohexane sulfonate (PFHxS), by oral gavage for 7 days, and their effects were compared to that of PPARα agonist WY-14643 (WY), which does not cause steatosis. Increases in liver weight and cell size, and decreases in DNA content per mg of liver, were observed for all compounds in WT mice, and were also seen in PPARα-null mice for PFOA, PFNA, and PFHxS, but not for WY. In Oil Red O stained sections, WT liver showed increased lipid accumulation in all treatment groups, whereas in PPARα-null livers, accumulation was observed after PFNA and PFHxS treatment, adding to the burden of steatosis observed in control (untreated) PPARα-null mice. Liver triglyceride (TG) levels were elevated in WT mice by all PFAAs and in PPARα-null mice only by PFNA. In vitro β-oxidation of palmitoyl carnitine by isolated rat

  18. Effect of WeiJia on carbon tetrachloride induced chronic liver injury

    Science.gov (United States)

    Cheung, Pik-Yuen; Zhang, Qi; Zhang, Ya-Ou; Bai, Gan-Rong; Lin, Marie Chia-Mi; Chan, Bernard; Fong, Chi-Chun; Shi, Lin; Shi, Yue-Feng; Chun, Jay; Kung, Hsiang-Fu; Yang, Mengsu

    2006-01-01

    AIM: To study the effect of WeiJia on chronic liver injury using carbon tetrachloride (CCl4) induced liver injury animal model. METHODS: Wistar rats weighing 180-220g were randomly divided into three groups: normal control group (Group A), CCl4 induced liver injury control group (Group B) and CCl4 induction with WeiJia treatment group (Group C). Each group consisted of 14 rats. Liver damage and fibrosis was induced by subcutaneous injection with 40% CCl4 in olive oil at 3 mL/kg body weight twice a week for eight weeks for Groups B and C rats whereas olive oil was used for Group A rats. Starting from the third week, Group C rats also received daily intraperitoneal injection of WeiJia at a dose of 1.25 μg/kg body weight. Animals were sacrificed at the fifth week (4 male, 3 female), and eighth week (4 male, 3 female) respectively. Degree of fibrosis were measured and serological markers for liver fibrosis and function including hyaluronic acid (HA), type IV collagen (CIV), γ-glutamyl transferase (γ-GT), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were determined. Alpha smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA) immunohistochemistry were also performed. RESULTS: CCl4 induction led to the damage of liver and development of fibrosis in Group B and Group C rats when compared to Group A rats. The treatment of WeiJia in Group C rats could reduce the fibrosis condition significantly compared to Group B rats. The effect could be observed after three weeks of treatment and was more obvious after eight weeks of treatment. Serum HA, CIV, ALT, AST and γ-GT levels after eight weeks of treatment for Group C rats were 58±22 µg/L (P0.05) respectively, similar to normal control group (Group A), but significantly different from CCl4 induced liver injury control group (Group B). An increase in PCNA and decrease in α-SMA expression level was also observed. CONCLUSION: WeiJia could improve liver function and reduce liver

  19. Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury

    DEFF Research Database (Denmark)

    Schmidt, Lars E; Dalhoff, Kim

    2005-01-01

    An increase in alpha-fetoprotein (AFP) following hepatic necrosis is considered indicative of hepatic regeneration. This study evaluated the prognostic value of serial AFP measurements in patients with severe acetaminophen-induced liver injury. Prospectively, serial measurements of AFP were...

  20. Protection effect of piper betel leaf extract against carbon tetrachloride-induced liver fibrosis in rats.

    Science.gov (United States)

    Young, Shun-Chieh; Wang, Chau-Jong; Lin, Jing-Jing; Peng, Pei-Ling; Hsu, Jui-Ling; Chou, Fen-Pi

    2007-01-01

    Piper betel leaves (PBL) are used in Chinese folk medicine for the treatment of various disorders. PBL has the biological capabilities of detoxication, antioxidation, and antimutation. In this study, we evaluated the antihepatotoxic effect of PBL extract on the carbon tetrachloride (CCl(4))-induced liver injury in a rat model. Fibrosis and hepatic damage, as reveled by histology and the activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were induced in rats by an administration of CCl(4) (8%, 1 ml/kg body weight) thrice a week for 4 weeks. PBL extract significantly inhibited the elevated AST and ALT activities caused by CCl(4) intoxication. It also attenuated total glutathione S-transferase (GST) activity and GST alpha isoform activity, and on the other hand, enhanced superoxide dismutase (SOD) and catalase (CAT) activities. The histological examination showed the PBL extract protected liver from the damage induced by CCl(4) by decreasing alpha-smooth muscle actin (alpha-sma) expression, inducing active matrix metalloproteinase-2 (MMP2) expression though Ras/Erk pathway, and inhibiting TIMP2 level that consequently attenuated the fibrosis of liver. The data of this study support a chemopreventive potential of PBL against liver fibrosis.

  1. Study on bone marrow mesenchymal stem cells in repairing of radiation induced acute liver injury of rats

    International Nuclear Information System (INIS)

    Bao Yongxing; Lou Fan; Zhao Huarong; Zhu Huhu; Ma Yan; Wen Hao

    2010-01-01

    Objective: To investigate the role of mesenchymal stem cells in the repair of radiation induced liver injury. Methods: 12 female SD rats were irradiated with 20 Gy 6 MV X-rays on the right lobe of the liver, to establish the model of radiation induced liver injury. The rats were divided randomly into two groups as invention group and control group, and transplanted with 1 ml male mesenchymal suspension or 1 ml normal saline in 4 hours after radiotherapy. The morphological changes of liver were observed. The existence of sex determining gene Y(SRY) and the level of alpha-smooth muscle actin (a-SMA) were detected. Results: Some injury of right lobe liver in two groups were observed, and the injury degree of right lobe liver in intervention group were lower than that of control group. The amount of SRY positive cells in the right lobe liver of intervention group was higher than that in the left lobe liver (t = 3.77, P <0.05). The positive expression rate of a-SMA in right lobe liver of intervention group was lower than that of control group. Conclusions: Acute radiation induced liver injury could lead BMSCs' homing in order to decrease the degree of liver fibrosis. (authors)

  2. Role of hypoxia inducing factor-1β in alcohol-induced autophagy, steatosis and liver injury in mice.

    Directory of Open Access Journals (Sweden)

    Hong-Min Ni

    Full Text Available Chronic alcohol causes liver hypoxia and steatosis, which eventually develops into alcoholic liver disease (ALD. While it has been known that alcohol consumption activates hepatic hypoxia inducing factor-1α (HIF-1α, conflicting results regarding the role of HIF-1α in alcohol-induced liver injury and steatosis in mice have been reported. In the present study, we aimed to use hepatocyte-specific HIF-1β knockout mice to eliminate the possible compensatory effects of the single knockout of the 1α subunit of HIF to study the role of HIFs in ALD. C57BL/6 wild type mice were treated with acute ethanol to mimic human binge drinking. Matched wild-type and hepatocyte specific HIF-1β knockout mice were also subjected to a recently established Gao-binge alcohol model to mimic chronic plus binge conditions, which is quite common in human alcoholics. We found that acute alcohol treatment increased BNIP3 and BNIP3L/NIX expression in primary cultured hepatocytes and in mouse livers, suggesting that HIF may be activated in these models. We further found that hepatocyte-specific HIF-1β knockout mice developed less steatosis and liver injury following the Gao-binge model or acute ethanol treatment compared with their matched wild type mice. Mechanistically, protection against Gao-binge treatment-induced steatosis and liver injury was likely associated with increased FoxO3a activation and subsequent induction of autophagy in hepatocyte-specific HIF-1β knockout mice.

  3. The Protective Role of Zinc Sulphate on Ethanol -Induced Liver and Kidney Damages in Rats

    International Nuclear Information System (INIS)

    Al-Damegh, Mona Abdalla

    2007-01-01

    Around the world more and more people suffer from alcoholism. Addiction problems, alcoholism and excessive use of drugs both medical and nonmedical, are major causes of liver and kidney damage in adults. The purpose of this study was to investigate on the protective role of zinc sulphate on liver and kidney in rats with acute alcoholism. Wistar albino rats were divided into four groups. Group I; control group, group 2; given only Zinc Sulphate (100 mg/kg/day for 3days), group 3; rats given absolute ethanol (1 ml of absolute ethanol administrated by gavage technique to each rat), group 4 given Zinc sulphate prior to the administration of absolute ethanol. The results of this study revealed that acute ethanol exposure caused degenerative morphological changes in the liver and kidney. Significant difference were found in the levels of serum, liver, kidney super oxide dismutase(SOD), catalase (CAT), nitric oxide(NO), and malondialdehyde (MDA) in the ethanol group compared to the control group. Moreover ,serum urea, creatnine, uric acid, alkaline phoshpatase and transaminases activities (GOTand GPT) were increased in the ethanol group compared to the control group. On the other hand,administration of zinc sulphate in the ethanol group caused a significant decrease in the degenerative changes, lipid peroxidation, antioxidant enzymes, and nitric oxide in serum, liver, and kidney. It can be concluded that zinc Sulphate has a protective role on the ethanol induced liver and kidney injury. In addition ,nitric oxide is involved in the mechanism of acute alcohol intoxication. (author)

  4. Risk assessment of silica nanoparticles on liver injury in metabolic syndrome mice induced by fructose.

    Science.gov (United States)

    Li, Jianmei; He, Xiwei; Yang, Yang; Li, Mei; Xu, Chenke; Yu, Rong

    2018-07-01

    This study aims to assess the effects and the mechanisms of silica nanoparticles (SiNPs) on hepatotoxicity in both normal and metabolic syndrome mouse models induced by fructose. Here, we found that SiNPs exposure lead to improved insulin resistance in metabolic syndrome mice, but markedly worsened hepatic ballooning, inflammation infiltration, and fibrosis. Moreover, SiNPs exposure aggravated liver injury in metabolic syndrome mice by causing serious DNA damage. Following SiNPs exposure, liver superoxide dismutase and catalase activities in metabolic syndrome mice were stimulated, which is accompanied by significantly increased malondialdehyde and 8-hydroxy-2-deoxyguanosine levels as compared to normal mice. Scanning electron microscope (SEM) revealed that SiNPs were more readily deposited in the liver mitochondria of metabolic syndrome mice, resulting in more severe mitochondrial injury as compared to normal mice. We speculated that SiNPs-induced mitochondrial injury might be the cause of hepatic oxidative stress, which further lead to a series of liver lesions as observed in mice following SiNPs exposure. Based on these results, it is likely that SiNPs will increase the risk and severity of liver disease in individuals with metabolic syndrome. Therefore, SiNPs should be used cautiously in food additives and clinical settings. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: a systematic review.

    Science.gov (United States)

    Wang, Ran; Qi, Xingshun; Yoshida, Eric M; Méndez-Sánchez, Nahum; Teschke, Rolf; Sun, Mingyu; Liu, Xu; Su, Chunping; Deng, Jiao; Deng, Han; Hou, Feifei; Guo, Xiaozhong

    2018-04-01

    Traditional Chinese medicine (TCM) is becoming increasingly popular and related adverse events are often ignored or underestimated. This systematic review aimed to evaluate the clinical characteristics and outcomes of TCM-induced liver injury (TCM-ILI) and to estimate the proportion of TCM-ILI in all drug-induced liver injuries (DILI). China National Knowledge Infrastructure, Wanfang, VIP, PubMed, and Embase databases were searched. Demographic, clinical, and survival data were extracted and pooled. Factors associated with worse outcomes were calculated. For the proportion meta-analyses, the data were pooled by using a random-effects model. Overall, 21,027 articles were retrieved, of which 625 were finally included. There was a predominance of female and older patients. The proportion of liver transplantation was 2.18% (7/321). The mortality was 4.67% (15/321). Male, higher aspartate aminotransferase and direct bilirubin, and lower albumin were significantly associated with an increased risk of death/liver transplantation in TCM-ILI patients. The proportion of TCM-ILI in all DILI was 25.71%. The proportion was gradually increased with year. Our work summarises current knowledge regarding clinical presentation, disease course, and prognosis of TCM-ILI. TCM can result in hepatotoxicity, even death or necessitate life-saving liver transplantation. Governmental regulation of TCM products should be strictly established.

  6. Gal-3 regulates the capacity of dendritic cells to promote NKT-cell-induced liver injury.

    Science.gov (United States)

    Volarevic, Vladislav; Markovic, Bojana Simovic; Bojic, Sanja; Stojanovic, Maja; Nilsson, Ulf; Leffler, Hakon; Besra, Gurdyal S; Arsenijevic, Nebojsa; Paunovic, Verica; Trajkovic, Vladimir; Lukic, Miodrag L

    2015-02-01

    Galectin-3 (Gal-3), an endogenous lectin, exhibits pro- and anti-inflammatory effects in various disease conditions. In order to explore the role of Gal-3 in NKT-cell-dependent pathology, we induced hepatitis in C57BL/6 WT and Gal-3-deficient mice by using specific ligand for NKT cells: α-galactosylceramide, glycolipid Ag presented by CD1d. The injection of α-galactosylceramide significantly enhanced expression of Gal-3 in liver NKT and dendritic cells (DCs). Genetic deletion or selective inhibition of Gal-3 (induced by Gal-3-inhibitor TD139) abrogated the susceptibility to NKT-cell-dependent hepatitis. Blood levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12) and their production by liver DCs and NKT cells were also downregulated. Genetic deletion or selective inhibition of Gal-3 alleviated influx of inflammatory CD11c(+) CD11b(+) DCs in the liver and favored tolerogenic phenotype and IL-10 production of liver NKT and DCs. Deletion of Gal-3 attenuated the capacity of DCs to support liver damage in the passive transfer experiments and to produce pro-inflammatory cytokines in vitro. Gal-3-deficient DCs failed to optimally stimulate production of pro-inflammatory cytokines in NKT cells, in vitro and in vivo. In conclusion, Gal-3 regulates the capacity of DCs to support NKT-cell-mediated liver injury, playing an important pro-inflammatory role in acute liver injury. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. Opposite Expression of SPARC between the Liver and Pancreas in Streptozotocin-Induced Diabetic Rats.

    Directory of Open Access Journals (Sweden)

    Kanikkai Raja Aseer

    Full Text Available Secreted protein acidic and rich in cysteine (SPARC is a matricellular protein that regulates several cellular events, including inflammation and tissue remodelling. In this study, we investigated the tissue-specific expression of SPARC in streptozotocin (STZ-induced diabetes, and found that SPARC was significantly up-regulated in the liver while down-regulated in the pancreas of STZ-induced diabetic rats. Chronic inflammation occurred in the diabetic pancreas accompanied by up-regulation of CCAAT/enhancer-binding protein beta (C/EBPβ and its targets (TNFα, Il6, CRP, and Fn1 as well as myeloperoxidase (Mpo and C-X-C chemokine receptor type 2 (Cxcr2. Diabetic liver showed significant up-regulation of Tgfb1 as well as moderately less up-regulated TNFα and reduced Fn1, resulting in elevated fibrogenesis. PARP-1 was not up-regulated during CD95-mediated apoptosis, resulting in restoration of high ATP levels in the diabetic liver. On the contrary, CD95-dependent apoptosis was not observed in the diabetic pancreas due to up-regulation of PARP-1 and ATP depletion, resulting in necrosis. The cytoprotective machinery was damaged by pancreatic inflammation, whereas adequate antioxidant capacity indicates low oxidative stress in the diabetic liver. High and low cellular insulin content was found in the diabetic liver and pancreas, respectively. Furthermore, we identified six novel interacting partner proteins of SPARC by co-immunoprecipitation in the diabetic liver and pancreas, and their interactions with SPARC were predicted by bioinformatics tools. Taken together, opposite expression of SPARC in the diabetic liver and pancreas may be related to inflammation and immune cell infiltration, degrees of apoptosis and fibrosis, cytoprotective machinery, and cellular insulin levels.

  8. Determination of aluminium induced metabolic changes in mice liver: a Fourier transform infrared spectroscopy study.

    Science.gov (United States)

    Sivakumar, S; Sivasubramanian, J; Khatiwada, Chandra Prasad; Manivannan, J; Raja, B

    2013-06-01

    In this study, we made a new approach to evaluate aluminium induced metabolic changes in liver tissue of mice using Fourier transform infrared spectroscopy analysis taking one step further in correlation with strong biochemical evidence. This finding reveals the alterations on the major biochemical constituents, such as lipids, proteins, nucleic acids and glycogen of the liver tissues of mice. The peak area value of amide A significantly decrease from 288.278±3.121 to 189.872±2.012 between control and aluminium treated liver tissue respectively. Amide I and amide II peak area value also decrease from 40.749±2.052 to 21.170±1.311 and 13.167±1.441 to 8.953±0.548 in aluminium treated liver tissue respectively. This result suggests an alteration in the protein profile. The absence of olefinicCH stretching band and CO stretching of triglycerides in aluminium treated liver suggests an altered lipid levels due to aluminium exposure. Significant shift in the peak position of glycogen may be the interruption of aluminium in the calcium metabolism and the reduced level of calcium. The overall findings exhibit that the liver metabolic program is altered through increasing the structural modification in proteins, triglycerides and quantitative alteration in proteins, lipids, and glycogen. All the above mentioned modifications were protected in desferrioxamine treated mice. Histopathological results also revealed impairment of aluminium induced alterations in liver tissue. The results of the FTIR study were found to be in agreement with biochemical studies and which demonstrate FTIR can be used successfully to indicate the molecular level changes. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Opposite Expression of SPARC between the Liver and Pancreas in Streptozotocin-Induced Diabetic Rats

    Science.gov (United States)

    Aseer, Kanikkai Raja; Kim, Sang Woo; Choi, Myung-Sook; Yun, Jong Won

    2015-01-01

    Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates several cellular events, including inflammation and tissue remodelling. In this study, we investigated the tissue-specific expression of SPARC in streptozotocin (STZ)-induced diabetes, and found that SPARC was significantly up-regulated in the liver while down-regulated in the pancreas of STZ-induced diabetic rats. Chronic inflammation occurred in the diabetic pancreas accompanied by up-regulation of CCAAT/enhancer-binding protein beta (C/EBPβ) and its targets (TNFα, Il6, CRP, and Fn1) as well as myeloperoxidase (Mpo) and C-X-C chemokine receptor type 2 (Cxcr2). Diabetic liver showed significant up-regulation of Tgfb1 as well as moderately less up-regulated TNFα and reduced Fn1, resulting in elevated fibrogenesis. PARP-1 was not up-regulated during CD95-mediated apoptosis, resulting in restoration of high ATP levels in the diabetic liver. On the contrary, CD95-dependent apoptosis was not observed in the diabetic pancreas due to up-regulation of PARP-1 and ATP depletion, resulting in necrosis. The cytoprotective machinery was damaged by pancreatic inflammation, whereas adequate antioxidant capacity indicates low oxidative stress in the diabetic liver. High and low cellular insulin content was found in the diabetic liver and pancreas, respectively. Furthermore, we identified six novel interacting partner proteins of SPARC by co-immunoprecipitation in the diabetic liver and pancreas, and their interactions with SPARC were predicted by bioinformatics tools. Taken together, opposite expression of SPARC in the diabetic liver and pancreas may be related to inflammation and immune cell infiltration, degrees of apoptosis and fibrosis, cytoprotective machinery, and cellular insulin levels. PMID:26110898

  10. Fenofibrate, a peroxisome proliferator-activated receptor α ligand, prevents abnormal liver function induced by a fasting–refeeding process

    International Nuclear Information System (INIS)

    Lee, Joon No; Dutta, Raghbendra Kumar; Kim, Seul-Gi; Lim, Jae-Young; Kim, Se-Jin; Choe, Seong-Kyu; Yoo, Kyeong-Won; Song, Seung Ryel; Park, Do-Sim; So, Hong-Seob; Park, Raekil

    2013-01-01

    Highlights: •A fasting–refeeding high fat diet (HDF) model mimics irregular eating habit. •A fasting–refeeding HFD induces liver ballooning injury. •A fasting–refeeding HDF process elicits hepatic triglyceride accumulation. •Fenofibrate, PPARα ligand, prevents liver damage induced by refeeding HFD. -- Abstract: Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is an anti-hyperlipidemic agent that has been widely used in the treatment of dyslipidemia. In this study, we examined the effect of fenofibrate on liver damage caused by refeeding a high-fat diet (HFD) in mice after 24 h fasting. Here, we showed that refeeding HFD after fasting causes liver damage in mice determined by liver morphology and liver cell death. A detailed analysis revealed that hepatic lipid droplet formation is enhanced and triglyceride levels in liver are increased by refeeding HFD after starvation for 24 h. Also, NF-κB is activated and consequently induces the expression of TNF-α, IL1-β, COX-2, and NOS2. However, treating with fenofibrate attenuates the liver damage and triglyceride accumulation caused by the fasting–refeeding HFD process. Fenofibrate reduces the expression of NF-κB target genes but induces genes for peroxisomal fatty acid oxidation, peroxisome biogenesis and mitochondrial fatty acid oxidation. These results strongly suggest that the treatment of fenofibrate ameliorates the liver damage induced by fasting–refeeding HFD, possibly through the activation of fatty acid oxidation

  11. Fenofibrate, a peroxisome proliferator-activated receptor α ligand, prevents abnormal liver function induced by a fasting–refeeding process

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joon No; Dutta, Raghbendra Kumar; Kim, Seul-Gi; Lim, Jae-Young; Kim, Se-Jin; Choe, Seong-Kyu [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Yoo, Kyeong-Won [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Immune-network Pioneer Research Center, Department of Biochemistry, College of Medicine, Dong-A University, Busan (Korea, Republic of); Song, Seung Ryel [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Park, Do-Sim [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Department of Laboratory of Medicine, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); So, Hong-Seob [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Park, Raekil [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of)

    2013-12-06

    Highlights: •A fasting–refeeding high fat diet (HDF) model mimics irregular eating habit. •A fasting–refeeding HFD induces liver ballooning injury. •A fasting–refeeding HDF process elicits hepatic triglyceride accumulation. •Fenofibrate, PPARα ligand, prevents liver damage induced by refeeding HFD. -- Abstract: Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is an anti-hyperlipidemic agent that has been widely used in the treatment of dyslipidemia. In this study, we examined the effect of fenofibrate on liver damage caused by refeeding a high-fat diet (HFD) in mice after 24 h fasting. Here, we showed that refeeding HFD after fasting causes liver damage in mice determined by liver morphology and liver cell death. A detailed analysis revealed that hepatic lipid droplet formation is enhanced and triglyceride levels in liver are increased by refeeding HFD after starvation for 24 h. Also, NF-κB is activated and consequently induces the expression of TNF-α, IL1-β, COX-2, and NOS2. However, treating with fenofibrate attenuates the liver damage and triglyceride accumulation caused by the fasting–refeeding HFD process. Fenofibrate reduces the expression of NF-κB target genes but induces genes for peroxisomal fatty acid oxidation, peroxisome biogenesis and mitochondrial fatty acid oxidation. These results strongly suggest that the treatment of fenofibrate ameliorates the liver damage induced by fasting–refeeding HFD, possibly through the activation of fatty acid oxidation.

  12. Fetal MSCs

    Indian Academy of Sciences (India)

    First page Back Continue Last page Overview Graphics. Derived from extra embryonic tissues (amniotic fluid, placenta, cord blood, Wharton's Jelly) and fetal tissues (aborted fetuses). Derived from extra embryonic tissues (amniotic fluid, placenta, cord blood, Wharton's Jelly) and fetal tissues (aborted fetuses). In comparison ...

  13. The Use of Induced Pluripotent Stem Cells for the Study and Treatment of Liver Diseases.

    Science.gov (United States)

    Hansel, Marc C; Davila, Julio C; Vosough, Massoud; Gramignoli, Roberto; Skvorak, Kristen J; Dorko, Kenneth; Marongiu, Fabio; Blake, William; Strom, Stephen C

    2016-02-01

    Liver disease is a major global health concern. Liver cirrhosis is one of the leading causes of death in the world and currently the only therapeutic option for end-stage liver disease (e.g., acute liver failure, cirrhosis, chronic hepatitis, cholestatic diseases, metabolic diseases, and malignant neoplasms) is orthotropic liver transplantation. Transplantation of hepatocytes has been proposed and used as an alternative to whole organ transplant to stabilize and prolong the lives of patients in some clinical cases. Although these experimental therapies have demonstrated promising and beneficial results, their routine use remains a challenge due to the shortage of donor livers available for cell isolation, variable quality of those tissues, the potential need for lifelong immunosuppression in the transplant recipient, and high costs. Therefore, new therapeutic strategies and more reliable clinical treatments are urgently needed. Recent and continuous technological advances in the development of stem cells suggest they may be beneficial in this respect. In this review, we summarize the history of stem cell and induced pluripotent stem cell (iPSC) technology in the context of hepatic differentiation and discuss the potential applications the technology may offer for human liver disease modeling and treatment. This includes developing safer drugs and cell-based therapies to improve the outcomes of patients with currently incurable health illnesses. We also review promising advances in other disease areas to highlight how the stem cell technology could be applied to liver diseases in the future. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

  14. Anti-thromboxane B2 antibodies protect against acetaminophen-induced liver injury in mice

    Directory of Open Access Journals (Sweden)

    Ivan Ćavar

    2011-12-01

    Full Text Available Prostanoids are lipid compounds that mediate a variety of physiological and pathological functions in almost all body tissues and organs. Thromboxane (TX A2 is a powerful inducer of platelet aggregation and vasoconstriction and it has ulcerogenic activity in the gastrointestinal tract. Overdose or chronic use of a high dose of acetaminophen (N-acetyl-paminophenol, APAP is a major cause of acute liver failure in the Western world. We investigated whether TXA2 plays a role in host response to toxic effect of APAP. CBA/H Zg mice of both sexes were intoxicated with a single lethal or high sublethal dose of APAP, which was administered to animals by oral gavage. The toxicity of APAP was determined by observing the survival of mice during 48 h, by measuring concentration of alanine-aminotransferase (ALT in plasma 20-22 h after APAP administration and by liver histology. The results have shown that anti-thromboxane (TX B2 antibodies (anti-TXB2 and a selective inhibitor of thromboxane (TX synthase, benzylimidazole (BZI, were significantly hepatoprotective, while a selective thromboxane receptor (TPR antagonist, daltroban, was slightly protective in this model of acute liver injury. A stabile metabolite of TXA2, TXB2, and a stabile agonist of TPR, U-46619, had no influence on APAP-induced liver damage. Our findings suggest that TXA2 has a pathogenic role in acute liver toxicity induced with APAP, which was highly abrogated by administration of anti-TXB2. According to our results, this protection is mediated, at least in part, through decreased production of TXB2 by liver fragments ex vivo.

  15. Characteristics and significance of D-tagatose-induced liver enlargement in rats: An interpretative review.

    Science.gov (United States)

    Bär, A

    1999-04-01

    This review addresses the issue of asymptomatic liver enlargement in rats. It was necessitated by the observation of significantly increased liver weights in rats fed diets with 10 to 20% D-tagatose, a potential new bulk sweetener, for between 28 and 90 days. Increases of liver size without accompanying histopathological changes or impairment of organ function have been observed in rats in response to the ingestion of various xenobiotic compounds (including some food additives), changes of dietary composition (e.g. , high doses of fructose and sucrose), metabolic aberrations (e.g., diabetes), as well as normal pregnancy and lactation. The underlying mechanism(s) are not yet understood in detail but peroxisome proliferation, microsomal enzyme induction, increased storage of glycogen or lipids, and hyperfunction due to an excessive workload are well-established causes of hepatomegaly in rats. In D-tagatose- and fructose-fed rats, a treatment-related increase of hepatic glycogen storage was identified as a likely cause of the liver enlargement. Dietary levels of 5% and about 15-20% were determined as no-effect levels (NOEL) for D-tagatose- and fructose-induced liver enlargement, respectively. At doses above the NOEL, D-tagatose is about four times more efficient than fructose in inducing liver enlargement. On the other hand, the estimated intake of D-tagatose from its intended uses in food is about four times lower than the actual fructose intake. Consequently, a similar safety margin would apply for both sugars. Considering the similarity of the liver effects in rats of fructose, a safe food ingredient, and D-tagatose, the absence of histopathological changes in rats fed a diet with 20% D-tagatose for 90 days, and the absence of adverse long-term consequences of glycogen-induced liver enlargement in rats, it is concluded that the observed liver enlargement in D-tagatose-fed rats has no relevance for the assessment of human safety of this substance. Copyright 1999

  16. Antioxidant and antiapoptotic effects of green tea polyphenols against azathioprine-induced liver injury in rats.

    Science.gov (United States)

    El-Beshbishy, Hesham A; Tork, Ola M; El-Bab, Mohamed F; Autifi, Mohamed A

    2011-04-01

    Green tea polyphenols (GTP) is considered to have protective effects against several diseases. The hepatotoxicity of azathioprine (AZA) has been reported and was found to be associated with oxidative damage. This study was conducted to evaluate the role of GTP to protect against AZA-induced liver injury in rats. AZA was administered i.p. in a single dose (50mgkg(-1)) to adult male rats. AZA-intoxicated rats were orally administered GTP (either 100mgkg(-1)day(-1) or 300mgkg(-1)day(-1), for 21 consecutive days, started 7 days prior AZA injection). AZA administration to rats resulted in significant elevation of serum transaminases (sALT and sAST), alkaline phosphatase (sALP), depletion of hepatic reduced glutathione (GSH), catalase (CAT) and glutathione peroxidase (GPx), accumulation of oxidized glutathione (GSSG), elevation of lipid peroxides (LPO) expressed as malondialdehyde (MDA), reduction of the hepatic total antioxidant activity (TAA), decrease serum total proteins and elevation of liver protein carbonyl content. Significant rises in liver tumor necrosis factor-alpha (TNF-α) and caspase-3 levels were noticed in AZA-intoxicated rats. Treatment of the AZA-intoxicated rats with GTP significantly prevented the elevations of sALT, sAST and sALP, inhibited depletion of hepatic GSH, GPx, CAT and GSSG and inhibited MDA accumulation. Furthermore, GTP had normalized serum total proteins and hepatic TAA, CAT, TNF-α and caspase-3 levels of AZA-intoxicated rats. In addition, GTP prevented the AZA-induced apoptosis and liver injury as indicated by the liver histopathological analysis. The linear regression analysis showed significant correlation in either AZA-GTP100 or AZA-GTP300 groups between TNF-α and each of serum ALT, AST, ALP and total proteins and liver TAA, GPX, CAT, GSH, GSSG, MDA and caspase-3 levels. However, liver TNF-α produced non-significant correlation with the serum total proteins in both AZA-GTP100 and AZA-GTP300 groups. In conclusion, our data indicate

  17. MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice

    International Nuclear Information System (INIS)

    Uematsu, Yasuaki; Akai, Sho; Tochitani, Tomoaki; Oda, Shingo; Yamada, Toru; Yokoi, Tsuyoshi

    2016-01-01

    MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4 h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury. - Highlights: • Methimazole induced hepatic Th2 bias in the pathogenesis of liver injury in mice. • Rapid down-regulation of SOX4 and LEF1 may initiate and/or maintain hepatic Th2 bias. • Negative regulation of SOX4 by miR-29b-1-5p and LEF1 by miR-449a-5p was suggested.

  18. MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice

    Energy Technology Data Exchange (ETDEWEB)

    Uematsu, Yasuaki, E-mail: yasuaki-uematsu@ds-pharma.co.jp [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Akai, Sho [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Tochitani, Tomoaki [Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Oda, Shingo [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan); Yamada, Toru [Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka (Japan); Yokoi, Tsuyoshi [Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550 (Japan)

    2016-09-15

    MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4 h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury. - Highlights: • Methimazole induced hepatic Th2 bias in the pathogenesis of liver injury in mice. • Rapid down-regulation of SOX4 and LEF1 may initiate and/or maintain hepatic Th2 bias. • Negative regulation of SOX4 by miR-29b-1-5p and LEF1 by miR-449a-5p was suggested.

  19. Necrostatin-1 protects against reactive oxygen species (ROS-induced hepatotoxicity in acetaminophen-induced acute liver failure

    Directory of Open Access Journals (Sweden)

    Kenji Takemoto

    2014-01-01

    Full Text Available Excessive acetaminophen (APAP use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP-induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor-interacting protein kinase (RIPK-dependent necrosis (or necroptosis, which is controlled by the kinases RIPK1 and RIPK3. Although RIPK-dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia–reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP-induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK-dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP-induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP-induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP-injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK-dependent necrotic mechanism operates in the APAP-injured liver and inhibition of this pathway may be beneficial for APAP-induced fulminant hepatic failure.

  20. Effects of pregnancy on obesity-induced inflammation in a mouse model of fetal programming

    DEFF Research Database (Denmark)

    Ingvorsen, Camilla; Thysen, Anna Hammerich; Fernandez-Twinn, D.

    2014-01-01

    Objective Maternal obesity is associated with increased risk of metabolic dysfunction in the offspring. It is not clear whether it is the metabolic changes or chronic low-grade inflammation in the obese state that causes this metabolic programming. We therefore investigated whether low-grade infl......Objective Maternal obesity is associated with increased risk of metabolic dysfunction in the offspring. It is not clear whether it is the metabolic changes or chronic low-grade inflammation in the obese state that causes this metabolic programming. We therefore investigated whether low...... of the obese animals, which suggested that monocytes are being recruited from the blood to the liver and adipose tissue in the obese animals. Gestation reversed macrophage infiltration, such that obese dams showed a lower adipose tissue macrophage count at the end of gestation compared to pre-pregnancy obese...

  1. Steatosis induced CCL5 contributes to early-stage liver fibrosis in nonalcoholic fatty liver disease progress.

    Science.gov (United States)

    Li, Bing-Hang; He, Fang-Ping; Yang, Xin; Chen, Yuan-Wen; Fan, Jian-Gao

    2017-02-01

    The rapidly increasing prevalence of nonalcoholic fatty liver disease (NAFLD) has become one of the major public health threats in China and worldwide. However, during the development of NAFLD, the key mechanism underlying the progression of related fibrosis remains unclear, which greatly impedes the development of optimal NAFLD therapy. In the current study, we were endeavored to characterize a proinflammatory cytokine, CCL5, as a major contributor for fibrosis in NAFLD. The results showed that CCL5 was highly expressed in fatty liver and NASH patients. In NAFLD rats induced by 8-week-HFD, CCL5 and its receptor, CCR5, were significantly up-regulated and liver fibrosis exclusively occurred in this group. In addition, we showed that hepatocytes are the major source contributing to this CCL5 elevation. Interestingly, a CCL5 inhibitor Met-CCL5, significantly decreased liver fibrosis but not hepatic steatosis. Using a cell model of hepatic steatosis, we found that the conditioned medium of lipid-overloaded hepatocytes (Fa2N-4 cells) which produced excessive CCL5 stimulated the profibrotic activities of hepatic stellate cells (LX-2) as manifested by increased migration rate, proliferation and collagen production of LX-2 cells. CCL5 knockdown in Fa2N-4 cells, Met-CCL5 or CCR5 antibody treatment on LX-2 cells all significantly inhibited the conditioned medium of FFA-treated Fa2N-4 cells to exert stimulatory effects on LX-2 cells. Consistently, the conditioned medium of Fa2N-4 cells with CCL5 over-expression significantly enhanced migration rate, cell proliferation and collagen production of LX-2 cells. All these results support that CCL5 produced by steatotic hepatocytes plays an essential role in fibrotic signaling machinery of NAFLD. In addition, we were able to identify C/EBP-β as the up-stream regulator of CCL5 gene transcription in hepatocytes treated with free fatty acid (FFA). Our data strongly supported that CCL5 plays a pivotal regulatory role in

  2. Monitoring methotrexate-induced liver fibrosis in patients with psoriasis: utility of transient elastography

    Directory of Open Access Journals (Sweden)

    Cheng HS

    2018-05-01

    Full Text Available Harriet S Cheng,1 Marius Rademaker2 1Dermatology Service, Auckland City Hospital, Auckland, New Zealand; 2Waikato Clinical Campus, Auckland University Medical School, Hamilton, New Zealand Abstract: Increasingly, existing evidence indicates that methotrexate-associated liver injury is related to comorbid risk factors such as diabetes, alcoholism, and obesity, rather than to methotrexate itself. Despite this fact, significant effort continues to be expended in the monitoring of low-dose methotrexate in patients with psoriasis. The gold standard investigation has been liver biopsy, but this is associated with significant morbidity and mortality. As methotrexate-induced liver injury is uncommon, the risk/benefit ratio of liver biopsy has been questioned. Fortunately, a number of new technologies have been developed for the diagnosis of chronic liver disease, including transient elastography (TE. TE is a type of shear wave ultrasound elastography, which measures the speed of shear waves used to estimate hepatic tissue stiffness. Several meta-analyses show very high pooled sensitivity and specificity for the diagnosis of hepatic cirrhosis (87% and 91%, respectively in a variety of chronic liver disorders. It has a negative predictive value for cirrhosis of >90% and a positive predictive value of 75%. Recent European guidelines now advocate the use of TE as the first-line test for the assessment of fibrosis in alcohol- or hepatitis-related liver disease, including nonalcoholic fatty liver disease (NAFLD. As the prevalence of obesity and metabolic syndrome, including NAFLD, is significantly elevated in patients with psoriasis, TE may be worth considering as a routine investigation for any patient with psoriasis. Although high-quality studies comparing TE with standard liver biopsy in the monitoring of psoriatics on low-dose methotrexate are lacking, the evidence from multiple small cohort studies and case series demonstrates its effectiveness. A recent

  3. The effect of phytosterol protects rats against 4-nitrophenol-induced liver damage.

    Science.gov (United States)

    Chen, Jiaqin; Song, Meiyan; Li, Yansen; Zhang, Yonghui; Taya, Kazuyoshi; Li, ChunMei

    2016-01-01

    We investigated the effect of phytosterol (PS) in regard to liver damage induced by 4-nitrophenol (PNP). Twenty rats were randomly divided into four groups (Control, PS, PNP, and PNP+PS). The PS and PNP+PS groups were pretreated with PS for one week. The PNP and PNP+PS groups were injected subcutaneously with PNP for 28 days. The control group received a basal diet and was injected with vehicle alone. Treatment with PS prevented the elevation of the total bilirubin levels, as well as an increase in serum alkaline transaminase and aspartate transaminase, which are typically caused by PNP-induced liver damage. Histopathologically showed that liver damage was significantly mitigated by PS treatment. However, there was no significant change in antioxidant enzyme activities, and the Nrf2-antioxidant system was not activated after treatment with PS. These results suggest that PS could mitigate liver damage induced by PNP, but does not enhance antioxidant capacity. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Hepatoprotective effects of pecan nut shells on ethanol-induced liver damage.

    Science.gov (United States)

    Müller, Liz Girardi; Pase, Camila Simonetti; Reckziegel, Patrícia; Barcelos, Raquel C S; Boufleur, Nardeli; Prado, Ana Cristina P; Fett, Roseane; Block, Jane Mara; Pavanato, Maria Amália; Bauermann, Liliane F; da Rocha, João Batista Teixeira; Burger, Marilise Escobar

    2013-01-01

    The hepatoprotective activity of the aqueous extract of the shells of pecan nut was investigated against ethanol-induced liver damage. This by-product of the food industry is popularly used to treat toxicological diseases. We evaluated the phytochemical properties of pecan shell aqueous extract (AE) and its in vitro and ex vivo antioxidant activity. The AE was found to have a high content of total polyphenols (192.4±1.9 mg GAE/g), condensed tannins (58.4±2.2 mg CE/g), and antioxidant capacity, and it inhibited Fe(2+)-induced lipid peroxidation (LP) in vitro. Rats chronically treated with ethanol (Et) had increased plasmatic transaminases (ALT, AST) and gamma glutamyl transpeptidase (GGT) levels (96%, 59.13% and 465.9%, respectively), which were effectively prevented (87; 41 and 383%) by the extract (1:40, w/v). In liver, ethanol consumption increased the LP (121%) and decreased such antioxidant defenses as glutathione (GSH) (33%) and superoxide dismutase (SOD) (47%) levels, causing genotoxicity in erythrocytes. Treatment with pecan shell AE prevented the development of LP (43%), GSH and SOD depletion (33% and 109%, respectively) and ethanol-induced erythrocyte genotoxicity. Catalase activity in the liver was unchanged by ethanol but was increased by the extract (47% and 73% in AE and AE+Et, respectively). Therefore, pecan shells may be an economic agent to treat liver diseases related to ethanol consumption. Copyright © 2011 Elsevier GmbH. All rights reserved.

  5. Hepatoprotective activity of Mentha arvensis Linn. leaves against CCL4 induced liver damage in rats

    Directory of Open Access Journals (Sweden)

    Kalpana Patil

    2012-05-01

    Full Text Available Objective: To study the Hepatoprotective activity of ethanol, chloroform and aqueous extracts of Mentha arvensis leaves against CCL4 induced liver damage in rats. Methods: Hepatotoxicity was induced by CCL4 and the biochemical parameters such as serum glutamate pyruvate transminase (sGPT, serum glutamate oxaloacetate transaminase (sGOT, alkaline phosphatase (sALP, serum bilirubin (sB and histopathological changes in liver were studied along with silymarin as standard Hepatoprotective agents. Results: The Phytochemical investigation of the extracts showed presence of flavonoids, steroids, triterpenoids, alkaloids, glycosides, carbohydrates, tannins, phenolic compounds. Treatment of the rats with chloroform, ethanol and aqueous extract with CCL 4 administration caused a significant reduction in the values of sGOT, sGPT, sALP and sB (P<0.01 almost comparable to the silymarin. The Hepatoprotective was confirmed by histopathological examination of the liver tissue of control and treated animals. Conclusions: From the results it can be concluded that Mentha arvensis possesses Hepatoprotective effect against CCL4 induced liver damage in rats.

  6. TRAIL enhances paracetamol-induced liver sinusoidal endothelial cell death in a Bim- and Bid-dependent manner

    Science.gov (United States)

    Badmann, A; Langsch, S; Keogh, A; Brunner, T; Kaufmann, T; Corazza, N

    2012-01-01

    Paracetamol (acetaminophen, APAP) is a universally used analgesic and antipyretic agent. Considered safe at therapeutic doses, overdoses cause acute liver damage characterized by centrilobular hepatic necrosis. One of the major clinical problems of paracetamol-induced liver disease is the development of hemorrhagic alterations. Although hepatocytes represent the main target of the cytotoxic effect of paracetamol overdose, perturbations within the endothelium involving morphological changes of liver sinusoidal endothelial cells (LSECs) have also been described in paracetamol-induced liver disease. Recently, we have shown that paracetamol-induced liver damage is synergistically enhanced by the TRAIL signaling pathway. As LSECs are constantly exposed to activated immune cells expressing death ligands, including TRAIL, we investigated the effect of TRAIL on paracetamol-induced LSEC death. We here demonstrate for the first time that TRAIL strongly enhances paracetamol-mediated LSEC death with typical features of apoptosis. Inhibition of caspases using specific inhibitors resulted in a strong reduction of cell death. TRAIL appears to enhance paracetamol-induced LSEC death via the activation of the pro-apoptotic BH3-only proteins Bid and Bim, which initiate the mitochondrial apoptotic pathway. Taken together this study shows that the liver endothelial layer, mainly LSECs, represent a direct target of the cytotoxic effect of paracetamol and that activation of TRAIL receptor synergistically enhances paracetamol-induced LSEC death via the mitochondrial apoptotic pathway. TRAIL-mediated acceleration of paracetamol-induced cell death may thus contribute to the pathogenesis of paracetamol-induced liver damage. PMID:23254290

  7. SET mediates TCE-induced liver cell apoptosis through dephosphorylation and upregulation of nucleolin.

    Science.gov (United States)

    Ren, Xiaohu; Huang, Xinfeng; Yang, Xifei; Liu, Yungang; Liu, Wei; Huang, Haiyan; Wu, Desheng; Zou, Fei; Liu, Jianjun

    2017-06-20

    Trichloroethylene (TCE) is an occupational and environmental chemical that can cause severe hepatotoxicity. While our previous studies showed that the phosphatase inhibitor SET is a key mediator of TCE-induced liver cell apoptosis, the molecular mechanisms remain elusive. Using quantitative phosphoproteomic analysis, we report here that nucleolin is a SET-regulated phosphoprotein in human liver HL-7702 cells. Functional analysis suggested that SET promoted dephosphorylation of nucleolin, decreased its binding to its transcriptional activator, c-myc, and upregulated nucleolin expression in TCE-treated cells. Importantly, TCE-induced hepatocyte apoptosis was significantly attenuated when nucleolin was downregulated with specific siRNAs. These findings indicate that TCE may induce hepatocyte apoptosis via SET-mediated dephosphorylation and overexpression of nucleolin.

  8. Protective Effects of Lemon Juice on Alcohol-Induced Liver Injury in Mice

    Directory of Open Access Journals (Sweden)

    Tong Zhou

    2017-01-01

    Full Text Available Chronic excessive alcohol consumption (more than 40–80 g/day for males and more than 20–40 g/day for females could induce serious liver injury. In this study, effects of lemon juice on chronic alcohol-induced liver injury in mice were evaluated. The serum biochemical profiles and hepatic lipid peroxidation levels, triacylglycerol (TG contents, antioxidant enzyme activities, and histopathological changes were examined for evaluating the hepatoprotective effects of lemon juice in mice. In addition, the in vitro antioxidant capacities of lemon juice were determined. The results showed that lemon juice significantly inhibited alcohol-induced increase of alanine transaminase (ALT, aspartate transaminase (AST, hepatic TG, and lipid peroxidation levels in a dose-dependent manner. Histopathological changes induced by alcohol were also remarkably improved by lemon juice treatment. These findings suggest that lemon juice has protective effects on alcohol-induced liver injury in mice. The protective effects might be related to the antioxidant capacity of lemon juice because lemon juice showed in vitro antioxidant capacity.

  9. Estrogen protects the liver and intestines against sepsis-induced injury in rats.

    Science.gov (United States)

    Sener, Göksel; Arbak, Serap; Kurtaran, Pelin; Gedik, Nursal; Yeğen, Berrak C

    2005-09-01

    Sepsis is commonly associated with enhanced generation of reactive oxygen metabolites, leading to multiple organ dysfunctions. The aim of this study was to examine the putative protective role of estradiol against sepsis-induced oxidative organ damage. Sepsis was induced by cecal ligation and puncture method in Wistar albino rats. Sham-operated (control) and sepsis groups received saline or estradiol propionate (10 mg/kg) intraperitoneally immediately after the operation and at 12 h. Twenty-four hours after the surgery, rats were decapitated and malondialdehyde, glutathione levels, and myeloperoxidase activity were determined in the liver and ileum, while oxidant-induced tissue fibrosis was determined by collagen contents. Tissues were also examined microscopically. Serum aspartate aminotransferase, alanine aminotransferase levels, and lactate dehydrogenase were measured for the evaluation of liver functions and tissue damage, respectively. Tumor necrosis factor-alpha was also assayed in serum samples. In the saline-treated sepsis group, glutathione levels were decreased significantly, while the malondialdehyde levels, myeloperoxidase activity, and collagen content were increased in the tissues (P Liver function tests and tumor necrosis factor-alpha levels, which were increased significantly (P < 0.001) following sepsis, were decreased (P < 0.05 to P < 0.001) with estradiol treatment. The results demonstrate the role of oxidative mechanisms in sepsis-induced tissue damage, and estradiol, by its antioxidant properties, ameliorates oxidative organ injury, implicating that treatment with estrogens might be applicable in clinical situations to ameliorate multiple organ damage induced by sepsis.

  10. Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study

    Directory of Open Access Journals (Sweden)

    Qin eDong

    2015-10-01

    Full Text Available Heshouwu (HSW, the dry roots of Polygonum multiflorum, a classical traditional Chinese medicine is used as a tonic for a wide range of conditions,particularly those associated with aging. However, it tends to be taken overdose or long term in these years, which has resulted in liver damage reported in many countries. In this study, the indicative roles of nine bile acids (BAs were evaluated to offer potential biomarkers for HSW induced liver injury. Nine BAs including cholic acid (CA and chenodeoxycholic acid (CDCA, taurocholic acid (TCA, glycocholic acid (GCA, glycochenodeoxycholic acid (GCDCA, deoxycholic acid (DCA, glycodeoxycholic acid (GDCA, ursodeoxycholic acid (UDCA and hyodeoxycholic acid (HDCA in rat bile and serum were detected by a developed LC-MS method after 42 days treatment. Partial least square-discriminate analysis (PLS-DA was applied to evaluate the indicative roles of the nine BAs, and metabolism of the nine BAs was summarized. Significant change was observed for the concentrations of nine BAs in treatment groups compared with normal control; In the PLS-DA plots of nine BAs in bile, normal control and raw HSW groups were separately clustered and could be clearly distinguished, GDCA was selected as the distinguished components for raw HSW overdose treatment group. In the PLS-DA plots of nine BAs in serum, the normal control and raw HSW overdose treatment group were separately clustered and could be clearly distinguished, and HDCA was selected as the distinguished components for raw HSW overdose treatment group. The results indicated the perturbation of nine BAs was associated with HSW induced liver injury; GDCA in bile, as well as HDCA in serum could be selected as potential biomarkers for HSW induced liver injury; it also laid the foundation for the further search on the mechanisms of liver injury induced by HSW .

  11. Dietary Fisetin Supplementation Protects Against Alcohol-Induced Liver Injury in Mice.

    Science.gov (United States)

    Sun, Qian; Zhang, Wenliang; Zhong, Wei; Sun, Xinguo; Zhou, Zhanxiang

    2016-10-01

    Overproduction of reactive oxygen species is associated with the development of alcoholic liver disease (ALD). Plant polyphenols have been used as dietary interventions for multiple diseases including ALD. The objective of this study was to determine whether dietary supplementation with fisetin, a novel flavonoid, exerts beneficial effect on alcohol-induced liver injury. C57BL/6J mice were pair-fed with the Lieber-DeCarli control or ethanol (EtOH) diet for 4 weeks with or without fisetin supplementation at 10 mg/kg/d. Alcohol feeding induced lipid accumulation in the liver and increased plasma alanine aminotransferase and aspartate aminotransferase activities, which were attenuated by fisetin supplementation. The EtOH concentrations in the plasma and liver were significantly elevated by alcohol exposure but were reduced by fisetin supplementation. Although fisetin did not affect the protein expression of alcohol metabolism enzymes, the aldehyde dehydrogenase activities were significantly increased by fisetin compared to the alcohol alone group. In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4-hydroxynonenal levels after alcohol exposure. Alcohol-induced apoptosis and up-regulation of Fas and cleaved caspase-3 in the liver were prevented by fisetin. Moreover, fisetin supplementation attenuated alcohol-induced hepatic steatosis through increasing plasma adiponectin levels and hepatic protein levels of p-AMPK, ACOX1, CYP4A, and MTTP. This study demonstrated that the protective effect of fisetin on ALD is achieved by accelerating EtOH clearance and inhibition of oxidative stress. The data suggest that fisetin has a therapeutical potential for treating ALD. Copyright © 2016 by the Research Society on Alcoholism.

  12. Methimazole-induced hypothyroidism causes cellular damage in the spleen, heart, liver, lung and kidney.

    Science.gov (United States)

    Cano-Europa, Edgar; Blas-Valdivia, Vanessa; Franco-Colin, Margarita; Gallardo-Casas, Carlos Angel; Ortiz-Butrón, Rocio

    2011-01-01

    It is known that a hypothyroidism-induced hypometabolic state protects against oxidative damage caused by toxins. However, some workers demonstrated that antithyroid drug-induced hypothyroidism can cause cellular damage. Our objective was to determine if methimazole (an antithyroid drug) or hypothyroidism causes cellular damage in the liver, kidney, lung, spleen and heart. Twenty-five male Wistar rats were divided into 5 groups: euthyroid, false thyroidectomy, thyroidectomy-induced hypothyroidism, methimazole-induced hypothyroidism (60 mg/kg), and treatment with methimazole (60 mg/kg) and a T₄ injection (20 μg/kg/d sc). At the end of the treatments (4 weeks for the pharmacological groups and 8 weeks for the surgical groups), the animals were anesthetized with sodium pentobarbital and they were transcardially perfused with 10% formaldehyde. The spleen, heart, liver, lung and kidney were removed and were processed for embedding in paraffin wax. Coronal sections were stained with hematoxylin-eosin. At the end of treatment, animals with both the methimazole- and thyroidectomy-induced hypothyroidism had a significant reduction of serum concentration of thyroid hormones. Only methimazole-induced hypothyroidism causes cellular damage in the kidney, lung, liver, heart, kidney and spleen. In addition, animals treated with methimazole and T₄ showed cellular damage in the lung, spleen and renal medulla with lesser damage in the liver, renal cortex and heart. The thyroidectomy only altered the lung structure. The alterations were prevented by T₄ completely in the heart and partially in the kidney cortex. These results indicate that tissue damage found in hypothyroidism is caused by methimazole. Copyright © 2009 Elsevier GmbH. All rights reserved.

  13. Fetal rat metabonome alteration by prenatal caffeine ingestion probably due to the increased circulatory glucocorticoid level and altered peripheral glucose and lipid metabolic pathways

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Yansong [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan University, Wuhan, 430071 (China); Xu, Dan [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan University, Wuhan, 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan, 430071 (China); Feng, Jianghua, E-mail: jianghua.feng@xmu.edu.cn [Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430071 (China); Department of Electronic Science, Fujian Provincial Key Laboratory of Plasma and Magnetic Resonance, Xiamen University, Xiamen, 361005 (China); Kou, Hao; Liang, Gai [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan University, Wuhan, 430071 (China); Yu, Hong; He, Xiaohua; Zhang, Baifang; Chen, Liaobin [Research Center of Food and Drug Evaluation, Wuhan University, Wuhan, 430071 (China); Magdalou, Jacques [UMR 7561 CNRS-Nancy Université, Faculté de Médicine, Vandoeuvre-lès-Nancy (France); Wang, Hui, E-mail: wanghui19@whu.edu.cn [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan University, Wuhan, 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan, 430071 (China)

    2012-07-15

    The aims of this study were to clarify the metabonome alteration in fetal rats after prenatal caffeine ingestion and to explore the underlying mechanism pertaining to the increased fetal circulatory glucocorticoid (GC). Pregnant Wistar rats were daily intragastrically administered with different doses of caffeine (0, 20, 60 and 180 mg/kg) from gestational days (GD) 11 to 20. Metabonome of fetal plasma and amniotic fluid on GD20 were analyzed by {sup 1}H nuclear magnetic resonance-based metabonomics. Gene and protein expressions involved in the GC metabolism, glucose and lipid metabolic pathways in fetal liver and gastrocnemius were measured by real-time RT-PCR and immunohistochemistry. Fetal plasma metabonome were significantly altered by caffeine, which presents as the elevated α- and β‐glucose, reduced multiple lipid contents, varied apolipoprotein contents and increased levels of a number of amino acids. The metabonome of amniotic fluids showed a similar change as that in fetal plasma. Furthermore, the expressions of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD-2) were decreased, while the level of blood GC and the expressions of 11β-HSD-1 and glucocorticoid receptor (GR) were increased in fetal liver and gastrocnemius. Meanwhile, the expressions of insulin-like growth factor 1 (IGF-1), IGF-1 receptor and insulin receptor were decreased, while the expressions of adiponectin receptor 2, leptin receptors and AMP-activated protein kinase α2 were increased after caffeine treatment. Prenatal caffeine ingestion characteristically change the fetal metabonome, which is probably attributed to the alterations of glucose and lipid metabolic pathways induced by increased circulatory GC, activated GC metabolism and enhanced GR expression in peripheral metabolic tissues. -- Highlights: ► Prenatal caffeine ingestion altered the metabonome of IUGR fetal rats. ► Caffeine altered the glucose and lipid metabolic pathways of IUGR fetal rats. ► Prenatal caffeine

  14. Fetal rat metabonome alteration by prenatal caffeine ingestion probably due to the increased circulatory glucocorticoid level and altered peripheral glucose and lipid metabolic pathways

    International Nuclear Information System (INIS)

    Liu, Yansong; Xu, Dan; Feng, Jianghua; Kou, Hao; Liang, Gai; Yu, Hong; He, Xiaohua; Zhang, Baifang; Chen, Liaobin; Magdalou, Jacques; Wang, Hui

    2012-01-01

    The aims of this study were to clarify the metabonome alteration in fetal rats after prenatal caffeine ingestion and to explore the underlying mechanism pertaining to the increased fetal circulatory glucocorticoid (GC). Pregnant Wistar rats were daily intragastrically administered with different doses of caffeine (0, 20, 60 and 180 mg/kg) from gestational days (GD) 11 to 20. Metabonome of fetal plasma and amniotic fluid on GD20 were analyzed by 1 H nuclear magnetic resonance-based metabonomics. Gene and protein expressions involved in the GC metabolism, glucose and lipid metabolic pathways in fetal liver and gastrocnemius were measured by real-time RT-PCR and immunohistochemistry. Fetal plasma metabonome were significantly altered by caffeine, which presents as the elevated α- and β‐glucose, reduced multiple lipid contents, varied apolipoprotein contents and increased levels of a number of amino acids. The metabonome of amniotic fluids showed a similar change as that in fetal plasma. Furthermore, the expressions of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD-2) were decreased, while the level of blood GC and the expressions of 11β-HSD-1 and glucocorticoid receptor (GR) were increased in fetal liver and gastrocnemius. Meanwhile, the expressions of insulin-like growth factor 1 (IGF-1), IGF-1 receptor and insulin receptor were decreased, while the expressions of adiponectin receptor 2, leptin receptors and AMP-activated protein kinase α2 were increased after caffeine treatment. Prenatal caffeine ingestion characteristically change the fetal metabonome, which is probably attributed to the alterations of glucose and lipid metabolic pathways induced by increased circulatory GC, activated GC metabolism and enhanced GR expression in peripheral metabolic tissues. -- Highlights: ► Prenatal caffeine ingestion altered the metabonome of IUGR fetal rats. ► Caffeine altered the glucose and lipid metabolic pathways of IUGR fetal rats. ► Prenatal caffeine ingestion

  15. Evaluation of methanolic extract of Phragmites karka on carbon tetrachloride-induced liver fibrosis in rat

    Directory of Open Access Journals (Sweden)

    Atta ur Rehman

    2017-07-01

    Full Text Available Phragmites karka has been reported for its anti-inflammatory and analgesic activities. Here, extracts of leaf and rhizome of the plant were individually investigated in CCl4-induced hepatofibrosis in male Wistar rats by administering CCl4 intraperitoneally biweekly for 6 weeks. Afterwards the animals were investigated for liver fibrosis at biochemical, molecular and histological levels, and it showed a profound increase (p<0.001 in elevation of serum levels of transaminases, γ-glutamyl transpeptidase, mRNA expression of α smooth muscle actin, collagen and transforming growth factor beta (TGFβ, and extracellular matrix deposition and perilobular necrosis. Both extracts markedly (p<0.001 decreased the elevated levels of these markers. Histopathological investigations also substantiated the above results by exhibiting a decreased in extracellular matrix deposition in post-treatment animals. In conclusion, both extracts had substantially modified the biochemical and molecular markers of liver fibrosis, in addition to histological improvement in architecture of liver.

  16. MRI-guided laser-induced thermotherapy (LITT) of liver metastases: clinical evaluation

    International Nuclear Information System (INIS)

    Vogl, T.J.; Weinhold, N.; Mueller, P.; Mack, M.; Scholz, W.; Philipp, C.; Roggan, A.; Felix, R.

    1996-01-01

    The goal was to perform an evaluation of MRI-guided laser-induced thermotherapy (LITT) of liver metastases as a clinical method. In a prospective study, 50 patients with liver metastases of colorectal carcinoma (35 patients), or other primary tumors (15 patients) were treated with LITT. For preparation and intermittent controls of therapy, standardized MRI examinations were made. Online monitoring during the the LITT was done with temperature-sensitive T1-weighted sequences (FLASH-2D, TurboFLASH). All in all, 83 metastases of a volume between 1 and 282 cubic centimeters (median = ± 10 cm 3 ) were treated.During performance of the LITT, a decrease of signal intensity in the thermosensitive sequences was measured for the application area, and was correlated with fluorine-optical temperature measurements. The MRI-guided LITT is a novel, potential modality for treatment of liver metastases, and poses only minimal clinical risks. (orig./VHE) [de

  17. Factors influencing radiation-induced impairment of rat liver mitochondrial oxidative phosphorylation

    International Nuclear Information System (INIS)

    Alexander, K.C.; Aiyar, A.S.; Sreenivasan, A.

    1975-01-01

    The influence of some experimental conditions on the radiation-induced impairment of oxidative phosphorylation in rat liver mitochondria has been studied. Shielding of the liver during whole body irradiation of the animal does not significantly alter the decreased efficiency of phosphorylation. There exists a great disparity in the in vivo and in vitro radiation doses required for the manifestation of damage to liver mitochondria. While these observations point to the abscopal nature of the radiation effects, direct involvement of the adrenals has been ruled out by studies with adrenalectomised rats. Prior administration of the well known radio-protective agents, serotonin or 2-aminoethyl isothiouronium bromide hydrobromide, is effective in preventing the derangement of mitochondrial function following radioexposure. The hypocholesterolemic drug ethyl-α-p-chlorophenoxy isobutyrate, which is known to influence hepatic mitochondrial turnover, does not afford any significant protection against either mitochondrial damage or the mortality of the animals due to whole body irradiation. (author)

  18. Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells

    Energy Technology Data Exchange (ETDEWEB)

    Soeda, Junpei; Morgan, Maelle; McKee, Chad; Mouralidarane, Angelina; Lin, ChingI [University College London, Centre for Hepatology, Royal Free Hospital, London NW3 2PF (United Kingdom); Roskams, Tania [Department of Morphology and Molecular Pathology, University of Leuven (Belgium); Oben, Jude A., E-mail: j.oben@ucl.ac.uk [University College London, Centre for Hepatology, Royal Free Hospital, London NW3 2PF (United Kingdom); Department of Gastroenterology and Hepatology, Guy' s and St Thomas' Hospital, London SE1 7EH (United Kingdom)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Cigarette smoke may induce liver fibrosis via nicotine receptors. Black-Right-Pointing-Pointer Nicotine induces proliferation of hepatic stellate cells (HSCs). Black-Right-Pointing-Pointer Nicotine activates hepatic fibrogenic pathways. Black-Right-Pointing-Pointer Nicotine receptor antagonists attenuate HSC proliferation. Black-Right-Pointing-Pointer Nicotinic receptor antagonists may have utility as novel anti-fibrotic agents. -- Abstract: Background and aims: Cigarette smoke (CS) may cause liver fibrosis but possible involved mechanisms are unclear. Among the many chemicals in CS is nicotine - which affects cells through nicotinic acetylcholine receptors (nAChR). We studied the effects of nicotine, and involved pathways, on human primary hepatic stellate cells (hHSCs), the principal fibrogenic cells in the liver. We then determined possible disease relevance by assaying nAChR in liver samples from human non-alcoholic steatohepatitis (NASH). Methods: hHSC were isolated from healthy human livers and nAChR expression analyzed - RT-PCR and Western blotting. Nicotine induction of hHSC proliferation, upregulation of collagen1-{alpha}2 and the pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-{beta}1) was determined along with involved intracellular signaling pathways. nAChR mRNA expression was finally analyzed in whole liver biopsies obtained from patients diagnosed with non-alcoholic steatohepatitis (NASH). Results: hHSCs express muscle type ({alpha}1, {beta}1, delta and epsilon) and neuronal type ({alpha}3, {alpha}6, {alpha}7, {beta}2 and {beta}4) nAChR subunits at the mRNA level. Among these subunits, {alpha}3, {alpha}7, {beta}1 and {epsilon} were predominantly expressed as confirmed by Western blotting. Nicotine induced hHSC proliferation was attenuated by mecamylamine (p < 0.05). Additionally, collagen1-{alpha}2 and TGF-{beta}1 mRNA expression were significantly upregulated by nicotine and inhibited by

  19. Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells

    International Nuclear Information System (INIS)

    Soeda, Junpei; Morgan, Maelle; McKee, Chad; Mouralidarane, Angelina; Lin, ChingI; Roskams, Tania; Oben, Jude A.

    2012-01-01

    Highlights: ► Cigarette smoke may induce liver fibrosis via nicotine receptors. ► Nicotine induces proliferation of hepatic stellate cells (HSCs). ► Nicotine activates hepatic fibrogenic pathways. ► Nicotine receptor antagonists attenuate HSC proliferation. ► Nicotinic receptor antagonists may have utility as novel anti-fibrotic agents. -- Abstract: Background and aims: Cigarette smoke (CS) may cause liver fibrosis but possible involved mechanisms are unclear. Among the many chemicals in CS is nicotine – which affects cells through nicotinic acetylcholine receptors (nAChR). We studied the effects of nicotine, and involved pathways, on human primary hepatic stellate cells (hHSCs), the principal fibrogenic cells in the liver. We then determined possible disease relevance by assaying nAChR in liver samples from human non-alcoholic steatohepatitis (NASH). Methods: hHSC were isolated from healthy human livers and nAChR expression analyzed – RT-PCR and Western blotting. Nicotine induction of hHSC proliferation, upregulation of collagen1-α2 and the pro-fibrogenic cytokine transforming growth factor beta 1 (TGF-β1) was determined along with involved intracellular signaling pathways. nAChR mRNA expression was finally analyzed in whole liver biopsies obtained from patients diagnosed with non-alcoholic steatohepatitis (NASH). Results: hHSCs express muscle type (α1, β1, delta and epsilon) and neuronal type (α3, α6, α7, β2 and β4) nAChR subunits at the mRNA level. Among these subunits, α3, α7, β1 and ε were predominantly expressed as confirmed by Western blotting. Nicotine induced hHSC proliferation was attenuated by mecamylamine (p < 0.05). Additionally, collagen1-α2 and TGF-β1 mRNA expression were significantly upregulated by nicotine and inhibited by mecamylamine. α1 and α3-nAChR mRNA expression was significantly upregulated in NASH fibrosis compared to normal livers. Conclusion: Nicotine at levels in smokers’ blood is pro-fibrogenic, through

  20. Arsenite induced oxidative damage in mouse liver is associated with increased cytokeratin 18 expression

    Energy Technology Data Exchange (ETDEWEB)

    Gonsebatt, M.E. [UNAM, Ciudad Universitaria, Dept. Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Mexico (Mexico); Razo, L.M. del; Sanchez-Pena, L.C. [Seccion de Toxicologia, CINVESTAV, Mexico (Mexico); Cerbon, M.A. [Facultad de Quimica, UNAM, Departamento de Biologia, Mexico (Mexico); Zuniga, O.; Ramirez, P. [Facultad de Estudios Superiores Cuautitlan, UNAM, Laboratorio de Toxicologia Celular, Coordinacion General de Estudios de Posgrado e Investigacion, Cuautitlan Izcalli, Estado de Mexico (Mexico)

    2007-09-15

    Cytokeratins (CK) constitute a family of cytoskeletal intermediate filament proteins that are typically expressed in epithelial cells. An abnormal structure and function are effects that are clearly related to liver diseases as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. We have previously observed that sodium arsenite (SA) induced the synthesis of CK18 protein and promotes a dose-related disruption of cytoplasmic CK18 filaments in a human hepatic cell line. Both abnormal gene expression and disturbance of structural organization are toxic effects that are likely to cause liver disease by interfering with normal hepatocyte function. To investigate if a disruption in the CK18 expression pattern is associated with arsenite liver damage, we investigated CK18 mRNA and protein levels in liver slices treated with low levels of SA. Organotypic cultures were incubated with 0.01, 1 and 10 {mu}M of SA in the absence and presence of N-acetyl cysteine (NAC). Cell viability and inorganic arsenic metabolism were determined. Increased expression of CK18 was observed after exposure to SA. The addition of NAC impeded the oxidative effects of SA exposure, decreasing the production of thiobarbituric acid-reactive substances and significantly diminishing the up regulation of CK18 mRNA and protein. Liver arsenic levels correlated with increased levels of mRNA. Mice treated with intragastric single doses of 2.5 and 5 mg/kg of SA showed an increased expression of CK18. Results suggest that CK18 expression may be a sensible early biomarker of oxidative stress and damage induced by arsenite in vitro and in vivo. Then, during SA exposure, altered CK expression may compromise liver function. (orig.)

  1. Streptozotocin-induced diabetes mellitus affects lysosomal enzymes in rat liver

    Directory of Open Access Journals (Sweden)

    G.B. Peres

    2014-06-01

    Full Text Available It has been previously shown that dextran sulfate administered to diabetic rats accumulates in the liver and kidney, and this could be due to a malfunction of the lysosomal digestive pathway. The aim of the present study was to evaluate the expression and activities of lysosomal enzymes that act upon proteins and sulfated polysaccharides in the livers of diabetic rats. Diabetes mellitus was induced by streptozotocin in 26 male Wistar rats (12 weeks old, while 26 age-matched controls received only vehicle. The livers were removed on either the 10th or the 30th day of the disease, weighed, and used to evaluate the activity, expression, and localization of lysosomal enzymes. A 50-60% decrease in the specific activities of cysteine proteases, especially cathepsin B, was observed in streptozotocin-induced diabetes mellitus. Expression (mRNA of cathepsins B and L was also decreased on the 10th, but not on the 30th day. Sulfatase decreased 30% on the 30th day, while glycosidases did not vary (or presented a transitory and slight decrease. There were no apparent changes in liver morphology, and immunohistochemistry revealed the presence of cathepsin B in hepatocyte granules. The decrease in sulfatase could be responsible for the dextran sulfate build-up in the diabetic liver, since the action of sulfatase precedes glycosidases in the digestive pathway of sulfated polysaccharides. Our findings suggest that the decreased activities of cathepsins resulted from decreased expression of their genes, and not from general lysosomal failure, because the levels of glycosidases were normal in the diabetic liver.

  2. Immunohistochemical Analysis of Platelet Extract Effects on Liver Injury Induced by CCl4 in Male Rats

    Directory of Open Access Journals (Sweden)

    Zahra Hesami

    2016-01-01

    Full Text Available Backgrounds & objectives: Liver damage results in a large accumulation of external cellular matrix that affects the function of this important body organ in a long term and finally stops its function completely. The growth factors existing in platelet extract are more cost-effective, available, and stable than recombinant ones. To determine whether the platelet extract effects on histological changes in liver injury induced by carbon tetrachloride (CCl4, we used immunohistochemical analysis in male rats. Methods: In this project the 28 male Wistar rats (250-300 g were randomly divided into 4 groups, each consisting of 7 animals. The rats were divided into four experimental groups as follows: the first group (sham intraperitoneally received only olive oil as the solvent of carbon tetrachloride; second group (CCl4 intraperitoneally received carbon tetrachloride dissolved in olive oil (ratio of about 1: 1 at a concentration of 1 ml/kg and a twice a week for eight weeks; third group subcutaneously received only platelet extract at a concentration of 0.5 ml/kg twice a week for three weeks; and fourth group received both CCl4 intraperitoneally for eight weeks and platelet extract subcutaneously for last three weeks. After 8 weeks of trial blood and liver sampling were done. Blood samples sent for enzymatic (AST, ALT tests and liver samples tested for histological and immunohistochemical studies. The data were analyzed using  one-way ANOVA followed by Tukey test by Graph pad Prism 5 software and data were considered significant at p≤ 0.05. Results: The results show that platelet extract causes a significant (p≤ 0.001 decrease in liver enzymes and albumin improves the function of liver. The level of alfa smooth muscle actin (α-SMA as an index of hepatic stellate cell activation was decreased by platelet extract administration which eventually reduced the necrosis and fibrosis induced by carbon tetrachloride in studied rats

  3. Streptozotocin-induced diabetes mellitus affects lysosomal enzymes in rat liver

    International Nuclear Information System (INIS)

    Peres, G.B.; Juliano, M.A.; Aguiar, J.A.K.; Michelacci, Y.M.

    2014-01-01

    It has been previously shown that dextran sulfate administered to diabetic rats accumulates in the liver and kidney, and this could be due to a malfunction of the lysosomal digestive pathway. The aim of the present study was to evaluate the expression and activities of lysosomal enzymes that act upon proteins and sulfated polysaccharides in the livers of diabetic rats. Diabetes mellitus was induced by streptozotocin in 26 male Wistar rats (12 weeks old), while 26 age-matched controls received only vehicle. The livers were removed on either the 10 th or the 30 th day of the disease, weighed, and used to evaluate the activity, expression, and localization of lysosomal enzymes. A 50-60% decrease in the specific activities of cysteine proteases, especially cathepsin B, was observed in streptozotocin-induced diabetes mellitus. Expression (mRNA) of cathepsins B and L was also decreased on the 10 th , but not on the 30 th day. Sulfatase decreased 30% on the 30 th day, while glycosidases did not vary (or presented a transitory and slight decrease). There were no apparent changes in liver morphology, and immunohistochemistry revealed the presence of cathepsin B in hepatocyte granules. The decrease in sulfatase could be responsible for the dextran sulfate build-up in the diabetic liver, since the action of sulfatase precedes glycosidases in the digestive pathway of sulfated polysaccharides. Our findings suggest that the decreased activities of cathepsins resulted from decreased expression of their genes, and not from general lysosomal failure, because the levels of glycosidases were normal in the diabetic liver

  4. Dietary Supplementation with Lactobacillus casei Alleviates Lipopolysaccharide-Induced Liver Injury in a Porcine Model

    Directory of Open Access Journals (Sweden)

    Di Zhao

    2017-11-01

    Full Text Available This study aims to determine whether Lactobacillus casei (L. casei could relieve liver injury in piglets challenged with lipopolysaccharide (LPS. Piglets were randomly allocated into one of the three groups: control, LPS, and L. casei. The control and LPS groups were fed a corn- and soybean meal-based diet, whereas the L. casei group was fed the basal diet supplemented with 6 × 106 cfu/g L. casei. On Day 31 of the trial, piglets in the LPS and L. casei groups received intraperitoneal administration of LPS (100 µg/kg body weight, while the control group received the same volume of saline. Blood and liver samples were collected for analysis. Results showed that L. casei supplementation decreased the feed/gain ratio (p = 0.027 and diarrhea incidence (p < 0.001, and attenuated LPS-induced liver histomorphological abnormalities. Compared with the control group, LPS challenge dramatically increased glutamyl transpeptidase activity (p = 0.001 in plasma as well as the concentrations of Interleukin 6 (IL-6 (p = 0.048, Tumor necrosis factor-alpha (TNF-α (p = 0.041, and Malondialdehyde (MDA (p = 0.001 in the liver, while decreasing the hepatic SOD activity. LPS also increased (p < 0.05 the mRNA levels for IL-6, IL-8, TNF-α, Toll-like receptors 4 (TLR4, Nuclear factor κB (NF-κB and Heat shock protein 70 (HSP70 in the liver. The adverse effects of LPS challenge were ameliorated by L. casei supplementation. In conclusion, dietary L. casei alleviates LPS-induced liver injury via reducing pro-inflammatory cytokines and increasing anti-oxidative capacity.

  5. Streptozotocin-induced diabetes mellitus affects lysosomal enzymes in rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Peres, G.B. [Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Bioquímica, São Paulo, SP, Brasil, Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP (Brazil); Juliano, M.A. [Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Biofísica, São Paulo, SP, Brasil, Departamento de Biofísica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP (Brazil); Aguiar, J.A.K.; Michelacci, Y.M. [Universidade Federal de São Paulo, Escola Paulista de Medicina, Departamento de Bioquímica, São Paulo, SP, Brasil, Departamento de Bioquímica, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP (Brazil)

    2014-05-09

    It has been previously shown that dextran sulfate administered to diabetic rats accumulates in the liver and kidney, and this could be due to a malfunction of the lysosomal digestive pathway. The aim of the present study was to evaluate the expression and activities of lysosomal enzymes that act upon proteins and sulfated polysaccharides in the livers of diabetic rats. Diabetes mellitus was induced by streptozotocin in 26 male Wistar rats (12 weeks old), while 26 age-matched controls received only vehicle. The livers were removed on either the 10{sup th} or the 30{sup th} day of the disease, weighed, and used to evaluate the activity, expression, and localization of lysosomal enzymes. A 50-60% decrease in the specific activities of cysteine proteases, especially cathepsin B, was observed in streptozotocin-induced diabetes mellitus. Expression (mRNA) of cathepsins B and L was also decreased on the 10{sup th}, but not on the 30{sup th} day. Sulfatase decreased 30% on the 30{sup th} day, while glycosidases did not vary (or presented a transitory and slight decrease). There were no apparent changes in liver morphology, and immunohistochemistry revealed the presence of cathepsin B in hepatocyte granules. The decrease in sulfatase could be responsible for the dextran sulfate build-up in the diabetic liver, since the action of sulfatase precedes glycosidases in the digestive pathway of sulfated polysaccharides. Our findings suggest that the decreased activities of cathepsins resulted from decreased expression of their genes, and not from general lysosomal failure, because the levels of glycosidases were normal in the diabetic liver.

  6. Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes.

    Directory of Open Access Journals (Sweden)

    Jeffrey J Sutherland

    2016-03-01

    Full Text Available The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH from Drug Matrix (DM and open TG-GATEs (TG, human primary hepatocytes (HPH from TG, and mouse liver/HepG2 results from the Gene Expression Omnibus (GEO repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1 gene level for 9071 high expression genes in rat liver, 2 gene set analysis (GSA using canonical pathways and gene ontology sets, 3 weighted gene co-expression network analysis (WGCNA. Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance.

  7. Pathological Lesions and Inducible Nitric Oxide Synthase Expressions in the Liver of Mice Experimentally Infected with Clonorchis sinensis.

    Science.gov (United States)

    Yang, Qing-Li; Shen, Ji-Qing; Xue, Yan; Cheng, Xiao-Bing; Jiang, Zhi-Hua; Yang, Yi-Chao; Chen, Ying-Dan; Zhou, Xiao-Nong

    2015-12-01

    The nitric oxide (NO) formation and intrinsic nitrosation may be involved in the possible mechanisms of liver fluke-associated carcinogenesis. We still do not know much about the responses of inducible NO synthase (iNOS) induced by Clonorchis sinensis infection. This study was conducted to explore the pathological lesions and iNOS expressions in the liver of mice with different infection intensity levels of C. sinensis. Extensive periductal inflammatory cell infiltration, bile duct hyperplasia, and fibrosis were commonly observed during the infection. The different pathological responses in liver tissues strongly correlated with the infection intensity of C. sinensis. Massive acute spotty necrosis occurred in the liver parenchyma after a severe infection. The iNOS activity in liver tissues increased, and iNOS-expressing cells with morphological differences were observed after a moderate or severe infection. The iNOS-expressing cells in liver tissues had multiple origins.

  8. N-cadherin{sup +} HSCs in fetal liver exhibit higher long-term bone marrow reconstitution activity than N-cadherin{sup -} HSCs

    Energy Technology Data Exchange (ETDEWEB)

    Toyama, Hirofumi; Arai, Fumio; Hosokawa, Kentaro; Ikushima, Yoshiko Matsumoto [Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan); Suda, Toshio, E-mail: sudato@z3.keio.jp [Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, School of Medicine, Keio University, 35 Shinano-machi, Shinjuku-ku, Tokyo 160-8582 (Japan)

    2012-11-23

    Highlights: Black-Right-Pointing-Pointer High N-cad expression was detected in E12.5 mouse FL LT-HSCs (EPCR{sup +} LSK cells). Black-Right-Pointing-Pointer Immunohistochemically, N-cad{sup +} HSCs co-localized with sinusoidal ECs (Lyve-1{sup +} cells) in E12.5 FL, but these gradually detached in E15.5 and E18.5 FL. Black-Right-Pointing-Pointer N-cad{sup +} LSK cells in E12.5 FL exhibited higher LTR activity versus N-cad{sup -} LSK cells, which decreased in E15.5 and E18.5. Black-Right-Pointing-Pointer N-cad expression may confer high LTR activity to HSCs by facilitating interactions with the perisinusoidal niche in FL. -- Abstract: Adult hematopoietic stem cells (HSCs) are maintained in a microenvironment known as the stem cell niche. The regulation of HSCs in fetal liver (FL) and their niche, however, remains to be elucidated. In this study, we investigated the role of N-cadherin (N-cad) in the maintenance of HSCs during FL hematopoiesis. By using anti-N-cad antibodies (Abs) produced by our laboratory, we detected high N-cad expression in embryonic day 12.5 (E12.5) mouse FL HSCs, but not in E15.5 and E18.5 FL. Immunofluorescence staining revealed that N-cad{sup +}c-Kit{sup +} and N-cad{sup +} endothelial protein C receptor (EPCR){sup +} HSCs co-localized with Lyve-1{sup +} sinusoidal endothelial cells (ECs) in E12.5 FL and that some of these cells also expressed N-cad. However, N-cad{sup +} HSCs were also observed to detach from the perisinusoidal niche at E15.5 and E18.5, concomitant with a down-regulation of N-cad and an up-regulation of E-cadherin (E-cad) in hepatic cells. Moreover, EPCR{sup +} long-term (LT)-HSCs were enriched in the N-cad{sup +}Lin{sup -}Sca-1{sup +}c-Kit{sup +} (LSK) fraction in E12.5 FL, but not in E15.5 or E18.5 FL. In a long-term reconstitution (LTR) activity assay, higher engraftment associated with N-cad{sup +} LSK cells versus N-cad{sup -} LSK cells in E12.5 FL when transplanted into lethally irradiated recipient mice. However, the

  9. N-cadherin+ HSCs in fetal liver exhibit higher long-term bone marrow reconstitution activity than N-cadherin− HSCs

    International Nuclear Information System (INIS)

    Toyama, Hirofumi; Arai, Fumio; Hosokawa, Kentaro; Ikushima, Yoshiko Matsumoto; Suda, Toshio

    2012-01-01

    Highlights: ► High N-cad expression was detected in E12.5 mouse FL LT-HSCs (EPCR + LSK cells). ► Immunohistochemically, N-cad + HSCs co-localized with sinusoidal ECs (Lyve-1 + cells) in E12.5 FL, but these gradually detached in E15.5 and E18.5 FL. ► N-cad + LSK cells in E12.5 FL exhibited higher LTR activity versus N-cad − LSK cells, which decreased in E15.5 and E18.5. ► N-cad expression may confer high LTR activity to HSCs by facilitating interactions with the perisinusoidal niche in FL. -- Abstract: Adult hematopoietic stem cells (HSCs) are maintained in a microenvironment known as the stem cell niche. The regulation of HSCs in fetal liver (FL) and their niche, however, remains to be elucidated. In this study, we investigated the role of N-cadherin (N-cad) in the maintenance of HSCs during FL hematopoiesis. By using anti-N-cad antibodies (Abs) produced by our laboratory, we detected high N-cad expression in embryonic day 12.5 (E12.5) mouse FL HSCs, but not in E15.5 and E18.5 FL. Immunofluorescence staining revealed that N-cad + c-Kit + and N-cad + endothelial protein C receptor (EPCR) + HSCs co-localized with Lyve-1 + sinusoidal endothelial cells (ECs) in E12.5 FL and that some of these cells also expressed N-cad. However, N-cad + HSCs were also observed to detach from the perisinusoidal niche at E15.5 and E18.5, concomitant with a down-regulation of N-cad and an up-regulation of E-cadherin (E-cad) in hepatic cells. Moreover, EPCR + long-term (LT)-HSCs were enriched in the N-cad + Lin − Sca-1 + c-Kit + (LSK) fraction in E12.5 FL, but not in E15.5 or E18.5 FL. In a long-term reconstitution (LTR) activity assay, higher engraftment associated with N-cad + LSK cells versus N-cad − LSK cells in E12.5 FL when transplanted into lethally irradiated recipient mice. However, the higher engraftment of N-cad + LSK cells decreased subsequently in E15.5 and E18.5 FL. It is possible that N-cad expression conferred higher LTR activity to HSCs by facilitating

  10. Possible gasoline-induced chronic liver injury due to occupational malpractice in a motor mechanic: a case report.

    Science.gov (United States)

    Gunathilaka, Mahesh Lakmal; Niriella, Madunil Anuk; Luke, Nathasha Vihangi; Piyarathna, Chathura Lakmal; Siriwardena, Rohan Chaminda; De Silva, Arjuna Priyadarshin; de Silva, Hithanadura Janaka

    2017-07-03

    Hydrocarbon-induced occupational liver injury is a well-known clinical entity among petroleum industry workers. There are many types of hydrocarbon exposure, with inhalation being the most common. Hydrocarbon-induced occupational liver injury is a rarely suspected and commonly missed etiological agent for liver injury. We report a case of a non-petroleum industry worker with chronic liver disease secondary to hydrocarbon-induced occupational liver injury caused by chronic low-grade hydrocarbon ingestion due to occupational malpractice. A 23-year-old Sri Lankan man who was a motor mechanic presented to our hospital with decompensated cirrhosis. He had been chronically exposed to gasoline via inadvertent ingestion due to occupational malpractice. He used to remove gasoline from carburetors by sucking and failed to practice mouth washing thereafter. On evaluation, he had histologically proven established cirrhosis. A comprehensive history and workup ruled out other nonoccupational etiologies for cirrhosis. The patient's long-term occupational gasoline exposure and clinical course led us to a diagnosis of hydrocarbon-induced occupational liver injury leading to decompensated cirrhosis. Hydrocarbon-induced occupational liver injury should be considered as a cause when evaluating a patient with liver injury with possible exposure in relevant occupations.

  11. Sulforaphane Protects the Liver against CdSe Quantum Dot-Induced Cytotoxicity.

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    Wei Wang

    Full Text Available The potential cytotoxicity of cadmium selenide (CdSe quantum dots (QDs presents a barrier to their use in biomedical imaging or as diagnostic and therapeutic agents. Sulforaphane (SFN is a chemoprotective compound derived from cruciferous vegetables which can up-regulate antioxidant enzymes and induce apoptosis and autophagy. This study reports the effects of SFN on CdSe QD-induced cytotoxicity in immortalised human hepatocytes and in the livers of mice. CdSe QDs induced dose-dependent cell death in hepatocytes with an IC50 = 20.4 μM. Pre-treatment with SFN (5 μM increased cell viability in response to CdSe QDs (20 μM from 49.5 to 89.3%. SFN induced a pro-oxidant effect characterized by depletion of intracellular reduced glutathione during short term exposure (3-6 h, followed by up-regulation of antioxidant enzymes and glutathione levels at 24 h. SFN also caused Nrf2 translocation into the nucleus, up-regulation of antioxidant enzymes and autophagy. siRNA knockdown of Nrf2 suggests that the Nrf2 pathway plays a role in the protection against CdSe QD-induced cell death. Wortmannin inhibition of SFN-induced autophagy significantly suppressed the protective effect of SFN on CdSe QD-induced cell death. Moreover, the role of autophagy in SFN protection against CdSe QD-induced cell death was confirmed using mouse embryonic fibroblasts lacking ATG5. CdSe QDs caused significant liver damage in mice, and this was decreased by SFN treatment. In conclusion, SFN attenuated the cytotoxicity of CdSe QDs in both human hepatocytes and in the mouse liver, and this protection was associated with the induction of Nrf2 pathway and autophagy.

  12. PROTECTIVE EFFECT OF MORINGA PEREGRINA LEAVES EXTRACT ON ACETAMINOPHEN -INDUCED LIVER TOXICITY IN ALBINO RATS.

    Science.gov (United States)

    Azim, Samy Abdelfatah Abdel; Abdelrahem, Mohamed Taha; Said, Mostafa Mohamed; Khattab, Alshaimaa

    2017-01-01

    Acetaminophen is a common antipyretic drug but at overdose can cause severe hepatotoxicity that may further develop into liver failure and hepatic centrilobular necrosis in experimental animals and humans. This study was undertaken to assess the ameliorative role of Moringa peregrina leaves extract against acetaminophen toxicity in rats. Induction of hepatotoxicity was done by chronic oral administration of acetaminophen (750 mg/kg bwt) for 4 weeks. To study the possible hepatoprotective effect, Moringa peregrina leaves extract (200 mg/kg bwt) or Silymarin (50 mg/kg bwt) was administered orally, for 4 weeks, along with acetaminophen. acetaminophen significantly increased serum liver enzymes and caused oxidative stress, evidenced by significantly increased tissue malondialdehyde, glutathione peroxidase, hepatic DNA fragmentation, and significant decrease of glutathione and antioxidant enzymes in liver, blood and brain. On the other hand, administration of Moringa peregrina leaves extract reversed acetaminophen-related toxic effects through: powerful malondialdehyde suppression, glutathione peroxidase normalization and stimulation of the cellular antioxidants synthesis represented by significant increase of glutathione, catalase and superoxide dismutase in liver, blood and brain, besides, DNA fragmentation was significantly decreased in the liver tissue. acetaminophen induced oxidative damage can be improved by Moringa peregrina leaves extract-treatment, due to its antioxidant potential.

  13. Vitamin K1 attenuates bile duct ligation-induced liver fibrosis in rats.

    Science.gov (United States)

    Jiao, Kun; Sun, Quan; Chen, Baian; Li, Shengli; Lu, Jing

    2014-06-01

    Vitamin K1 is used as a liver protection drug for cholestasis-induced liver fibrosis in China, but the mechanism of vitamin K1's action in liver fibrosis is unclear. In this study, a model of liver fibrosis was achieved via bile duct ligation in rats. The rats were then injected with vitamin K1, and the levels of serum aspartate aminotransferase, alanine transaminase, total bilirubin and the fibrotic grade score, collagen content, the expressions of α-smooth muscle actin (SMA) and cytokeratin 19 (CK19) were measured on day 28 after ligation. The levels of the biochemical parameters, fibrotic score and collagen content were significantly reduced by treatment with vitamin K1 in bile duct-ligated rats. In addition, α-SMA and CK19 expression was significantly reduced by vitamin K1 treatment in bile duct-ligated rats. These results suggested that vitamin K1 may attenuate liver fibrosis by inhibiting hepatic stellate cell activation in bile duct-ligated rats.

  14. Agmatine protects rat liver from nicotine-induced hepatic damage via antioxidative, antiapoptotic, and antifibrotic pathways.

    Science.gov (United States)

    El-Sherbeeny, Nagla A; Nader, Manar A; Attia, Ghalia M; Ateyya, Hayam

    2016-12-01

    Tobacco smoking with its various forms is a global problem with proved hazardous effects to human health. The present work was planned to study the defending role of agmatine (AGM) on hepatic oxidative stress and damage induced by nicotine in rats. Thirty-two rats divided into four groups were employed: control group, nicotine-only group, AGM group, and AGM-nicotine group. Measurements of serum hepatic biochemical markers, lipid profile, and vascular cell adhesion molecule-1 were done. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) activity, and nitrate/nitrite (NOx) levels were estimated in the liver homogenates. Immunohistochemistry for Bax and transforming growth factor beta (TGF-β1) and histopathology of the liver were also included. Data of the study demonstrated that nicotine administration exhibited marked liver deterioration, an increase in liver enzymes, changes in lipid profile, and an elevation in MDA with a decline in levels of SOD, GSH, and NOx (nitrate/nitrite). Also, levels of proapoptotic Bax and profibrotic TGF-β1 showed marked elevation in the liver. AGM treatment to rats in nicotine-only group ameliorated all the previous changes. These findings indicate that AGM could successfully overcome the nicotine-evoked hepatic oxidative stress and tissue injury, apoptosis, and fibrosis.

  15. Protective Effects of Korean Red Ginseng against Alcohol-Induced Fatty Liver in Rats

    Directory of Open Access Journals (Sweden)

    Hyo Jin Lee

    2015-06-01

    Full Text Available The present study tested the hypothesis that Korean red ginseng (KRG provides a protective effect against alcoholic fatty liver. Male Sprague-Dawley rats were divided into four groups and fed a modified Lieber-DeCarli diet containing 5% (w/v alcohol or an isocaloric amount of dextrin-maltose for the controls for 6 weeks: normal control (CON, alcohol control (ET, and ET treated with 125 or 250 mg/kg body weight/day of KRG (RGL or RGH, respectively. Compared with the CON group, the ET group exhibited a significant increase in triglycerides, total cholesterol and the presence of lipid droplets in the liver, and a decrease in fat mass, which were all attenuated by KRG supplementation in adose-dependent manner. The mitigation was accompanied by AMP-activated protein kinase (AMPK signaling pathways in the liver and adipose tissue. In addition, suppression in the alcohol-induced changes of adipose adipokine mRNA expression was also observed in KRG supplementation group. These findings suggest that KRG may have the potential to ameliorate alcoholic fatty liver by suppressing inappropriate lysis of adipose tissue and preventing unnecessary de novo lipogenesis in the liver, which are mediated by AMPK signaling pathways. A mechanism for an interplay between the two organs is still needed to be examined with further assays.

  16. Ganoderma tsugae Hepatoprotection against Exhaustive Exercise-Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Wan-Teng Lin

    2013-01-01

    Full Text Available Several studies have been shown that accelerated apoptosis is involved in post-exercise lymphocytopenia and tissue damage after high-intensity exercise. Ganoderma tsugae (GT is one of the well-known medicinal mushrooms that possess various pharmacological functions. This mushroom has traditionally been used for health promotion purposes. This study investigates the hepatoprotective effects of GT on exhaustive exercise-induced liver damage. Twenty-four male Sprague-Dawley rats were randomly divided into four groups and designated as exhaustive exercise only (E, exhaustive exercise with low dosage (EL, medium dosage (EM and high dosage (EH GT at 0, 0.1875, 0.9375 and 1.875 g/kg/day, respectively. After 30 days all rats were euthanized immediately after an exhaustive running challenge on a motorized treadmill. The rat livers were immediately harvested. Evidence of apoptotic liver cell death was revealed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL assay and caspases mediated cascade events. DNA fragmentation, an apoptosis process, can be examined using TUNEL assay. A few TUNEL-positive hepatocytes, compared to the exercise only group, were observed in the livers from exhaustive animals supplemented with GT. Immunoblot analysis also showed that caspase-6-mediated specific cleavage of lamin A/C was increased significantly in the livers of group E, but was significantly decreased in the EM and EH groups. Our observations demonstrate that GT possesses anti-apoptotic and hepatoprotective potential after exhaustive exercise.

  17. Ganoderma tsugae hepatoprotection against exhaustive exercise-induced liver injury in rats.

    Science.gov (United States)

    Huang, Chi-Chang; Huang, Wen-Ching; Yang, Suh-Ching; Chan, Chih-Chi; Lin, Wan-Teng

    2013-01-29

    Several studies have been shown that accelerated apoptosis is involved in post-exercise lymphocytopenia and tissue damage after high-intensity exercise. Ganoderma tsugae (GT) is one of the well-known medicinal mushrooms that possess various pharmacological functions. This mushroom has traditionally been used for health promotion purposes. This study investigates the hepatoprotective effects of GT on exhaustive exercise-induced liver damage. Twenty-four male Sprague-Dawley rats were randomly divided into four groups and designated as exhaustive exercise only (E), exhaustive exercise with low dosage (EL), medium dosage (EM) and high dosage (EH) GT at 0, 0.1875, 0.9375 and 1.875 g/kg/day, respectively. After 30 days all rats were euthanized immediately after an exhaustive running challenge on a motorized treadmill. The rat livers were immediately harvested. Evidence of apoptotic liver cell death was revealed using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and caspases mediated cascade events. DNA fragmentation, an apoptosis process, can be examined using TUNEL assay. A few TUNEL-positive hepatocytes, compared to the exercise only group, were observed in the livers from exhaustive animals supplemented with GT. Immunoblot analysis also showed that caspase-6-mediated specific cleavage of lamin A/C was increased significantly in the livers of group E, but was significantly decreased in the EM and EH groups. Our observations demonstrate that GT possesses anti-apoptotic and hepatoprotective potential after exhaustive exercise.

  18. Case Characterization, Clinical Features and Risk Factors in Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Aida Ortega-Alonso

    2016-05-01

    Full Text Available Idiosyncratic drug-induced liver injury (DILI caused by xenobiotics (drugs, herbals and dietary supplements presents with a range of both phenotypes and severity, from acute hepatitis indistinguishable of viral hepatitis to autoimmune syndromes, steatosis or rare chronic vascular syndromes, and from asymptomatic liver test abnormalities to acute liver failure. DILI pathogenesis is complex, depending on the interaction of drug physicochemical properties and host factors. The awareness of risk factors for DILI is arising from the analysis of large databases of DILI cases included in Registries and Consortia networks around the world. These networks are also enabling in-depth phenotyping with the identification of predictors for severe outcome, including acute liver failure and mortality/liver transplantation. Genome wide association studies taking advantage of these large cohorts have identified several alleles from the major histocompatibility complex system indicating a fundamental role of the adaptive immune system in DILI pathogenesis. Correct case definition and characterization is crucial for appropriate phenotyping, which in turn will strengthen sample collection for genotypic and future biomarkers studies.

  19. The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury

    International Nuclear Information System (INIS)

    Mandal, Mili; Gardner, Carol R.; Sun, Richard; Choi, Hyejeong; Lad, Sonali; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2016-01-01

    Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300 mg/kg, i.p.) to control mice resulted in an increase in CD11b + infiltrating Ly6G + granulocytic and Ly6G − monocytic cells in the spleen and the liver. The majority of the Ly6G + cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G − cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80 + ) and immature (F4/80 − ) pro-inflammatory Ly6C hi macrophages and mature anti-inflammatory (Ly6C lo ) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3 + macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs. - Highlights: • Multiple inflammatory cell subpopulations accumulate in the spleen and liver following acetaminophen (APAP) intoxication. • Splenectomy alters liver inflammatory cell populations responding to APAP. • Inflammatory cells accumulating in the liver in response to APAP originate from the spleen and the bone marrow. • Hepatotoxicity is reduced in

  20. The spleen as an extramedullary source of inflammatory cells responding to acetaminophen-induced liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Mandal, Mili, E-mail: milimandal@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Gardner, Carol R., E-mail: cgardner@pharmacy.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Sun, Richard, E-mail: fishpower52@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Choi, Hyejeong, E-mail: choi@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Lad, Sonali, E-mail: sonurose92@gmail.com [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Mishin, Vladimir, E-mail: mishinv@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Jeffrey D., E-mail: jlaskin@eohsi.rutgers.edu [Department of Environmental and Occupational Health, School of Public Health, Rutgers University, Piscataway, NJ 08854 (United States); Laskin, Debra L., E-mail: laskin@eohsi.rutgers.edu [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854 (United States)

    2016-08-01

    Macrophages have been shown to play a role in acetaminophen (APAP)-induced hepatotoxicity, contributing to both pro- and anti-inflammatory processes. In these studies, we analyzed the role of the spleen as an extramedullary source of hepatic macrophages. APAP administration (300 mg/kg, i.p.) to control mice resulted in an increase in CD11b{sup +} infiltrating Ly6G{sup +} granulocytic and Ly6G{sup −} monocytic cells in the spleen and the liver. The majority of the Ly6G{sup +} cells were also positive for the monocyte/macrophage activation marker, Ly6C, suggesting a myeloid derived suppressor cell (MDSC) phenotype. By comparison, Ly6G{sup −} cells consisted of 3 subpopulations expressing high, intermediate, and low levels of Ly6C. Splenectomy was associated with increases in mature (F4/80{sup +}) and immature (F4/80{sup −}) pro-inflammatory Ly6C{sup hi} macrophages and mature anti-inflammatory (Ly6C{sup lo}) macrophages in the liver after APAP; increases in MDSCs were also noted in the livers of splenectomized (SPX) mice after APAP. This was associated with increases in APAP-induced expression of chemokine receptors regulating pro-inflammatory (CCR2) and anti-inflammatory (CX3CR1) macrophage trafficking. In contrast, APAP-induced increases in pro-inflammatory galectin-3{sup +} macrophages were blunted in livers of SPX mice relative to control mice, along with hepatic expression of TNF-α, as well as the anti-inflammatory macrophage markers, FIZZ-1 and YM-1. These data demonstrate that multiple subpopulations of pro- and anti-inflammatory cells respond to APAP-induced injury, and that these cells originate from distinct hematopoietic reservoirs. - Highlights: • Multiple inflammatory cell subpopulations accumulate in the spleen and liver following acetaminophen (APAP) intoxication. • Splenectomy alters liver inflammatory cell populations responding to APAP. • Inflammatory cells accumulating in the liver in response to APAP originate from the spleen and the

  1. Carvacrol attenuates N-nitrosodiethylamine induced liver injury in experimental Wistar rats

    Directory of Open Access Journals (Sweden)

    Balan Rajan

    2015-06-01

    Full Text Available Carvacrol is a main constituent in the essential oils of countless aromatic plants including Origanum Vulgare and Thymus vulgari, which has been assessed for substantial pharmacological properties. In recent years, notable research has been embarked on to establish the biological actions of Carvacrol for its promising use in clinical applications. The present study is an attempt to reveal the protective role of Carvacrol against N-Nitrosodiethylamine (DEN induced hepatic injury in male Wistar albino rats. DEN is an egregious toxin, present in numerous environmental factors, which enhances chemical driven liver damage by inducing oxidative stress and cellular injury. Administration of DEN (200 mg/kg bodyweight, I.P to rats results in elevated marker enzymes (in both serum and tissue. Carvacrol (15 mg/kg body weight suppressed the elevation of marker enzymes (in both serum and tissue and augmented the antioxidants levels. The hoisted activities of Phase I enzymes and inferior activities of Phase II enzymes were observed in DEN-administered animals, whereas Carvacrol treated animals showed improved near normal activity. Histological observations also support the protective role of Carvacrol against DEN induced liver damage. Final outcome from our findings intimate that Carvacrol might be beneficial in attenuating toxin induced liver damage.

  2. Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort.

    Directory of Open Access Journals (Sweden)

    Michelle Rook

    Full Text Available Intrahepatic cholestasis of pregnancy (ICP has important fetal implications. There is increased risk for poor fetal outcomes, including preterm delivery, meconium staining of amniotic fluid, respiratory distress, fetal distress and demise.One hundred and one women diagnosed with ICP between January 2005 and March 2009 at San Francisco General Hospital were included in this study. Single predictor logistic regression models were used to assess the associations of maternal clinical and biochemical predictors with fetal complications. Clinical predictors analyzed included age, race/ethnicity, gravidity, parity, history of liver or biliary disease, history of ICP in previous pregnancies, and induction. Biochemical predictors analyzed included serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, albumin, total protein, and total bile acids (TBA.The prevalence of ICP was 1.9%. Most were Latina (90%. Labor was induced in the majority (87% and most were delivered by normal spontaneous vaginal delivery (84%. Fetal complications occurred in 33% of the deliveries, with respiratory distress accounting for the majority of complications. There were no statistically significant clinical or biochemical predictors associated with an increased risk of fetal complications. Elevated TBA had little association with fetal complications until reaching greater than 100 µmoL/L, with 3 out of 5 having reported complications. ICP in previous pregnancies was associated with decreased risk of fetal complications (OR 0.21, p = 0.046. There were no cases of late term fetal demise.Maternal clinical and laboratory features, including elevated TBA, did not appear to be substantial predictors of fetal complications in ICP.

  3. Dietary moderately oxidized oil induces expression of fibroblast growth factor 21 in the liver of pigs

    Directory of Open Access Journals (Sweden)

    Varady Juliane

    2012-03-01

    Full Text Available Abstract Background Fibroblast growth factor 21 (FGF21, whose expression is induced by peroxisome proliferator-activated receptor α (PPARα, has been recently identified as a novel metabolic regulator which plays a crucial role in glucose homeostasis, lipid metabolism, insulin sensitivity and obesity. Previous studies have shown that administration of oxidized fats leads to an activation of PPARα in the liver. Therefore, the present study investigated the hypothesis that feeding of oxidized fats causes an induction of FGF21 in the liver. Methods Twenty four crossbred pigs were allocated to two groups of 12 pigs each and fed nutritionally adequate diets with either fresh rapeseed oil or oxidized rapeseed oil prepared by heating at a temperature of 175°C for 72 h. Results In pigs fed the oxidized fat mRNA abundance and protein concentrations of FGF21 in liver were significantly increased (P P P Conclusion The present study shows for the first time that administration of an oxidized fat induces the expression of FGF21 in the liver, probably mediated by activation of PPARα. Induction of FGF21 could be involved in several effects observed in animals administered an oxidized fat.

  4. Protective role of garlic against gamma radiation induced histological and histochemical changes in rat liver

    International Nuclear Information System (INIS)

    Abdel Motaal, N.A.; Abdel Maguid, A.

    2007-01-01

    The present work was planned to evaluate the radioprotective effect of garlic (Allium sativum) against the hazardous action of gamma radiation on liver of rat one and ten days post-exposure. Garlic was orally administered (100 mg/ kg body wt) to rats daily for two weeks before exposure to single dose whole body gamma-irradiation (5Gy). The results showed that exposure of rats to gamma- irradiation caused massive portal infiltration with inflammatory cells, dilatation of blood sinusoids, an increase in the number of Kupffer cells, vacuolation of some hepatocytes as well as pyknosis and karyolysis of hepatic nuclei in the liver tissue. Histochemical examination of liver one day post- irradiation illustrated weak to moderate glycogen particles. While, on ten days post-irradiation, a strong activity for glycogen was detected. The disturbance in carbohydrate metabolism is closely related to the radiation induced histological damage in the liver tissue. Administration of garlic for 2 weeks pre-irradiation reduced the radiation induced histopathological changes and showed marked protection against the tissue damaging effect of radiation. It could be concluded that treatment of rats with garlic before exposure to gamma-irradiation offered a noticeable radioprotective effect of the studied organ

  5. Experimental Protoporphyria: Effect of Bile Acids on Liver Damage Induced by Griseofulvin

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    María del Carmen Martinez

    2015-01-01

    Full Text Available The effect of bile acids administration to an experimental mice model of Protoporphyria produced by griseofulvin (Gris was investigated. The aim was to assess whether porphyrin excretion could be accelerated by bile acids treatment in an attempt to diminish liver damage induced by Gris. Liver damage markers, heme metabolism, and oxidative stress parameters were analyzed in mice treated with Gris and deoxycholic (DXA, dehydrocholic (DHA, chenodeoxycholic, or ursodeoxycholic (URSO. The administration of Gris alone increased the activities of glutathione reductase (GRed, superoxide dismutase (SOD, alkaline phosphatase (AP, gamma glutamyl transpeptidase (GGT, and glutathione-S-transferase (GST, as well as total porphyrins, glutathione (GSH, and cytochrome P450 (CYP levels in liver. Among the bile acids studied, DXA and DHA increased PROTO IX excretion, DXA also abolished the action of Gris, reducing lipid peroxidation and hepatic GSH and CYP levels, and the activities of GGT, AP, SOD, and GST returned to control values. However, porphyrin accumulation was not prevented by URSO; instead this bile acid reduced ALA-S and the antioxidant defense enzymes system activities. In conclusion, we postulate that DXA acid would be more effective to prevent liver damage induced by Gris.

  6. Hepatoprotective Effects of Panus giganteus (Berk. Corner against Thioacetamide- (TAA- Induced Liver Injury in Rats

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    Wei-Lun Wong

    2012-01-01

    Full Text Available Panus giganteus, a culinary and medicinal mushroom consumed by selected indigenous communities in Malaysia, is currently being considered for large scale cultivation. This study was undertaken to investigate the hepatoprotective effects of P. giganteus against thioacetamide- (TAA- induced liver injury in Sprague-Dawley rats. The rats were injected intraperitoneally with TAA thrice weekly and were orally administered freeze-dried fruiting bodies of P. giganteus (0.5 or 1 g/kg daily for two months, while control rats were given vehicle or P. giganteus only. After 60 days, rats administered with P. giganteus showed lower liver body weight ratio, restored levels of serum liver biomarkers and oxidative stress parameters comparable to treatment with the standard drug silymarin. Gross necropsy and histopathological examination further confirmed the hepatoprotective effects of P. giganteus. This is the first report on hepatoprotective effects of P. giganteus. The present study showed that P. giganteus was able to prevent or reduce the severity of TAA-induced liver injury.

  7. Portulaca oleracea L. alleviates liver injury in streptozotocin-induced diabetic mice

    Science.gov (United States)

    Peng, Hao; Gu, Wei; Li, Min; Chen, Zhe

    2018-01-01

    Purslane is a widespread succulent herb that exhibits various pharmacological effects. The purpose of this study was to evaluate the protective effect of Portulaca oleracea L. (purslane) on streptozotocin-induced diabetes in mice. Oral glucose-tolerance tests were carried out to assess blood glucose levels and body weight and food intake were recorded. The biochemical parameters anti-aspartate aminotransferase, alanine aminotransferase, insulin, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα were also measured. The pathological condition of liver tissues were examined by hematoxylin–eosin staining. Rho, ROCK1, ROCK2, NFκBp65, p-NFκBp65, IκBα, and p-IκBα expression in liver tissue were analyzed by Western blot. Purslane increased body weight and decreased food intake. Purslane also significantly reduced concentrations of glucose, anti-aspartate aminotransferase, alanine aminotransferase, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα in serum. Serum insulin was elevated with purslane treatment. In addition, pathologic liver changes in diabetic mice were also alleviated by purslane. Obtained data revealed that purslane restored the levels of Rho–NFκB signaling-related proteins in comparison with those of diabetic mice. Above all, it can be assumed that purslane might play a positive role in regulating streptozotocin-induced liver injury through suppressing the Rho–NFκB pathway. PMID:29343942

  8. Immunohistochemical study of macrophage migration inhibitory factor in rat liver fibrosis induced by thioacetamide

    Directory of Open Access Journals (Sweden)

    Y Hori

    2009-06-01

    Full Text Available Macrophage migration inhibitory factor (MIF is a molecule known to regulate macrophage accumulation at sites of inflammation. To elucidate the role of MIF in progression of liver fibrosis, the immunohistochemical localization of MIF and macrophages in the liver were examined. Male Wistar rats received thioacetamide (TA injections (200 mg/kg, i.p. for 1 or 6 weeks. In biochemical and histological tests, it was confirmed that liver fibrosis was induced. In immunohistochemical analyses, the expression of MIF protein was seen in hepatocytes in the areas extending out from the central veins to the portal tracts. In particular, at 6 weeks, immunoreactivity was detected in degenerated hepatocytes adjacent to the fibrotic areas but hardly observed in the fibrotic areas. On the other hand, a number of exudate macrophages stained by antibody ED1 were seen in the areas from the central veins to the portal tracts at 1 week and in the fibrotic areas at 6 weeks. Macrophages also showed a significant increase in number as compared with controls. These results revealed that there was a close relationship between the appearance of MIF expression and ED1-positive exudate macrophages in degenerated hepatocytes during the progression of TA-induced liver fibrosis.

  9. Immunohistochemical study of macrophage migration inhibitory factor in rat liver fibrosis induced by thioacetamide.

    Science.gov (United States)

    Hori, Y; Sato, S; Yamate, J; Kurasaki, M; Nishihira, J; Hosokawa, T; Fujita, H; Saito, T

    2003-01-01

    Macrophage migration inhibitory factor (MIF) is a molecule known to regulate macrophage accumulation at sites of inflammation. To elucidate the role of MIF in progression of liver fibrosis, the immunohistochemical localization of MIF and macrophages in the liver were examined. Male Wistar rats received thioacetamide (TA) injections (200 mg/kg, i.p.) for 1 or 6 weeks. In biochemical and histological tests, it was confirmed that liver fibrosis was induced. In immunohistochemical analyses, the expression of MIF protein was seen in hepatocytes in the areas extending out from the central veins to the portal tracts. In particular, at 6 weeks, immunoreactivity was detected in degenerated hepatocytes adjacent to the fibrotic areas but hardly observed in the fibrotic areas. On the other hand, a number of exudate macrophages stained by antibody ED1 were seen in the areas from the central veins to the portal tracts at 1 week and in the fibrotic areas at 6 weeks. Macrophages also showed a significant increase in number as compared with controls. These results revealed that there was a close relationship between the appearance of MIF expression and ED1-positive exudate macrophages in degenerated hepatocytes during the progression of TA-induced liver fibrosis.

  10. Protective Effect of Cymbopogon citratus Essential Oil in Experimental Model of Acetaminophen-Induced Liver Injury.

    Science.gov (United States)

    Uchida, Nancy Sayuri; Silva-Filho, Saulo Euclides; Aguiar, Rafael Pazinatto; Wiirzler, Luiz Alexandre Marques; Cardia, Gabriel Fernando Esteves; Cavalcante, Heitor Augusto Otaviano; Silva-Comar, Francielli Maria de Souza; Becker, Tânia Cristina Alexandrino; Silva, Expedito Leite; Bersani-Amado, Ciomar Aparecida; Cuman, Roberto Kenji Nakamura

    2017-01-01

    To investigate the hepatoprotective effect of Cymbopogon citratus or lemongrass essential oil (LGO), it was used in an animal model of acute liver injury induced by acetaminophen (APAP). Swiss mice were pretreated with LGO (125, 250 and 500[Formula: see text]mg/kg) and SLM (standard drug, 200[Formula: see text]mg/kg) for a duration of seven days, followed by the induction of hepatotoxicity of APAP (single dose, 250[Formula: see text]mg/kg). The liver function markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and gamma-glutamyl transferase were determined to evaluate the hepatoprotective effects of the LGO. The livers were used to determine myeloperoxidase (MPO) activity, nitric oxide (NO) production and histological analysis. The effect of LGO on leukocyte migration was evaluated in vitro. Anti-oxidant activity was performed by assessing the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) in vitro. LGO pretreatment decreased significantly the levels of ALT, AST and ALP compared with APAP group. MPO activity and NO production were decreased. The histopathological analysis showed an improved of hepatic lesions in mice after LGO pretreatment. LGO inhibited neutrophil migration and exhibited anti-oxidant activity. Our results suggest that LGO has protective activity against liver toxicity induced by paracetamol.

  11. A case of probable esomeprazole-induced transient liver injury in a pregnant woman with hyperemesis

    Directory of Open Access Journals (Sweden)

    Thomas B

    2016-12-01

    Full Text Available Binny Thomas,1-3 Mahmoud Mohamed,1,3,4 Moza Al Hail,1-3 Fatma Alzahra Y Awwad,1 Ramy M Wahba,1 Sabir B Hassan,1 Khalid Omar,1 Wessam El Kassem,1 Palivalappila Abdul Rouf1 1Hamad Medical Corporation, Doha, Qatar; 2Robert Gordon University, Aberdeen, Scotland, UK; 3Qatar University, Doha, 4Weill Cornell Medical College, Ar-Rayyan, Qatar Abstract: We report a case of 22-year-old primigravida presented to Women’s Hospital – Hamad Medical Corporation emergency with severe epigastric pain, nausea, and vomiting. On admission, she was dehydrated with remarkably worsening symptoms. Laboratory findings revealed significantly elevated liver enzymes with unknown etiology. Her past medical history showed an admission for nausea and vomiting 3 weeks previously and she was discharged on antiemetics, and esomeprazole for the first time. Due to the predominantly elevated liver enzymes, the clinical pharmacist discussed the possibility of esomeprazole-induced adverse effects and suggested to suspend esomeprazole based on the evidence from literature review. The liver enzymes showed a substantial improvement within days after the discontinuation of the drug; however, a rechallenge was not done since it could have adversely affected the mother or the fetus. Using the Naranjo Adverse Drug Reaction Probability scales, the adverse reaction due to esomeprazole was classified as “probably”. Keywords: hyperemesis, drug-induced liver injury, esomeprazole, adverse drug reaction, ADR, proton pump inhibitor

  12. PASS-Predicted Hepatoprotective Activity of Caesalpinia sappan in Thioacetamide-Induced Liver Fibrosis in Rats

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    Farkaad A. Kadir

    2014-01-01

    Full Text Available The antifibrotic effects of traditional medicinal herb Caesalpinia sappan (CS extract on liver fibrosis induced by thioacetamide (TAA and the expression of transforming growth factor β1 (TGF-β1, α-smooth muscle actin (αSMA, and proliferating cell nuclear antigen (PCNA in rats were studied. A computer-aided prediction of antioxidant and hepatoprotective activities was primarily performed with the Prediction Activity Spectra of the Substance (PASS Program. Liver fibrosis was induced in male Sprague Dawley rats by TAA administration (0.03% w/v in drinking water for a period of 12 weeks. Rats were divided into seven groups: control, TAA, Silymarin (SY, and CS 300 mg/kg body weight and 100 mg/kg groups. The effect of CS on liver fibrogenesis was determined by Masson’s trichrome staining, immunohistochemical analysis, and western blotting. In vivo determination of hepatic antioxidant activities, cytochrome P450 2E1 (CYP2E1, and matrix metalloproteinases (MPPS was employed. CS treatment had significantly increased hepatic antioxidant enzymes activity in the TAA-treated rats. Liver fibrosis was greatly alleviated in rats when treated with CS extract. CS treatment was noted to normalize the expression of TGF-β1, αSMA, PCNA, MMPs, and TIMP1 proteins. PASS-predicted plant activity could efficiently guide in selecting a promising pharmaceutical lead with high accuracy and required antioxidant and hepatoprotective properties.

  13. Role of PGC-1{alpha} in exercise and fasting induced adaptations in mouse liver

    DEFF Research Database (Denmark)

    Haase, Tobias Nørresø; Jørgensen, Stine Ringholm; Leick, Lotte

    2011-01-01

    The transcriptional coactivator peroxisome proliferator activated receptor (PPAR)-¿ coactivator (PGC)-1a plays a role in regulation of several metabolic pathways. By use of whole body PGC-1a knockout (KO) mice we investigated the role of PGC-1a in fasting, acute exercise and exercise training ind...... role in regulation of Cyt c and COXI expression in the liver in response to a single exercise bout and prolonged exercise training, which implies that exercise training induced improvements in oxidative capacity of the liver is regulated by PGC-1a.......The transcriptional coactivator peroxisome proliferator activated receptor (PPAR)-¿ coactivator (PGC)-1a plays a role in regulation of several metabolic pathways. By use of whole body PGC-1a knockout (KO) mice we investigated the role of PGC-1a in fasting, acute exercise and exercise training...... induced regulation of key proteins in gluconeogenesis and metabolism in the liver. In both wild type (WT) and PGC-1a KO mice liver, the mRNA content of the gluconeogenic proteins glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) was upregulated during fasting. Pyruvate...

  14. A cellular model to study drug-induced liver injury in nonalcoholic fatty liver disease: Application to acetaminophen

    Energy Technology Data Exchange (ETDEWEB)

    Michaut, Anaïs; Le Guillou, Dounia [INSERM, U991, Université de Rennes 1, Rennes (France); Moreau, Caroline [INSERM, U991, Université de Rennes 1, Rennes (France); Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes (France); Bucher, Simon [INSERM, U991, Université de Rennes 1, Rennes (France); McGill, Mitchell R. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Martinais, Sophie [INSERM, U991, Université de Rennes 1, Rennes (France); Gicquel, Thomas; Morel, Isabelle [INSERM, U991, Université de Rennes 1, Rennes (France); Service de Biochimie et Toxicologie, CHU Pontchaillou, Rennes (France); Robin, Marie-Anne [INSERM, U991, Université de Rennes 1, Rennes (France); Jaeschke, Hartmut [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Fromenty, Bernard, E-mail: bernard.fromenty@inserm.fr [INSERM, U991, Université de Rennes 1, Rennes (France)

    2016-02-01

    Obesity and nonalcoholic fatty liver disease (NAFLD) can increase susceptibility to hepatotoxicity induced by some xenobiotics including drugs, but the involved mechanisms are poorly understood. For acetaminophen (APAP), a role of hepatic cytochrome P450 2E1 (CYP2E1) is suspected since the activity of this enzyme is consistently enhanced during NAFLD. The first aim of our study was to set up a cellular model of NAFLD characterized not only by triglyceride accumulation but also by higher CYP2E1 activity. To this end, human HepaRG cells were incubated for one week with stearic acid or oleic acid, in the presence of different concentrations of insulin. Although cellular triglycerides and the expression of lipid-responsive genes were similar with both fatty acids, CYP2E1 activity was significantly increased only by stearic acid. CYP2E1 activity was reduced by insulin and this effect was reproduced in cultured primary human hepatocytes. Next, APAP cytotoxicity was assessed in HepaRG cells with or without lipid accretion and CYP2E1 induction. Experiments with a large range of APAP concentrations showed that the loss of ATP and glutathione was almost always greater in the presence of stearic acid. In cells pretreated with the CYP2E1 inhibitor chlormethiazole, recovery of ATP was significantly higher in the presence of stearate with low (2.5 mM) or high (20 mM) concentrations of APAP. Levels of APAP-glucuronide were significantly enhanced by insulin. Hence, HepaRG cells can be used as a valuable model of NAFLD to unveil important metabolic and hormonal factors which can increase susceptibility to drug-induced hepatotoxicity. - Highlights: • Nonalcoholic fatty liver disease (NAFLD) is frequent in obese individuals. • NAFLD can favor hepatotoxicity induced by some drugs including acetaminophen (APAP). • A model of NAFLD was set up by using HepaRG cells incubated with stearate or oleate. • Stearate-loaded HepaRG cells presented higher cytochrome P450 2E1 (CYP2E1

  15. Fetal Ultrasound

    Science.gov (United States)

    ... isn't recommended simply to determine a baby's sex. Similarly, fetal ultrasound isn't recommended solely for the purpose of producing keepsake videos or pictures. If your health care provider doesn' ...

  16. Fetal Macrosomia

    Science.gov (United States)

    ... re more likely to have a large baby. Maternal obesity. Fetal macrosomia is more likely if you're ... is more likely to be a result of maternal diabetes, obesity or weight gain during pregnancy than other causes. ...

  17. Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice

    International Nuclear Information System (INIS)

    Shimizu, Masahito; Tanaka, Takuji; Moriwaki, Hisataka; Yasuda, Yoichi; Sakai, Hiroyasu; Kubota, Masaya; Terakura, Daishi; Baba, Atsushi; Ohno, Tomohiko; Kochi, Takahiro; Tsurumi, Hisashi

    2011-01-01

    Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-db/db (db/db) obese mice. Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks. At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of TNF-α and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition. Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals

  18. Activation of AMPK in human fetal membranes alleviates infection-induced expression of pro-inflammatory and pro-labour mediators.

    Science.gov (United States)

    Lim, R; Barker, G; Lappas, M

    2015-04-01

    In non-gestational tissues, the activation of adenosine monophosphate (AMP)-activated kinase (AMPK) is associated with potent anti-inflammatory actions. Infection and/or inflammation, by stimulating pro-inflammatory cytokines and matrix metalloproteinase (MMP)-9, play a central role in the rupture of fetal membranes. However, no studies have examined the role of AMPK in human labour. Fetal membranes, from term and preterm, were obtained from non-labouring and labouring women, and after preterm pre-labour rupture of membranes (PPROM). AMPK activity was assessed by Western blotting of phosphorylated AMPK expression. To determine the effect of AMPK activators on pro-inflammatory cytokines, fetal membranes were pre-treated with AMPK activators then stimulated with bacterial products LPS and flagellin or viral dsDNA analogue poly(I:C). Primary amnion cells were used to determine the effect of AMPK activators on IL-1β-stimulated MMP-9 expression. AMPK activity was decreased with term labour. There was no effect of preterm labour. AMPK activity was also decreased in preterm fetal membranes, in the absence of labour, with PROM compared to intact membranes. AMPK activators AICAR, phenformin and A769662 significantly decreased IL-6 and IL-8 stimulated by LPS, flagellin and poly(I:C). Primary amnion cells treated with AMPK activators significantly decreased IL-1β-induced MMP-9 expression. The decrease in AMPK activity in fetal membranes after spontaneous term labour and PPROM indicates an anti-inflammatory role for AMPK in human labour and delivery. The use of AMPK activators as possible therapeutics for threatened preterm labour would be an exciting future avenue of research. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Antioxidant activity of the oyster mushroom, Pleurotus ostreatus, on CCl(4)-induced liver injury in rats.

    Science.gov (United States)

    Jayakumar, T; Ramesh, E; Geraldine, P

    2006-12-01

    This study was undertaken to investigate the putative antioxidant activity of the oyster mushroom Pleurotus ostreatus on CCl(4)-induced liver damage in male Wistar rats. Intraperitoneal administration of CCl(4) (2ml/kg) to rats for 4 days resulted in significantly elevated (pSALP) compared to controls. In the liver, significantly elevated levels (pSALP levels reverted to near normal, while the hepatic concentration of GSH, CAT, SOD and Gpx were significantly increased (p<0.05) and that of MDA significantly (p<0.05) lowered, when compared to CCl(4)-exposed untreated rats. Histopathological studies confirmed the hepatoprotective effect conferred by the extract of P. ostreatus. These results suggest that an extract of P. ostreatus is able to significantly alleviate the hepatotoxicity induced by CCl(4) in the rat.

  20. Factors affecting drug-induced liver injury: antithyroid drugs as instances

    Directory of Open Access Journals (Sweden)

    Reza Heidari

    2014-09-01

    Full Text Available Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.

  1. Fructose Induced Endotoxemia in Pediatric Nonalcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Ran Jin

    2014-01-01

    Full Text Available In preclinical studies of fructose-induced NAFLD, endotoxin appears to play an important role. We retrospectively examined samples from three pediatric cohorts (1 to investigate whether endotoxemia is associated with the presence of hepatic steatosis; (2 to evaluate postprandial endotoxin levels in response to fructose beverage in an acute 24-hour feeding challenge, and (3 to determine the change of fasting endotoxin amounts in a 4-week randomized controlled trial comparing fructose to glucose beverages in NAFLD. We found that adolescents with hepatic steatosis had elevated endotoxin levels compared to obese controls and that the endotoxin level correlated with insulin resistance and several inflammatory cytokines. In a 24-hour feeding study, endotoxin levels in NAFLD adolescents increased after fructose beverages (consumed with meals as compared to healthy children. Similarly, endotoxin was significantly increased after adolescents consumed fructose beverages for 2 weeks and remained high although not significantly at 4 weeks. In conclusion, these data provide support for the concept of low level endotoxemia contributing to pediatric NAFLD and the possible role of fructose in this process. Further studies are needed to determine if manipulation of the microbiome or other methods of endotoxin reduction would be useful as a therapy for pediatric NAFLD.

  2. Acetaminophen (Paracetamol induced acute liver failure – A social problem in an era of increasing tendency to self-treatment

    Directory of Open Access Journals (Sweden)

    Tadeusz Wróblewski

    2015-12-01

    Paracetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.

  3. The effects of X-irradiation, N-ethyl-N-nitrosourea or combined treatment on O6-alkylguanine-DNA alkyltransferase activity in fetal rat brain and liver and the induction of CNS tumours

    International Nuclear Information System (INIS)

    Stammberger, I.; Nice, L.; Schmahl, W.

    1990-01-01

    Wistar rats were treated in utero on day 16 of gestation either by X-irradiation, N-ethyl-N-nitrosourea (ENU), or both in combination. The O 6 -alkylguanine-DNA alkyltransferase (AT) activity of the fetal brain and liver was analyzed and long-term observations were made to reveal any relationship between the O 6 -ethylguanine repair capability and tumour incidence in the organs of the offspring. The AT activity in the brain was affected to the same extent in the fetuses as in the dams. There was a 60.9% decrease in AT activity in fetuses 24 h after ENU treatment. This correlates with a significant increase in the incidence of brain tumours in the treated offspring (44.1%) compared to control animals. The inductive effect of X-irradiation on AT activity corresponded in turn with a reduction of the incidence of tumours after the combined treatment. In the liver of the rat fetuses, there was generally no effect of treatment on AT activity in contrast to the results obtained for the dams, where an increased AT activity was observed. There were no tumours of the liver observed in the offspring after either treatment alone or after combined treatment. It is suggested that the combined treatment of rat fetuses could significantly reduce the incidence of brain tumours in adult life. (author)

  4. The effects of X-irradiation, N-ethyl-N-nitrosourea or combined treatment on O sup 6 -alkylguanine-DNA alkyltransferase activity in fetal rat brain and liver and the induction of CNS tumours

    Energy Technology Data Exchange (ETDEWEB)

    Stammberger, I.; Nice, L. (Muenchen Univ. (Germany, F.R.). Walter-Straub-Institut fuer Pharmakologie und Toxikologie); Schmahl, W. (Gesellschaft fuer Strahlen- und Umweltforschung mbH Muenchen, Neuherberg (Germany, F.R.). Inst. fuer Pathologie)

    1990-02-01

    Wistar rats were treated in utero on day 16 of gestation either by X-irradiation, N-ethyl-N-nitrosourea (ENU), or both in combination. The O{sup 6}-alkylguanine-DNA alkyltransferase (AT) activity of the fetal brain and liver was analyzed and long-term observations were made to reveal any relationship between the O{sup 6}-ethylguanine repair capability and tumour incidence in the organs of the offspring. The AT activity in the brain was affected to the same extent in the fetuses as in the dams. There was a 60.9% decrease in AT activity in fetuses 24 h after ENU treatment. This correlates with a significant increase in the incidence of brain tumours in the treated offspring (44.1%) compared to control animals. The inductive effect of X-irradiation on AT activity corresponded in turn with a reduction of the incidence of tumours after the combined treatment. In the liver of the rat fetuses, there was generally no effect of treatment on AT activity in contrast to the results obtained for the dams, where an increased AT activity was observed. There were no tumours of the liver observed in the offspring after either treatment alone or after combined treatment. It is suggested that the combined treatment of rat fetuses could significantly reduce the incidence of brain tumours in adult life. (author).

  5. Protective Effects of Fetal Zone Steroids Are Comparable to Estradiol in Hyperoxia-Induced Cell Death of Immature Glia.

    Science.gov (United States)

    Hübner, Stephanie; Sunny, Donna E; Pöhlke, Christine; Ruhnau, Johanna; Vogelgesang, Antje; Reich, Bettina; Heckmann, Matthias

    2017-05-01

    Impaired neurodevelopment in preterm infants is caused by prematurity itself; however, hypoxia/ischemia, inflammation, and hyperoxia contribute to the extent of impairment. Because preterm birth is accompanied by a dramatic decrease in 17β-estradiol (E2) and progesterone, preliminary clinical studies have been carried out to substitute these steroids in preterm infants; however, they failed to confirm significantly improved neurologic outcomes. We therefore hypothesized that the persistently high postnatal production of fetal zone steroids [mainly dehydroepiandrosterone (DHEA)] until term could interfere with E2-mediated protection. We investigated whether E2 could reduce hyperoxia-mediated apoptosis in three immature glial cell types and detected the involved receptors. Thereafter, we investigated protection by the fetal zone steroids DHEA, 16α-hydroxy-DHEA, and androstenediol. For DHEA, the involved receptors were evaluated. We examined aromatases, which convert fetal zone steroids into more estrogenic compounds. Finally, cotreatment was compared against single hormone treatment to investigate synergism. In all cell types, E2 and fetal zone steroids resulted in significant dose-dependent protection, whereas the mediating receptors differed. The neuroprotection by fetal zone steroids highly depended on the cell type-specific expression of aromatases, the receptor repertoire, and the potency of the fetal zone steroids toward these receptors. No synergism in fetal zone steroid and E2 cotreatment was detected in two of three cell types. Therefore, E2 supplementation may not be beneficial with respect to neuroprotection because fetal zone steroids circulate in persistently high concentrations until term in preterm infants. Hence, a refined experimental model for preterm infants is required to investigate potential treatments. Copyright © 2017 Endocrine Society.

  6. Vildagliptin Can Alleviate Endoplasmic Reticulum Stress in the Liver Induced by a High Fat Diet

    OpenAIRE

    Ma, Xiaoqing; Du, Wenhua; Shao, Shanshan; Yu, Chunxiao; Zhou, Lingyan; Jing, Fei

    2018-01-01

    Purpose. We investigated whether a DDP-4 inhibitor, vildagliptin, alleviated ER stress induced by a high fat diet and improved hepatic lipid deposition. Methods. C57BL/6 mice received standard chow diet (CD), high fat diet (HFD), and HFD administered with vildagliptin (50 mg/Kg) (V-HFD). After administration for 12 weeks, serum alanine aminotransferase, glucose, cholesterol, triglyceride, and insulin levels were analyzed. Samples of liver underwent histological examination and transmission el...

  7. The effect of streptozotocin-induced diabetes on phenylalanine hydroxylase expression in rat liver.

    OpenAIRE

    Taylor, D S; Dahl, H H; Mercer, J F; Green, A K; Fisher, M J

    1989-01-01

    The impact of experimentally induced diabetes on the expression of rat liver phenylalanine hydroxylase has been investigated. A significant elevation in maximal enzymic activity was observed in diabetes. This was associated with significant increases in the amount of enzyme, the phenylalanine hydroxylase-specific translational activity of hepatic RNA and the abundance of phenylalanine hydroxylase-specific mRNA. These changes in phenylalanine hydroxylase expression were not observed when diabe...

  8. Potential Effect of Bacopa monnieri on Nitrobenzene Induced Liver Damage in Rats

    OpenAIRE

    Menon, B. Rajalakshmy; Rathi, M. A.; Thirumoorthi, L.; Gopalakrishnan, V. K.

    2010-01-01

    The study was designed to evaluate the hepatoprotective activity of ethanolic extract of Bacopa monnieri in acute experimental liver injury induced by Nitrobenzene in rats. The extract at the dose of 200 mg/kg body weight was administered orally once every day for 10 days. The increased serum marker enzymes, Aspartate transaminase, Alanine transaminase and alkaline phosphatase were restored towards normalization significantly by the extract. Significant increase in SOD, CAT and GPx was observ...

  9. Effects of renal denervation on tubular sodium handling in rats with CBL-induced liver cirrhosis

    DEFF Research Database (Denmark)

    Jonassen, T.E.; Brond, L.; Torp, M.

    2003-01-01

    This study was designed to examine the effect of bilateral renal denervation (DNX) on thick ascending limb of Henle's loop (TAL) function in rats with liver cirrhosis induced by common bile duct ligation (CBL). The CBL rats had, as previously shown, sodium retention associated with hypertrophy...... renal sympathetic nerve activity known to be present in CBL rats plays a significant role in the formation of sodium retention by stimulating sodium reabsorption in the TAL via increased renal abundance of NKCC2....

  10. Gestational age dependent changes of the fetal brain, liver and adipose tissue fatty acid compositions in a population with high fish intakes

    NARCIS (Netherlands)

    Kuipers, Remko S.; Luxwolda, Martine F.; Offringa, Pieter J.; Boersma, E. Rudy; Dijck-Brouwer, D. A. Janneke; Muskiet, Frits A. J.

    2012-01-01

    Introduction: There are no data on the intrauterine fatty acid (FA) compositions of brain, liver and adipose tissue of infants born to women with high fish intakes. Subjects and methods: We analyzed the brain (n = 18), liver (n = 14) and adipose tissue (n = 11) FA compositions of 20 stillborn

  11. Modulation of O-GlcNAc Levels in the Liver Impacts Acetaminophen-Induced Liver Injury by Affecting Protein Adduct Formation and Glutathione Synthesis.

    Science.gov (United States)

    McGreal, Steven R; Bhushan, Bharat; Walesky, Chad; McGill, Mitchell R; Lebofsky, Margitta; Kandel, Sylvie E; Winefield, Robert D; Jaeschke, Hartmut; Zachara, Natasha E; Zhang, Zhen; Tan, Ee Phie; Slawson, Chad; Apte, Udayan

    2018-04-01

    Overdose of acetaminophen (APAP) results in acute liver failure. We have investigated the role of a posttranslational modification of proteins called O-GlcNAcylation, where the O-GlcNAc transferase (OGT) adds and O-GlcNAcase (OGA) removes a single β-D-N-acetylglucosamine (O-GlcNAc) moiety, in the pathogenesis of APAP-induced liver injury. Hepatocyte-specific OGT knockout mice (OGT KO), which have reduced O-GlcNAcylation, and wild-type (WT) controls were treated with 300 mg/kg APAP and the development of injury was studied over a time course from 0 to 24 h. OGT KO mice developed significantly lower liver injury as compared with WT mice. Hepatic CYP2E1 activity and glutathione (GSH) depletion following APAP treatment were not different between WT and OGT KO mice. However, replenishment of GSH and induction of GSH biosynthesis genes were significantly faster in the OGT KO mice. Next, male C57BL/6 J mice were treated Thiamet-G (TMG), a specific inhibitor of OGA to induce O-GlcNAcylation, 1.5 h after APAP administration and the development of liver injury was studied over a time course of 0-24 h. TMG-treated mice exhibited significantly higher APAP-induced liver injury. Treatment with TMG did not affect hepatic CYP2E1 levels, GSH depletion, APAP-protein adducts, and APAP-induced mitochondrial damage. However, GSH replenishment and GSH biosynthesis genes were lower in TMG-treated mice after APAP overdose. Taken together, these data indicate that induction in cellular O-GlcNAcylation exacerbates APAP-induced liver injury via dysregulation of hepatic GSH replenishment response.

  12. Cellular and molecular etiology of hepatocyte injury in a murine model of environmentally induced liver abnormality

    Directory of Open Access Journals (Sweden)

    M.A. Al-Griw

    2016-09-01

    Full Text Available Exposures to a wide variety of environmental substances are negatively associated with many biological cell systems both in humans and rodents. Trichloroethane (TCE, a ubiquitous environmental toxicant, is used in large quantities as a dissolvent, metal degreaser, chemical intermediate, and component of consumer products. This increases the likelihood of human exposure to these compounds through dermal, inhalation and oral routes. The present in vivo study was aimed to investigate the possible cellular and molecular etiology of liver abnormality induced by early exposure to TCE using a murine model. The results showed a significant increase in liver weight. Histopathological examination revealed a TCE-induced hepatotoxicity which appeared as heavily congested central vein and blood sinusoids as well as leukocytic infiltration. Mitotic figures and apoptotic changes such as chromatin condensation and nuclear fragments were also identified. Cell death analysis demonstrates hepatocellular apoptosis was evident in the treated mice compared to control. TCE was also found to induce oxidative stress as indicated by an increase in the levels of lipid peroxidation, an oxidative stress marker. There was also a significant decrease in the DNA content of the hepatocytes of the treated groups compared to control. Agarose gel electrophoresis also provided further biochemical evidence of apoptosis by showing internucleosomal DNA fragmentation in the liver cells, indicating oxidative stress as the cause of DNA damage. These results suggest the need for a complete risk assessment of any new chemical prior to its arrival into the consumer market.

  13. Hepatoprotective effects of Arctium lappa on carbon tetrachloride- and acetaminophen-induced liver damage.

    Science.gov (United States)

    Lin, S C; Chung, T C; Lin, C C; Ueng, T H; Lin, Y H; Lin, S Y; Wang, L Y

    2000-01-01

    The root of Arctium lappa Linne (A. lappa) (Compositae), a perennial herb, has been cultivated for a long time as a popular vegetable. In order to investigate the hepatoprotective effects of A. lappa, male ICR mice were injected with carbon tetrachloride (CCl4, 32 microl/kg, i.p.) or acetaminophen (600 mg/kg, i.p.). A. lappa suppressed the SGOT and SGPT elevations induced by CCl4 or acetaminophen in a dose-dependent manner and alleviated the severity of liver damage based on histopathological observations. In an attempt to elucidate the possible mechanism(s) of this hepatoprotective effect, glutathione (GSH), cytochrome P-450 (P-450) and malondialdehyde (MDA) contents were studied. A. lappa reversed the decrease in GSH and P-450 induced by CCl4 and acetaminophen. It was also found that A. lappa decreased the malondialdehyde (MDA) content in CCl4 or acetaminophen-intoxicated mice. From these results, it was suggested that A. lappa could protect the liver cells from CCl4 or acetaminophen-induced liver damages, perhaps by its antioxidative effect on hepatocytes, hence eliminating the deleterious effects of toxic metabolites from CCl4 or acetaminophen.

  14. Liver lipid molecules induce PEPCK-C gene transcription and attenuate insulin action

    International Nuclear Information System (INIS)

    Chen Guoxun

    2007-01-01

    Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) plays key roles in gluconeogenesis, glyceroneogenesis, and cataplerosis. Experiments were designed to examine the effects of endogenous lipid molecules from rat livers on the expression of PEPCK-C gene in primary rat hepatocytes. The lipid extracts prepared from livers of Zucker fatty, lean, and Wistar rats induced the expression levels of PEPCK-C transcripts. Insulin-mediated reduction of PEPCK-C gene expression was attenuated by the same treatment. The lipid extracts induced the relative luciferase activity of reporter gene constructs that contain a 2.2-kb 5' promoter fragment of PEPCK-C gene, but not the construct that contains only the 3' untranslated region (UTR) of its mRNA. The estimated half life of PEPCK-C transcripts in the presence of the lipid extract is the same as that in the absence of it. My results demonstrate for the first time that endogenous lipid molecules induce PEPCK-C gene transcription and attenuate insulin action in liver

  15. Ethylenediaminetetraacetic acid induces antioxidant and anti-inflammatory activities in experimental liver fibrosis.

    Science.gov (United States)

    González-Cuevas, J; Navarro-Partida, J; Marquez-Aguirre, A L; Bueno-Topete, M R; Beas-Zarate, C; Armendáriz-Borunda, J

    2011-01-01

    Experimental liver fibrosis induced by carbon tetrachloride (CCl(4)) is associated with oxidative stress, lipid peroxidation, and inflammation. This work was focused on elucidating the anti-inflammatory and antioxidant effects of ethylenediaminetetraacetic acid (EDTA) in this model of hepatotoxicity. Wistar male rats were treated with CCl(4) and EDTA (60, 120, or 240 mg/kg). Morphometric analyses were carried out in Masson's stained liver sections to determine fibrosis index. Coagulation tests prothrombin time (PT) and partial thromboplastin time (PTT) were also determined. Gene expression for transforming growth factor beta (TGF-beta1), alpha1(I) procollagen gene (alpha1 Col I), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and superoxide dismutase (SOD) was monitored by real-time PCR. Antioxidant effect of EDTA was measured by its effects on lipid peroxidation; biological activity of ceruloplasmin (Cp), SOD, and catalase (Cat) were analyzed by zymography assays. Animals with CCl(4)-hepatic injury that received EDTA showed a decrement in fibrosis (20%) and lipid peroxidation (22%). The mRNA expression for TNF-alpha (55%), TGF-beta1 (50%), IL-6 (52%), and alpha1 Col I (60%) was also decreased. This group of animals showed increased Cp (62%) and SOD (25%) biological activities. Coagulation blood tests, Cat activity, and gene expression for SOD were not modified by EDTA treatment. This study demonstrates that EDTA treatment induces the activity of antioxidant enzymes, decreases lipid peroxidation, hepatic inflammation, and fibrosis in experimental liver fibrosis induced by CCl(4).

  16. Increased sensitivity of apolipoprotein E knockout mice to copper-induced oxidative injury to the liver.

    Science.gov (United States)

    Chen, Yuan; Li, Bin; Zhao, Ran-ran; Zhang, Hui-feng; Zhen, Chao; Guo, Li

    2015-04-10

    Apolipoprotein E (ApoE) genotypes are related to clinical presentations in patients with Wilson's disease, indicating that ApoE may play an important role in the disease. However, our understanding of the role of ApoE in Wilson's disease is limited. High copper concentration in Wilson's disease induces excessive generation of free oxygen radicals. Meanwhile, ApoE proteins possess antioxidant effects. We therefore determined whether copper-induced oxidative damage differ in the liver of wild-type and ApoE knockout (ApoE(-/-)) mice. Both wild-type and ApoE(-/-) mice were intragastrically administered with 0.2 mL of copper sulfate pentahydrate (200 mg/kg; a total dose of 4 mg/d) or the same volume of saline daily for 12 weeks, respectively. Copper and oxidative stress markers in the liver tissue and in the serum were assessed. Our results showed that, compared with the wild-type mice administered with copper, TBARS as a marker of lipid peroxidation, the expression of oxygenase-1 (HO-1), NAD(P)H dehydrogenase, and quinone 1 (NQO1) significantly increased in the ApoE(-/-) mice administered with copper, meanwhile superoxide dismutase (SOD) activity significantly decreased. Thus, it is concluded that ApoE may protect the liver from copper-induced oxidative damage in Wilson's disease. Copyright © 2015 Elsevier Inc. All rights reserved.

  17. Melatonin protects against taurolithocholic-induced oxidative stress in rat liver.

    Science.gov (United States)

    Fuentes-Broto, Lorena; Miana-Mena, Francisco J; Piedrafita, Eduardo; Berzosa, César; Martínez-Ballarín, Enrique; García-Gil, Francisco A; Reiter, Russel J; García, Joaquín J

    2010-08-01

    Cholestasis, encountered in a variety of clinical disorders, is characterized by intracellular accumulation of toxic bile acids in the liver. Furthermore, oxidative stress plays an important role in the pathogenesis of bile acids. Taurolithocholic acid (TLC) was revealed in previous studies as the most pro-oxidative bile acid. Melatonin, a well-known antioxidant, is a safe and widely used therapeutic agent. Herein, we investigated the hepatoprotective role of melatonin on lipid and protein oxidation induced by TLC alone and in combination with FeCl(3) and ascorbic acid in rat liver homogenates and hepatic membranes. The lipid peroxidation products, malondialdehyde and 4-hydroxyalkenals (MDA + 4-HDA), and carbonyl levels were quantified as indices of oxidative damage to hepatic lipids and proteins, respectively. In the current study, the rise in MDA + 4-HDA levels induced by TLC was inhibited by melatonin in a concentration-dependent manner in both liver homogenates and in hepatic membranes. Melatonin also had protective effects against structural damage to proteins induced by TLC in membranes. These results suggest that the indoleamine melatonin may potentially act as a protective agent in the therapy of those diseases that involve bile acid toxicity. Published 2010 Wiley-Liss, Inc.

  18. Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1β-induced chronic inflammation.

    Science.gov (United States)

    Liang, Wen; Lindeman, Jan H; Menke, Aswin L; Koonen, Debby P; Morrison, Martine; Havekes, Louis M; van den Hoek, Anita M; Kleemann, Robert

    2014-05-01

    The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1β (IL-1β), administered by slow-release minipumps) and metabolic dietary triggers (carbohydrate, cholesterol) of inflammation on the progression of bland liver steatosis (BS) to NASH. Transgenic APOE3*Leiden.huCETP (APOE3L.CETP) mice fed a high-fat diet (HFD) developed BS after 10 weeks. Then, inflammatory triggers were superimposed or not (control) for six more weeks. Mouse livers were analyzed with particular emphasis on hallmarks of inflammation which were defined in human liver biopsies with and without NASH. Livers of HFD-treated control mice remained steatotic and did not progress to NASH. All four inflammatory triggers activated hepatic nuclear factor-κB (NF-κB) significantly and comparably (≥5-fold). However, HFD+LPS or HFD+IL-1β did not induce a NASH-like phenotype and caused intrahepatic accumulation of almost exclusively mononuclear cells. By contrast, mice treated with metabolic triggers developed NASH, characterized by enhanced steatosis, hepatocellular hypertrophy, and formation of mixed-type inflammatory foci containing myeloperoxidase-positive granulocytes (neutrophils) as well as mononuclear cells, essentially as observed in human NASH. Specific for the metabolic inducers was an activation of the proinflammatory transcription factor activator protein-1 (AP-1), neutrophil infiltration, and induction of risk factors associated with human NASH, that is, dyslipidemia (by cholesterol) and insulin resistance (by carbohydrate). In conclusion, HFD feeding followed by NF-κB activation per se (LPS, IL-1β) does not promote the transition from BS to NASH. HFD feeding followed by metabolically evoked inflammation induces additional inflammatory components

  19. Putrescine treatment reverses α-tocopherol-induced desynchronization of polyamine and retinoid metabolism during rat liver regeneration

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    Lourdes Sánchez-Sevilla

    2016-10-01

    Full Text Available Abstract Background The pre-treatment with α-tocopherol inhibits progression of rat liver proliferation induced by partial hepatectomy (PH, by decreasing and/or desynchronizing cyclin D1 expression and activation into the nucleus, activation and nuclear translocation of STAT-1 and -3 proteins and altering retinoid metabolism. Interactions between retinoic acid and polyamines have been reported in the PH-induced rat liver regeneration. Therefore, we evaluated the effect of low dosage of α-tocopherol on PH-induced changes in polyamine metabolism. Methods This study evaluated the participation of polyamine synthesis and metabolism during α-tocopherol-induced inhibition of rat liver regeneration. In PH-rats (Wistar treated with α-tocopherol and putrescine, parameters indicative of cell proliferation, lipid peroxidation, ornithine decarboxylase expression (ODC, and polyamine levels, were determined. Results Pre-treatment with α-tocopherol to PH-animals exerted an antioxidant effect, shifting earlier the increased ODC activity and expression, temporally affecting polyamine synthesis and ornithine metabolism. Whereas administration of putrescine induced minor changes in PH-rats, the concomitant treatment actually counteracted most of adverse actions exerted by α-tocopherol on the remnant liver, restituting its proliferative potential, without changing its antioxidant effect. Putrescine administration to these rats was also associated with lower ODC expression and activity in the proliferating liver, but the temporally shifting in the amount of liver polyamines induced by α-tocopherol, was also “synchronized” by the putrescine administration. The latter is supported by the fact that a close relationship was observed between fluctuations of polyamines and retinoids. Conclusions Putrescine counteracted most adverse actions exerted by α-tocopherol on rat liver regeneration, restoring liver proliferative potential and restituting the decreased

  20. The Study of Fetal Rat Model of Intra-Amniotic Isoproterenol Injection Induced Heart Dysfunction and Phenotypic Switch of Contractile Proteins

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    Yifei Li

    2014-01-01

    Full Text Available To establish a reliable isoproterenol induced heart dysfunction fetal rat model and understand the switches of contractile proteins, 45 pregnant rats were divided into 15 mg/kg-once, 15 mg/kg-twice, sham-operated once, sham-operated twice, and control groups. And 18 adult rats were divided into isoproterenol-treated and control groups. H&E staining, Masson staining, and transmission electron microscope were performed. Apoptotic rate assessed by TUNEL analysis and expressions of ANP, BNP, MMP-2, and CTGF of hearts were measured. Intra-amniotic injections of isoproterenol were supplied on E14.5 and E15.5 for fetuses and 7-day continuous intraperitoneal injections were performed for adults. Then echocardiography was performed with M-mode view assessment on E18.5 and 6 weeks later, respectively. Isoproterenol twice treated fetuses exhibited significant changes in histological evaluation, and mitochondrial damages were significantly severe with increased apoptotic rate. ANP and BNP increased and that of MMP-2 increased in isoproterenol twice treated group compared to control group, without CTGF. The isoforms transition of troponin I and myosin heavy chain of fetal heart dysfunction were opposite to adult procedure. The administration of intra-amniotic isoproterenol to fetal rats could induce heart dysfunction and the regulation of contractile proteins of fetuses was different from adult procedure.

  1. Modulation of lipopolysaccharide-induced chorioamnionitis in fetal sheep by maternal betamethasone.

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    Wolfe, Katherine B; Snyder, Candice C; Gisslen, Tate; Kemp, Matthew W; Newnham, John P; Kramer, Boris W; Jobe, Alan H; Kallapur, Suhas

    2013-12-01

    We tested the hypothesis that the order of exposure to maternal betamethasone and intra-amniotic (IA) lipopolysaccharide (LPS) will differentially modulate inflammation in the chorioamnion. Time-mated Merino ewes with singleton fetuses received saline alone, IA LPS alone, maternal betamethasone before LPS, or betamethasone after LPS. We assessed inflammatory markers in the chorioamnion and the amniotic fluid. Inflammatory cell infiltration, expression of myeloperoxidase, serum amyloid A3 (acute phase reactant) in the chorioamnion, and levels of interleukin (IL)-8 in the amniotic fluid increased 7 days after LPS exposure. Betamethasone prior to LPS decreased infiltration of the inflammatory cells, CD3+ T cells, and decreased the levels of IL-1β and IL-8 in the amniotic fluid. Betamethasone 7 days prior to LPS exposure suppressed LPS-induced inflammation. The markers of inflammation largely had returned to the baseline 14 days after LPS exposure.

  2. Portulaca oleracea L. alleviates liver injury in streptozotocin-induced diabetic mice

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    Zheng G

    2017-12-01

    Full Text Available Guoyin Zheng,1,* Fengfeng Mo,2,* Chen Ling,3,* Hao Peng,1 Wei Gu,1 Min Li,2 Zhe Chen1 1Department of Traditional Chinese Medicine, Changhai Hospital, 2Department of Military Hygiene, Second Military Medical University, 3Department of Biology, School of Life Science, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Purslane is a widespread succulent herb that exhibits various pharmacological effects. The purpose of this study was to evaluate the protective effect of Portulaca oleracea L. (purslane on streptozotocin-induced diabetes in mice. Oral glucose-tolerance tests were carried out to assess blood glucose levels and body weight and food intake were recorded. The biochemical parameters anti-aspartate aminotransferase, alanine aminotransferase, insulin, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα were also measured. The pathological condition of liver tissues were examined by hematoxylin–eosin staining. Rho, ROCK1, ROCK2, NFκBp65, p-NFκBp65, IκBα, and p-IκBα expression in liver tissue were analyzed by Western blot. Purslane increased body weight and decreased food intake. Purslane also significantly reduced concentrations of glucose, anti-aspartate aminotransferase, alanine ­aminotransferase, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα in serum. Serum insulin was elevated with purslane treatment. In addition, pathologic liver changes in diabetic mice were also alleviated by purslane. Obtained data revealed that purslane restored the levels of Rho–NFκB signaling-related proteins in comparison with those of diabetic mice. Above all, it can be assumed that purslane might play a positive role in regulating streptozotocin-induced liver injury through suppressing the Rho–NFκB pathway. Keywords: Portulaca oleracea L., diabetes, liver injury, Rho–NFκB

  3. Patients with the worst outcomes after paracetamol (acetaminophen)-induced liver failure have an early monocytopenia.

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    Moore, J K; MacKinnon, A C; Man, T Y; Manning, J R; Forbes, S J; Simpson, K J

    2017-02-01

    Acute liver failure (ALF) is associated with significant morbidity and mortality. Studies have implicated the immune response, especially monocyte/macrophages as being important in dictating outcome. To investigate changes in the circulating monocytes and other immune cells serially in patients with ALF, relate these with cytokine concentrations, monocyte gene expression and patient outcome. In a prospective case-control study in the Scottish Liver Transplant Unit, Royal Infirmary Edinburgh, 35 consecutive patients admitted with paracetamol-induced liver failure (POD-ALF), 10 patients with non-paracetamol causes of ALF and 16 controls were recruited. The peripheral blood monocyte phenotype was analysed by flow cytometry, circulating cytokines quantified by protein array and monocyte gene expression array performed and related to outcome. On admission, patients with worst outcomes after POD-ALF had a significant monocytopenia, characterised by reduced classical and expanded intermediate monocyte population. This was associated with reduced circulating lymphocytes and natural killer cells, peripheral cytokine patterns suggestive of a 'cytokine storm' and increased concentrations of cytokines associated with monocyte egress from the bone marrow. Gene expression array did not differentiate patient outcome. At day 4, there was no significant difference in monocyte, lymphocyte or natural killer cells between survivors and the patients with adverse outcomes. Severe paracetamol liver failure is associated with profound changes in the peripheral blood compartment, particularly in monocytes, related with worse outcomes. This is not seen in patients with non-paracetamol-induced liver failure. Significant monocytopenia on admission may allow earlier clarification of prognosis, and it highlights a potential target for therapeutic intervention. © 2016 John Wiley & Sons Ltd.

  4. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

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    Z.G. Zhao

    2014-02-01

    Full Text Available The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL on lipopolysaccharide (LPS-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1, myeloperoxidase (MPO, and Na+-K+-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT and aspartate aminotransferase (AST in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na+-K+-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na+-K+-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

  5. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

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    Zhao, Z.G.; Zhang, L.L.; Niu, C.Y.; Zhang, J.

    2014-01-01

    The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na + -K + -ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na + -K + -ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na + -K + -ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis

  6. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

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    Zhao, Z.G.; Zhang, L.L.; Niu, C.Y.; Zhang, J. [Institute of Microcirculation, Hebei North University, Zhangjiakou, China, Institute of Microcirculation, Hebei North University, Zhangjiakou, Hebei (China)

    2014-02-17

    The liver is one of the target organs damaged by septic shock, wherein the spread of endotoxins begins. This study aimed to investigate the effects of exogenous normal lymph (ENL) on lipopolysaccharide (LPS)-induced liver injury in rats. Male Wistar rats were randomly divided into sham, LPS, and LPS+ENL groups. LPS (15 mg/kg) was administered intravenously via the left jugular vein to the LPS and LPS+ENL groups. At 15 min after the LPS injection, saline or ENL without cell components (5 mL/kg) was administered to the LPS and LPS+ENL groups, respectively, at a rate of 0.5 mL/min. Hepatocellular injury indices and hepatic histomorphology, as well as levels of P-selectin, intercellular adhesion molecule 1 (ICAM-1), myeloperoxidase (MPO), and Na{sup +}-K{sup +}-ATPase, were assessed in hepatic tissues. Liver tissue damage occurred after LPS injection. All levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma as well as the wet/dry weight ratio of hepatic tissue in plasma increased. Similarly, P-selectin, ICAM-1, and MPO levels in hepatic tissues were elevated, whereas Na{sup +}-K{sup +}-ATPase activity in hepatocytes decreased. ENL treatment lessened hepatic tissue damage and decreased levels of AST, ALT, ICAM-1, and MPO. Meanwhile, the treatment increased the activity of Na{sup +}-K{sup +}-ATPase. These results indicated that ENL could alleviate LPS-induced liver injury, thereby suggesting an alternative therapeutic strategy for the treatment of liver injury accompanied by severe infection or sepsis.

  7. The effect of androgen excess on maternal metabolism, placental function and fetal growth in obese dams.

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    Fornes, Romina; Maliqueo, Manuel; Hu, Min; Hadi, Laila; Jimenez-Andrade, Juan M; Ebefors, Kerstin; Nyström, Jenny; Labrie, Fernand; Jansson, Thomas; Benrick, Anna; Stener-Victorin, Elisabet

    2017-08-14

    Pregnant women with polycystic ovary syndrome (PCOS) are often overweight or obese. To study the effects of maternal androgen excess in obese dams on metabolism, placental function and fetal growth, female C57Bl6J mice were fed a control (CD) or a high fat/high sucrose (HF/HS) diet for 4-10 weeks, and then mated. On gestational day (GD) 15.5-17.5, dams were injected with dihydrotestosterone (CD-DHT, HF/HS-DHT) or a vehicle (CD-Veh, HF/HS-Veh). HF/HS dams had higher fat content, both before mating and on GD18.5, with no difference in glucose homeostasis, whereas the insulin sensitivity was higher in DHT-exposed dams. Compared to the CD groups, the livers from HF/HS dams weighed more on GD18.5, the triglyceride content was higher, and there was a dysregulation of liver enzymes related to lipogenesis and higher mRNA expression of Fitm1. Fetuses from HF/HS-Veh dams had lower liver triglyceride content and mRNA expression of Srebf1c. Maternal DHT exposure, regardless of diet, decreased fetal liver Pparg mRNA expression and increased placental androgen receptor protein expression. Maternal diet-induced obesity, together with androgen excess, affects maternal and fetal liver function as demonstrated by increased triglyceride content and dysfunctional expression of enzymes and transcription factors involved in de novo lipogenesis and fat storage.

  8. High regenerative capacity of the liver and irreversible injury of male reproductive system in carbon tetrachloride-induced liver fibrosis rat model.

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    Bubnov, Rostyslav V; Drahulian, Maria V; Buchek, Polina V; Gulko, Tamara P

    2018-03-01

    Liver fibrosis (LF) is a chronic disease, associated with many collateral diseases including reproductive dysfunction. Although the normal liver has a large regenerative capacity the complications of LF could be severe and irreversible. Hormone and sex-related issues of LF development and interactions with male reproductive have not been finally studied. The aim was to study the reproductive function of male rats in experimental CCl 4 -induced liver fibrosis rat model, and the capability for restoration of both the liver and male reproduction system. Studies were conducted on 20 3-month old Wistar male rats. The experimental animals were injected with freshly prepared 50% olive oil solution of carbohydrate tetrachloride (CCl 4 ). On the 8th week after injection we noted the manifestations of liver fibrosis. The rats were left to self-healing of the liver for 8 weeks. All male rats underwent ultrasound and biopsy of the liver and testes on the 8th and 16th weeks. The male rats were mated with healthy females before CCl 4 injection, after modeling LF on the 8th week, and after self-healing of the liver. Pregnancy was monitored on ultrasound. On the 8th week of experiment we observed ultrasound manifestation of advanced liver fibrosis, including hepatosplenomegaly, portal hypertension. Ultrasound exam of the rat testes showed testicular degeneration, hydrocele, fibrosis, scarring, petrifications, size reduction, and restriction of testicular descent; testes size decreased from 1.24 ± 0.62 ml to 0.61 ± 0.13, p  reproductive system and altering of fertility: the offspring of male rats with advanced LF was 4.71 ± 0.53 born alive vs 9.55 ± 0.47 born from mating with healthy males, p  reproductive system.

  9. Ginseng essence, a medicinal and edible herbal formulation, ameliorates carbon tetrachloride-induced oxidative stress and liver injury in rats

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    Kuan-Hung Lu

    2017-07-01

    Conclusion: These findings demonstrate that GE improves CCl4-induced liver inflammation and fibrosis by attenuating oxidative stress. Therefore, GE could be a promising hepatoprotective herbal formulation for future development of phytotherapy.

  10. Retardation of fetal dendritic development induced by gestational hyperglycemia is associated with brain insulin/IGF-I signals.

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    Jing, Yu-Hong; Song, Yan-Feng; Yao, Ya-Ming; Yin, Jie; Wang, De-Gui; Gao, Li-Ping

    2014-10-01

    Hyperglycemia is an essential risk factor for mothers and fetuses in gestational diabetes. Clinical observation has indicated that the offspring of mothers with diabetes shows impaired somatosensory function and IQ. However, only a few studies have explored the effects of hyperglycemia on fetal brain development. Neurodevelopment is susceptible to environmental conditions. Thus, this study aims to investigate the effects of maternal hyperglycemia on fetal brain development and to evaluate insulin and insulin-like growth factor-I (IGF-I) signals in fetal brain under hyperglycemia or controlled hyperglycemia. At day 1 of pregnancy, gestational rats were intraperitoneally injected with streptozocin (60 mg/kg). Some of the hyperglycemic gestational rats were injected with insulin (20 IU, two times a day) to control hyperglycemia; the others were injected with saline of equal volume. The gestational rats were sacrificed at days 14, 16, and 18 of embryo development. The dendritic spines of subplate cortex neurons in the fetal brain were detected by Golgi-Cox staining. The mRNA levels of insulin receptors (IRs) and IGF-IR in the fetal brain were measured using qRT-PCR. The protein levels of synaptophysin, IR, and IGF-IR in the fetal brain were detected by western blot. No significant difference in fetal brain formation was observed between the maternal hyperglycemic group and insulin-treated group. By contrast, obvious retardation of dendritic development in the fetus was observed in the maternal hyperglycemic group. Similarly, synaptophysin expression was lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. The mRNA and protein expression levels of IRs in the fetal brain were higher in the hyperglycemic group than in the insulin-treated group. By contrast, the levels of IGF-IR in the brain were lower in the fetus of the maternal hyperglycemic group than in that of the insulin-treated group. These results suggested that

  11. ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

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    Diane DeZwaan-McCabe

    2017-05-01

    Full Text Available The unfolded protein response (UPR, induced by endoplasmic reticulum (ER stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress.

  12. Liver sinusoidal endothelial cells induce immunosuppressive IL-10-producing Th1 cells via the Notch pathway.

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    Neumann, Katrin; Rudolph, Christine; Neumann, Christian; Janke, Marko; Amsen, Derk; Scheffold, Alexander

    2015-07-01

    Under homeostasis, liver sinusoidal endothelial cells (LSECs) shift intrahepatic T-cell responses towards tolerance. However, the role of LSECs in the regulation of T-cell-induced liver inflammation is less clear. Here, we studied the capacity of LSECs to modulate pro-inflammatory Th1-cell differentiation in mice. Using in vitro co-culture systems and subsequent cytokine analysis, we showed that LSECs induced high amounts of the anti-inflammatory cytokine IL-10 in developing Th1 cells. These LSEC-stimulated Th1 cells had no pro-inflammatory capacity in vivo but instead actively suppressed an inflammatory Th1-cell-induced delayed-type hypersensitivity reaction. Blockage of IL-10 signaling in vivo inhibited immunosuppressive activity of LSEC-stimulated Th1 cells. We identified the Notch pathway as a mechanism how LSECs trigger IL-10 expression in Th1 cells. LSECs expressed high levels of the Delta-like and Jagged family of Notch ligands and induced expression of the Notch target genes hes-1 and deltex-1 in Th1 cells. Blockade of Notch signaling selectively inhibited IL-10 induction in Th1 cells by LSECs. Our findings suggest that LSEC-induced IL-10 expression in Th1 cells via the Notch pathway may contribute to the control of hepatic inflammatory immune responses by induction of a self-regulatory mechanism in pro-inflammatory Th1 cells. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Alpha-fetoprotein is present in the fetal fluids and is increased in plasma of mares with experimentally induced ascending placentitis.

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    Canisso, Igor F; Ball, Barry A; Scoggin, Kirsten E; Squires, Edward L; Williams, Neil M; Troedsson, Mats H

    2015-03-01

    The objectives of this study were to: (i) determine alpha-fetoprotein (AFP) concentrations in fetal fluids (FF), and (ii) compare plasma concentrations of AFP in mares with placentitis (n=17) and gestationally age-matched control mares (n=17). Fetal fluid sampling (FFS, n=7/group) was performed at 0, 5 and 12 days post inoculation (DPI) or until abortion. Plasma was harvested daily for 12 days or until abortion. Placentitis was induced via intracervical inoculation of Streptococcus equi ssp. zooepidemicus. Proteins present in the FF were resolved by 1D-SDS-PAGE, and immunoblotting was used to detect the presence of AFP in fetal fluids. Concentrations of AFP in FF and plasma were determined with a chemiluminescence immunoassay. Mixed models for DPI, and for days from abortion (DFA) were used to analyze plasma concentrations of AFP. A protein band ∼68kDa consistent with the AFP size was present in all samples of fetal fluids examined. Immunoblotting for AFP revealed a single protein band (∼68kDa) in all samples. Concentrations of AFP in FF appeared higher than those in maternal plasma. There were effects of time (DPI p<0.0001; DFA p=0.0002) and time-by-group interactions (DPI*Group p<0.06; Group*DFA p<0.001). This study confirmed that AFP is present in the FF of mares during the third trimester of pregnancy. Experimentally induced placentitis was associated with an elevation in maternal plasma concentrations of AFP. Copyright © 2015 Elsevier B.V. All rights reserved.

  14. Thymoquinone restores liver fibrosis and improves oxidative stress status in a lipopolysaccharide-induced inflammation model in rats.

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    Asgharzadeh, Fereshteh; Bargi, Rahimeh; Beheshti, Farimah; Hosseini, Mahmoud; Farzadnia, Mehdi; Khazaei, Majid

    2017-01-01

    Liver fibrosis is the primary sign of chronic liver injury induced by various causes. Thymoquinone (TQ) is the major ingredient of Nigella sativa with several beneficial effects on the body. In the present study, we aimed to investigate the effect of TQ on liver fibrosis in a lipopolysaccharide (LPS)-induced inflammation in male rats. Fifty male Wistar rats were randomly divided into five groups (n=10 in each group) as follow: (1) control; (2) LPS (1 mg/kg/day; i.p); (3) LPS+TQ 2 mg/kg/day (i.p) (LPs+TQ2); (4) LPS+TQ 5 mg/kg/day (LPS+TQ5); (5) LPS+ TQ 10 mg/kg/day (LPS+ TQ10). After three weeks, blood samples were taken for evaluation of liver function tests. Then, the livers were harvested for histological evaluation of fibrosis and collagen content and measurement of oxidative stress markers including malondialdehyde (MDA), total thiol groups, superoxide dismutase (SOD) and catalase activity in tissue homogenates. LPS group showed higher levels of fibrosis and collagen content stained by Masson's trichrome in liver tissue with impaired liver function test and increased oxidative stress markers (pliver fibrosis, improved liver function tests and increased the levels of anti-oxidative enzymes (SOD and catalase), while reduced MDA concentration (pliver fibrosis possibly through affecting oxidative stress status. It seems that administration of TQ can be considered as a part of liver fibrosis management.

  15. Non-invasive index of liver fibrosis induced by alcohol, thioacetamide and schistosomal infection in mice

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    El-Beltagy Doha M

    2010-06-01

    Full Text Available Abstract Background Non invasive approaches will likely be increasing utilized to assess liver fibrosis. This work provides a new non invasive index to predict liver fibrosis induced in mice. Methods Fibrosis was generated by thioacetamide (TAA, chronic intake of ethanol, or infection with S. mansoni in 240 mice. Both progression and regression of fibrosis (after treatment with silymarin and/or praziquantel were monitored. The following methods were employed: (i The METAVIR system was utilized to grade and stage liver inflammation and fibosis; (ii Determination of hepatic hydroxyproline and collagen; and (iii Derivation of a new hepatic fibrosis index from the induced changes, and its prospective validation in a group of 70 mice. Results The index is composed of 4 serum variable including total proteins, γ-GT, bilirubin and reduced glutathione (GSH, measured in diseased, treated and normal mice. These parameters were highly correlated with both the histological stage and the grade. They were combined in a logarithmic formula, which non-invasively scores the severity of liver fibrosis through a range (0 to 2, starting with healthy liver (corresponding to stage 0 to advanced fibrosis (corresponding stage 3.Receiver operating characteristic curves (ROC for the accuracy of the index to predict the histological stages demonstrated that the areas under the curve (AUC were 0.954, 0.979 and 0.99 for index values corresponding to histological stages 1, 2 and 3, respectively. Also, the index was correlated with stage and grade, (0.947 and 0.859, respectively. The cut off values that cover the range between stages 0-1, 1-2 and 2-3 are 0.4, 1.12 and 1.79, respectively. The results in the validation group confirmed the accuracy of the test. The AUROC was 0.869 and there was good correlation with the stage of fibrosis and grade of inflammation. Conclusion The index fulfils the basic criteria of non-invasive marker of liver fibrosis since it is liver

  16. Andrographis paniculata leaf extract prevents thioacetamide-induced liver cirrhosis in rats.

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    Daleya Abdulaziz Bardi

    Full Text Available This study investigated the hepatoprotective effects of ethanolic Andrographis paniculata leaf extract (ELAP on thioacetamide-induced hepatotoxicity in rats. An acute toxicity study proved that ELAP is not toxic in rats. To examine the effects of ELAP in vivo, male Sprague Dawley rats were given intraperitoneal injections of vehicle 10% Tween-20, 5 mL/kg (normal control or 200 mg/kg TAA thioacetamide (to induce liver cirrhosis three times per week. Three additional groups were treated with thioacetamide plus daily oral silymarin (50 mg/kg or ELAP (250 or 500 mg/kg. Liver injury was assessed using biochemical tests, macroscopic and microscopic tissue analysis, histopathology, and immunohistochemistry. In addition, HepG2 and WRL-68 cells were treated in vitro with ELAP fractions to test cytotoxicity. Rats treated with ELAP exhibited significantly lower liver/body weight ratios and smoother, more normal liver surfaces compared with the cirrhosis group. Histopathology using Hematoxylin and Eosin along with Masson's Trichrome stain showed minimal disruption of hepatic cellular structure, minor fibrotic septa, a low degree of lymphocyte infiltration, and minimal collagen deposition after ELAP treatment. Immunohistochemistry indicated that ELAP induced down regulation of proliferating cell nuclear antigen. Also, hepatic antioxidant enzymes and oxidative stress parameters in ELAP-treated rats were comparable to silymarin-treated rats. ELAP administration reduced levels of altered serum liver biomarkers. ELAP fractions were non-cytotoxic to WRL-68 cells, but possessed anti-proliferative activity on HepG2 cells, which was confirmed by a significant elevation of lactate dehydrogenase, reactive oxygen species, cell membrane permeability, cytochrome c, and caspase-8,-9, and, -3/7 activity in HepG2 cells. A reduction of mitochondrial membrane potential was also detected in ELAP-treated HepG2 cells. The hepatoprotective effect of 500 mg/kg of ELAP is proposed

  17. Andrographis paniculata leaf extract prevents thioacetamide-induced liver cirrhosis in rats.

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    Abdulaziz Bardi, Daleya; Halabi, Mohammed Farouq; Hassandarvish, Pouya; Rouhollahi, Elham; Paydar, Mohammadjavad; Moghadamtousi, Soheil Zorofchian; Al-Wajeeh, Nahla Saeed; Ablat, Abdulwali; Abdullah, Nor Azizan; Abdulla, Mahmood Ameen

    2014-01-01

    This study investigated the hepatoprotective effects of ethanolic Andrographis paniculata leaf extract (ELAP) on thioacetamide-induced hepatotoxicity in rats. An acute toxicity study proved that ELAP is not toxic in rats. To examine the effects of ELAP in vivo, male Sprague Dawley rats were given intraperitoneal injections of vehicle 10% Tween-20, 5 mL/kg (normal control) or 200 mg/kg TAA thioacetamide (to induce liver cirrhosis) three times per week. Three additional groups were treated with thioacetamide plus daily oral silymarin (50 mg/kg) or ELAP (250 or 500 mg/kg). Liver injury was assessed using biochemical tests, macroscopic and microscopic tissue analysis, histopathology, and immunohistochemistry. In addition, HepG2 and WRL-68 cells were treated in vitro with ELAP fractions to test cytotoxicity. Rats treated with ELAP exhibited significantly lower liver/body weight ratios and smoother, more normal liver surfaces compared with the cirrhosis group. Histopathology using Hematoxylin and Eosin along with Masson's Trichrome stain showed minimal disruption of hepatic cellular structure, minor fibrotic septa, a low degree of lymphocyte infiltration, and minimal collagen deposition after ELAP treatment. Immunohistochemistry indicated that ELAP induced down regulation of proliferating cell nuclear antigen. Also, hepatic antioxidant enzymes and oxidative stress parameters in ELAP-treated rats were comparable to silymarin-treated rats. ELAP administration reduced levels of altered serum liver biomarkers. ELAP fractions were non-cytotoxic to WRL-68 cells, but possessed anti-proliferative activity on HepG2 cells, which was confirmed by a significant elevation of lactate dehydrogenase, reactive oxygen species, cell membrane permeability, cytochrome c, and caspase-8,-9, and, -3/7 activity in HepG2 cells. A reduction of mitochondrial membrane potential was also detected in ELAP-treated HepG2 cells. The hepatoprotective effect of 500 mg/kg of ELAP is proposed to result from

  18. Beneficial effect of honokiol on lipopolysaccharide induced anxiety-like behavior and liver damage in mice.

    Science.gov (United States)

    Sulakhiya, Kunjbihari; Kumar, Parveen; Gurjar, Satendra S; Barua, Chandana C; Hazarika, Naba K

    2015-02-26

    Anxiety disorders are commonly occurring co-morbid neuropsychiatric disorders with chronic inflammatory conditions such as live damage. Numerous studies revealed that peripheral inflammation, oxidative stress and brain derived neurotrophic factor (BDNF) play important roles in the pathophysiology of anxiety disorders. Honokiol (HNK) is a polyphenol, possessing multiple biological activities including antioxidant, anti-inflammatory, anxiolytic, antidepressant and hepatoprotection. The present study was designed to investigate the effect of HNK, in lipopolysaccharide (LPS)-induced anxiety-like behavior and liver damage in mice. Mice (n=6-10/group) were pre-treated with different doses of HNK (2.5 and 5mg/kg; i.p.) for two days, and challenged with saline or LPS (0.83mg/kg; i.p.) on third day. Anxiety-like behavior was monitored using elevated plus maze (EPM) and open field test (OFT). Animals were sacrificed to evaluate various biochemical parameters in plasma and liver. HNK pre-treatment provided significant (P<0.01) protection against LPS-induced reduction in body weight, food and water intake in mice. HNK at higher dose significantly (P<0.05) attenuated LPS-induced anxiety-like behavior by increasing the number of entries and time spent in open arm in EPM test, and by increasing the frequency in central zone in OFT. HNK pre-treatment ameliorated LPS-induced peripheral inflammation by reducing plasma IL-1β, IL-6, TNF-α level, and also improved the plasma BDNF level, prevented liver damage via attenuating transaminases (AST, ALT), liver oxidative stress and TNF-α activity in LPS challenged mice. In conclusion, the current investigation suggests that HNK provided beneficial effect against LPS-induced anxiety-like behavior and liver damage which may be governed by inhibition of cytokines production, oxidative stress and depletion of plasma BDNF level. Our result suggests that HNK could be a therapeutic approach for the treatment of anxiety and other

  19. Evaluation of radio-protective effect of melatonin on whole body irradiation induced liver tissue damage.

    Science.gov (United States)

    Shirazi, Alireza; Mihandoost, Ehsan; Ghobadi, Ghazale; Mohseni, Mehran; Ghazi-Khansari, Mahmoud

    2013-01-01

    Ionizing radiation interacts with biological systems to induce excessive fluxes of free radicals that attack various cellular components. Melatonin has been shown to be a direct free radical scavenger and indirect antioxidant via its stimulatory actions on the antioxidant system.The aim of this study was to evaluate the antioxidant role of melatonin against radiation-induced oxidative injury to the rat liver after whole body irradiation. In this experimental study,thirty-two rats were divided into four groups. Group 1 was the control group, group 2 only received melatonin (30 mg/kg on the first day and 30 mg/kg on the following days), group 3 only received whole body gamma irradiation of 10 Gy, and group 4 received 30 mg/kg melatonin 30 minutes prior to radiation plus whole body irradiation of 10 Gy plus 30 mg/kg melatonin daily through intraperitoneal (IP) injection for three days after irradiation. Three days after irradiation, all rats were sacrificed and their livers were excised to measure the biochemical parameters malondialdehyde (MDA) and glutathione (GSH). Each data point represents mean ± standard error on the mean (SEM) of at least eight animals per group. A one-way analysis of variance (ANOVA) was performed to compare different groups, followed by Tukey's multiple comparison tests (p<0.05). The results demonstrated that whole body irradiation induced liver tissue damage by increasing MDA levels and decreasing GSH levels. Hepatic MDA levels in irradiated rats that were treated with melatonin (30 mg/kg) were significantly decreased, while GSH levels were significantly increased, when compared to either of the control groups or the melatonin only group. The data suggest that administration of melatonin before and after irradiation may reduce liver damage caused by gamma irradiation.

  20. Hepatoprotective