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Sample records for fetal liver induced

  1. Circadian rhythms of fetal liver transcription persist in the absence of canonical circadian clock gene expression rhythms in vivo.

    Directory of Open Access Journals (Sweden)

    Chengwei Li

    Full Text Available The cellular circadian clock and systemic cues drive rhythmicity in the transcriptome of adult peripheral tissues. However, the oscillating status of the circadian clocks in fetal tissues, and their response to maternal cues, are less clear. Most clock genes do not cycle in fetal livers from mice and rats, although tissue level rhythms rapidly emerge when fetal mouse liver explants are cultured in vitro. Thus, in the fetal mouse liver, the circadian clock does not oscillate at the cellular level (but is induced to oscillate in culture. To gain a comprehensive overview of the clock status in the fetal liver during late gestation, we performed microarray analyses on fetal liver tissues. In the fetal liver we did not observe circadian rhythms of clock gene expression or many other transcripts known to be rhythmically expressed in the adult liver. Nevertheless, JTK_CYCLE analysis identified some transcripts in the fetal liver that were rhythmically expressed, albeit at low amplitudes. Upon data filtering by coefficient of variation, the expression levels for transcripts related to pancreatic exocrine enzymes and zymogen secretion were found to undergo synchronized daily fluctuations at high amplitudes. These results suggest that maternal cues influence the fetal liver, despite the fact that we did not detect circadian rhythms of canonical clock gene expression in the fetal liver. These results raise important questions on the role of the circadian clock, or lack thereof, during ontogeny.

  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: 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 ...

  4. 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 ...

  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: 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 ...

  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: 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 ...

  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. Drug-induced liver injuries

    African Journals Online (AJOL)

    2011-06-02

    Jun 2, 2011 ... Drug-induced liver injury (DILI) is a term increasingly being used by most clinicians and is synonymous with drug-induced hepatotoxicity. A succinct definition of a DILI is 'a liver injury induced by a drug or herbal medicine resulting in liver test abnormalities or liver dysfunction with a reasonable exclusion of ...

  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. 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.)

  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. 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

  18. Perspectives of treatment of anemias with cells of fetal liver, immobilized in macroporous alginate-gelatin carriers

    Directory of Open Access Journals (Sweden)

    Gritsay D.V.

    2014-06-01

    Full Text Available Aim of the work was to study possibility of erythropoiesis stimulation by transplantation of fetal liver cells, seeded into macro¬porous carriers to the rats with post-hemorrhargic anemia, induced by 70% hepatectomy. Fetal liver cells (FLC were isolated from fetuses of rats with 15 days’ gestation and were cryopreserved. Decryopreserved FLC were seeded into macroporous spongy alginate-gelatin scaffolds, which were covered by alginate capsule and implanted into omentum of rats with modeled liver insufficiency. It was shown that fetal liver cells, immobilized in macroporous scaffolds after implantation have positive effect on red blood count and hemoglobin content, indicating that this approach is promising for the development of new methods of anemia treatment.

  19. Purification of fetal liver stem/progenitor cells containing all the repopulation potential for normal adult rat liver

    DEFF Research Database (Denmark)

    Oertel, Michael; Menthena, Anuradha; Chen, Yuan-Qing

    2008-01-01

    BACKGROUND & AIMS: Previously, we showed high-level, long-term liver replacement after transplantation of unfractionated embryonic day (ED) 14 fetal liver stem/progenitor cells (FLSPC). However, for clinical applications, it will be essential to transplant highly enriched cells, while maintaining....... Rat ED14 FLSPC are alpha-fetoprotein(+)/cytokeratin-19(+) or alpha-fetoprotein(+)/cytokeratin-19(-) and contain all of the normal liver repopulation capacity found in fetal liver. Hematopoietic stem cells, a major component in crude fetal liver cell preparations that engraft in other organs...

  20. 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...

  1. Evaluation of fetal liver volume by tridimensional ultrasound in women with gestational diabetes mellitus.

    Science.gov (United States)

    Dubé, Marie-Christine; Girard, Mario; Morisset, Anne-Sophie; Tchernof, André; Weisnagel, S John; Bujold, Emmanuel

    2011-11-01

    To evaluate the effect of gestational diabetes mellitus (GDM) on fetal liver growth during the third trimester. We performed a longitudinal study of pregnant women recruited at the time of GDM screening (24 to 28 weeks of gestation), with follow-up visits at 32 weeks, 36 weeks, and delivery. Women with GDM were followed with nutritional recommendations and insulin when necessary according to the Canadian Diabetes Association guidelines. Fetal liver volume was evaluated using 3-D ultrasound at each antenatal visit, and fetal liver growth was compared between women with and without GDM. Twenty-seven women were recruited, 10 with normal glucose tolerance (NGT) and 17 with confirmed GDM, five who required insulin and 12 who were treated by diet only. We found no difference in fetal liver volume between groups at any of the three visits, and median birth weight was also similar between groups. On the other hand, we found a strong correlation between fetal liver volume at 36 weeks' gestation and birth weight (ρ = 0.61, P < 0.001). In our preliminary study, we found that fetal liver volume could be a strong predictor of infant birth weight independent of GDM status. This suggests that fetal liver volume of offspring of women with NGT is similar to that of offspring of women with GDM treated following recommended targets. Larger studies are required.

  2. 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.

  3. Cotyledonary responses to maternal selenium and dietary restriction may influence alteration in fetal weight and fetal liver glycogen sheep

    Science.gov (United States)

    To examine the effects of maternal supranutritional Se and nutrient restriction during mid and late gestation on placental characteristics and fetal liver glycogen, ewes received either adequate Se (ASe) or high Se (HSe) prior to breeding. On day 64 of gestation, ASe and HSe ewes remained at 100% of...

  4. 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.

  5. 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

  6. Antidepressant-induced liver injury.

    Science.gov (United States)

    DeSanty, Kevin P; Amabile, Celene M

    2007-07-01

    To review principles of drug-induced liver injury (DILI), summarize characteristics of antidepressant-mediated liver injury, and provide recommendations for monitoring and management. A search relating to antidepressant-induced liver injury was performed using MEDLINE (1966-March 2007). Search terms included antidepressant, cholestasis, hepatotoxicity, jaundice, liver injury, toxic hepatitis, and transaminases. Reference citations not identified in the initial database search were also utilized. All English-language case reports, letters, and review articles identified from the data sources were used. Case reports and letters relating to hepatotoxicity from antidepressant overdose were excluded. Antidepressant-induced liver injury described in published cases were of the idiopathic type and, by definition, cannot be predicted based on dose or specific risk factors. Paroxetine had the largest number of cases within the selective serotonin-reuptake inhibitor class. Nefazodone, a serotonin-norepinephrine reuptake inhibitor, appeared to have the most serious cases and is the only antidepressant agent that carries a Food and Drug Administration Black Box Warning regarding hepatotoxicity. The tricyclic antidepressants and monoamine oxidase inhibitors are capable of producing hepatotoxicity, but fewer cases with these agents have been reported in the past 15 years, possibly due to a decline in their use. Causality has not been well established in all reports due to the concurrent use of other drugs and/or underlying liver disease. Most antidepressant agents have the potential to produce idiopathic liver injury. There is no way to prevent idiopathic DILI, but the severity of the reaction may be minimized with prompt recognition and early withdrawal of the agent. The clinician must be careful to provide ongoing therapy of the underlying depressive disorder and be aware of possible drug discontinuation syndromes should potential hepatotoxicity be suspected.

  7. Radiation-Induced Liver Toxicity.

    Science.gov (United States)

    Munoz-Schuffenegger, Pablo; Ng, Sylvia; Dawson, Laura A

    2017-10-01

    The advent of highly conformal radiation therapy (RT) has defined a new role for RT in the treatment of both primary and metastatic liver cancer. Despite major advances in how RT is delivered, radiation-induced liver disease (RILD) remains a concern. Classic RILD, characterized by anicteric ascites and hepatomegaly, is unlikely to occur if treating to doses of ≤30Gy in 2Gy per fraction in patients with baseline Child-Pugh A liver function. On the other hand, nonclassic RILD is a spectrum of liver toxicity, including a general decline in liver function and elevation of liver enzymes. It is less well defined and less predictable, especially in patients with underlying liver disease. Scoring and quantifying RILD remains a challenge. The Child-Pugh score has been the most consistently used parameter. Other scoring systems such as the albumin-bilirubin score provide further discrimination in patients with hepatocellular carcinoma, although their value in patients treated with RT remains to be established. Many serum and imaging biomarkers of liver function are currently being investigated, and they will provide further useful information in the future for local and global liver function assessment, for planning optimization, and for treatment adaptation. To date, no pharmacological therapies have provided consistent results in mitigating RILD once it has manifested clinically. Numerous promising treatment strategies including TGFβ inhibition, Hedgehog inhibition, CXCR4 inhibition, hepatocyte transplantation, and bone marrow-derived stromal cell therapy, have potential to be helpful in the treatment of RILD in the future. Copyright © 2017 Elsevier Inc. All rights reserved.

  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. Left-right difference in fetal liver oxygenation during hypoxia estimated by BOLD MRI in a fetal sheep model.

    Science.gov (United States)

    Sørensen, A; Holm, D; Pedersen, M; Tietze, A; Stausbøl-Grøn, B; Duus, L; Uldbjerg, N

    2011-12-01

    The purpose of this study was to measure differences in oxygenation between the left and right sides of the fetal liver during varying oxygenation levels. Eight ewes carrying singleton fetuses at gestational age 125 days (term, 145 days) were included in the study. Under anesthesia the ewes were ventilated with gas containing different levels of oxygen, thereby subjecting the fetuses to hyperoxia (mean ± SD maternal arterial partial pressure of oxygen (pO2), 23.2 ± 8.2 kPa) and hypoxia (mean maternal arterial pO2, 7.1 ± 0.5 kPa). Changes in oxygenation within the fetal liver were assessed by blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI). During hyperoxia there was no difference between the BOLD signal in the left and right sides of the fetal liver; mean change in BOLD (ΔBOLD)(hyperox), -0.9 ± 3.7%. During hypoxia, however, the decrease in the BOLD signal was more pronounced in the right side as compared with the left side, thereby creating a significant increase in the left-right difference in the BOLD signal; mean ΔBOLD(hypox), 5.2 ± 2.2% (P = 0.002, paired t-test). The left-right difference was directly proportional to the degree of hypoxia (R2 = 0.86, P = 0.007). To our knowledge, this is the first study demonstrating differences in oxygenation between the left and right sides of the fetal liver during hypoxia, a difference that can be explained by increased ductus venosus shunting. Thus, the BOLD MRI technique is a promising non-invasive tool that might be useful for the future monitoring of the human fetus. Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.

  10. Sex-specific divergence of antioxidant pathways in fetal brain, liver, and skeletal muscles.

    Science.gov (United States)

    Al-Gubory, Kaïs H; Garrel, Catherine

    2016-01-01

    The sex-specific divergence of antioxidant pathways in fetal organs of opposite-sex twin is unknown and remains urgently in need of investigation. Such study faces many challenges, mainly the ethical impossibility of obtaining human fetal organs. Opposite-sex sheep twins represent a unique model for studying a sex dimorphism for antioxidant systems. The activity of total superoxide dismutase (SOD), SOD1, SOD2, glutathione peroxidase (GPX), glutathione reductase (GR) and catalase (CAT), the content of total glutathione, reduced glutathione (GSH), and oxidized glutathione (GSSG) were measured in brain, lung, liver, kidney, and skeletal muscles of female and male fetuses collected from sheep twin pregnancies at day 65 of gestation. Lipid peroxidation was assessed by measuring melondialdehyde (MDA) tissue content. Male brain has greater total SOD and SOD1 activities than female brain. Female liver has greater SOD2 activity than male liver. Male liver has greater GR activity than female liver. Male liver has higher total GSH and GSSG content than female liver. Male skeletal muscles have higher total GSH, GSH, and GSSG content than female skeletal muscles. Female brain and liver have higher MDA content than male brain and liver. This is the first report of a sex dimorphism for fetal organ antioxidative pathways. Brain, liver, and skeletal muscles of male and female fetuses display distinct antioxidant pathways. Such sexually dimorphic responses to early life oxidative stress might be involved in the sex-related difference in fetal development that may have a long-term effect on offspring. Our study urges researchers to take into consideration the importance of sex as a biologic variable in their investigations.

  11. Adverse Maternal Environment Increases Fetal Liver Hydroxymethylation and Alters the Transcriptome

    Science.gov (United States)

    Suboptimal maternal nutrition during fetal liver development can alter the offspring’s ability to metabolize excess fats and increases obesity in offspring. We developed a model of adverse maternal environment (AME) which overlays maternal prenatal stress with chronic exposure to a western diet. O...

  12. 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

    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...

  13. Steroidogenic enzyme expression in the human fetal liver and potential role in the endocrinology of pregnancy.

    Science.gov (United States)

    O'Shaughnessy, P J; Monteiro, A; Bhattacharya, S; Fraser, M J; Fowler, P A

    2013-03-01

    The human feto-maternal unit produces large amounts of steroid hormones, particularly estrogens, during the second and third trimesters. The fetal adrenal gland and the placenta are considered the principal tissues driving steroid production but the fetal liver is likely to play an essential role in this process. This study was designed to measure transcript expression of proteins involved in steroid synthesis, metabolism, conjugation and signalling in the human fetal liver and to examine sex differences and effects of maternal smoking. Liver samples were taken from 55 normal fetuses from women undergoing second trimester elective termination. Levels of 23 mRNA transcripts encoding steroid synthesis/metabolic/conjugation enzymes and steroid receptors were measured by real-time PCR. The expression of representative proteins was confirmed by western blotting and immunohistochemistry. The human fetal livers expressed high levels of CYP19A1, SULT2A1, SULT1E1, HSD17B2, SRD5A3 and CYP3A7. Lower levels of SULT1A1, STS, UGT2B17, GPER, AKR1C3, UGT2B15, AR, CYP11A1, CYP21A2, HSD17B3, HSD17B1 and SRD5A1 were also detectable. The expression of ESR, ESR2, CYP17A1 and HSD3B transcripts was undetectable in most fetal livers, although HSD3B was shown to be present by western blotting. Sex differences were limited to SRD5A3 (lower in females) and UGT2B17 (higher in females). Maternal smoking increased the expression of CYP19A1, SULT2A1, UGT2B17, HSD17B2 and AKR1C3 and reduced the expression of SRD5A3 in the male fetal liver. This study shows that the human fetal liver is likely to have an extensive effect on circulating steroid levels in the human fetus and mother. The most important of these effects will be alterations to the species, conjugation and availability of estrogens in the fetus. Maternal smoking is likely to reduce circulating androgen bioactivity in male fetuses.

  14. 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.

  15. 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.

  16. Defective haematopoiesis in fetal liver resulting from inactivation of the EKLF gene.

    Science.gov (United States)

    Nuez, B; Michalovich, D; Bygrave, A; Ploemacher, R; Grosveld, F

    1995-05-25

    Erythroid Krüppel-like factor (EKLF) was originally isolated from erythroid cell RNA by differential screening and shown to be erythroid-specific, although a low level of EKLF was found in mast cell lines. EKLF contains three zinc-fingers homologous to those found in the Krüppel family of transcription factors. Because it binds the sequence CCACACCCT, EKLF may affect erythroid development as a result of its ability to bind to the CAC box in the promoter of the beta-globin gene. Mutation of this element leads to reduced beta-globin expression and it appears to mediate the effect of the globin locus control region on the promoter. Here we inactivate the EKLF gene through insertion of a lacZ reporter gene by homologous recombination in embryonic stem (ES) cells. Heterozygous EKLF+/- mice show that the reporter gene is expressed in a developmentally specific manner in all types of erythroblasts in the fetal liver and adult bone marrow. Homozygous EKLF-/- mice appear normal during the embryonic stage of haematopoiesis in the yolk sac, but develop a fatal anaemia during early fetal life when haematopoiesis has switched to the fetal liver. Enucleated erythrocytes are formed but these do not contain the proper amount of haemoglobin. We conclude that the transcription factor EKLF is essential for the final steps of definitive erythropoiesis in fetal liver.

  17. Metabolism of 1,2-dibromoethane in the human fetal liver.

    Science.gov (United States)

    Kulkarni, A P; Edwards, J; Richards, I S

    1992-01-01

    1. Toxicity of 1,2-dibromoethane requires bioactivation via glutathione S-transferase. Since this enzyme is undetectable in the fetus of several laboratory animal species during early gestation, in vitro studies were carried out with human fetal liver to assess potential fetotoxicity. 2. Glutathione S-transferase occurs abundantly in the human fetal liver cytosol and its titer is equal to or exceeds that found in adult human liver when estimated using 1-chloro-2,4-nitrobenzene as the second substrate. 3. Human fetal liver cytosolic glutathione S-transferase metabolized 1,2-dibromoethane with a high efficiency (mean +/- SD specific activity of 3.10 +/- 0.83 nmol/min/mg protein). This reaction was enzymatic in nature and the rate of conjugation was proportional to the concentration of reduced glutathione, 1,2-dibromoethane and the enzyme present in the reaction medium. 4. A significant bioactivation with a possibility of only limited detoxication via cytochrome P-450-dependent oxidation suggests that human fetus may be at greater risk from 1,2-dibromoethane toxicity than adult.

  18. 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.

  19. Hydroxycut-induced Liver Toxicity

    African Journals Online (AJOL)

    hanumantp

    reducing and anti-cancer properties, contains Camellia Sinensis. There have been several cases that show an association of Camellia Sinensis with liver toxicity ranging from acute hepatitis to liver failure.[14-17]. Although, it is difficult to prove a ...

  20. 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)

  1. Alcohol Increases Liver Progenitor Populations and Induces Disease Phenotypes in Human IPSC-Derived Mature Stage Hepatic Cells

    OpenAIRE

    Tian, Lipeng; Deshmukh, Abhijeet; Prasad, Neha; Jang, Yoon-Young

    2016-01-01

    Alcohol consumption has long been a global problem affecting human health, and has been found to influence both fetal and adult liver functions. However, how alcohol affects human liver development and liver progenitor cells remains largely unknown. Here, we used human induced pluripotent stem cells (iPSCs) as a model to examine the effects of alcohol, on multi-stage hepatic cells including hepatic progenitors, early and mature hepatocyte-like cells derived from human iPSCs. While alcohol has...

  2. 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....... Metabolites from maternal and fetal livers, and placenta were identified using gas and liquid chromatography combined with mass spectrometry. Results: Maternal HF intake resulted in reduced fetal weight. Altered metabolite profiles were observed in the HF maternal and fetal liver, and placenta...... and fetal response to increased fat consumption seems likely to involve palmitoleic acid utilization as an adaptive response during maternal obesity....

  3. Glucocorticoids accelerate maturation of the heme pathway in fetal liver through effects on transcription and DNA methylation.

    Science.gov (United States)

    Khulan, Batbayar; Liu, Lincoln; Rose, Catherine M; Boyle, Ashley K; Manning, Jonathan R; Drake, Amanda J

    2016-01-01

    Glucocorticoids are widely used in threatened preterm labor to promote maturation in many organ systems in preterm babies and have significant beneficial effects on morbidity and mortality. We performed transcriptional profiling in fetal liver in a rat model of prenatal glucocorticoid exposure and identified marked gene expression changes in heme biosynthesis, utilization, and degradation pathways in late gestation. These changes in gene expression associated with alterations in DNA methylation and with a reduction in hepatic heme concentration. There were no persistent differences in gene expression, DNA methylation, or heme concentrations at 4 weeks of age, suggesting that these are transient effects. Our findings are consistent with glucocorticoid-induced accelerated maturation of the haematopoietic system and support the hypothesis that glucocorticoids can drive changes in gene expression in association with alterations in DNA methylation.

  4. Gene expression profiling in a mouse model identifies fetal liver- and placenta-derived potential biomarkers for Down Syndrome screening.

    Directory of Open Access Journals (Sweden)

    Jeroen L A Pennings

    Full Text Available BACKGROUND: As a first step to identify novel potential biomarkers for prenatal Down Syndrome screening, we analyzed gene expression in embryos of wild type mice and the Down Syndrome model Ts1Cje. Since current Down Syndrome screening markers are derived from placenta and fetal liver, these tissues were chosen as target. METHODOLOGY/PRINCIPAL FINDINGS: Placenta and fetal liver at 15.5 days gestation were analyzed by microarray profiling. We confirmed increased expression of genes located at the trisomic chromosomal region. Overall, between the two genotypes more differentially expressed genes were found in fetal liver than in placenta. Furthermore, the fetal liver data are in line with the hematological aberrations found in humans with Down Syndrome as well as Ts1Cje mice. Together, we found 25 targets that are predicted (by Gene Ontology, UniProt, or the Human Plasma Proteome project to be detectable in human serum. CONCLUSIONS/SIGNIFICANCE: Fetal liver might harbor more promising targets for Down Syndrome screening studies. We expect these new targets will help focus further experimental studies on identifying and validating human maternal serum biomarkers for Down Syndrome screening.

  5. Drug-induced liver injury

    DEFF Research Database (Denmark)

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

    2017-01-01

    and outcome. RESULTS: Of 43 patients, 25 (58%) were female with a mean age of 54 years. The two most frequent causes of DILI were Disulfiram (30%) and antibiotics (19%). The most common symptoms were jaundice, nausea, fatigue and gastrointestinal discomfort. At the time of admission, the most frequent...... and nine patients died. Jaundice, a moderately elevated bilirubin level or INR at presentation was predictive of severe outcome. CONCLUSION: In this retrospective study, 35% of patients with DILI developed severe acute liver failure and were either liver transplanted or died. Our results underline...

  6. 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

  7. 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

  8. Alcohol Increases Liver Progenitor Populations and Induces Disease Phenotypes in Human IPSC-Derived Mature Stage Hepatic Cells.

    Science.gov (United States)

    Tian, Lipeng; Deshmukh, Abhijeet; Prasad, Neha; Jang, Yoon-Young

    2016-01-01

    Alcohol consumption has long been a global problem affecting human health, and has been found to influence both fetal and adult liver functions. However, how alcohol affects human liver development and liver progenitor cells remains largely unknown. Here, we used human induced pluripotent stem cells (iPSCs) as a model to examine the effects of alcohol, on multi-stage hepatic cells including hepatic progenitors, early and mature hepatocyte-like cells derived from human iPSCs. While alcohol has little effect on endoderm development from iPSCs, it reduces formation of hepatic progenitor cells during early hepatic specification. The proliferative activities of early and mature hepatocyte-like cells are significantly decreased after alcohol exposure. Importantly, at a mature stage of hepatocyte-like cells, alcohol treatment increases two liver progenitor subsets, causes oxidative mitochondrial injury and results in liver disease phenotypes (i.e., steatosis and hepatocellular carcinoma associated markers) in a dose dependent manner. Some of the phenotypes were significantly improved by antioxidant treatment. This report suggests that fetal alcohol exposure may impair generation of hepatic progenitors at early stage of hepatic specification and decrease proliferation of fetal hepatocytes; meanwhile alcohol injury in post-natal or mature stage human liver may contribute to disease phenotypes. This human iPSC model of alcohol-induced liver injury can be highly valuable for investigating alcoholic injury in the fetus as well as understanding the pathogenesis and ultimately developing effective treatment for alcoholic liver disease in adults.

  9. Administration of Drug Induce Liver Injury to the Inpatients with Liver Disease

    Directory of Open Access Journals (Sweden)

    Sindy E. Cinthya

    2012-06-01

    Full Text Available Drug induced liver injury is a serious human health problems. Pre-existing liver diseases are risk factor of liver injury by the drugs. The study was conducted to evaluate the use of drug induced liver injury in patients hospitalized with liver disease at one hospital in Kota Tasikmalaya. Informations were collected retrospectively in the period 2010-2011 from the patient’s medical record. A total of 52 patients research subjects were discovered 50 patients (96% using drug induced liver injury and 2 patients (4% did not use it. Drug induced liver injury most widely used were ranitidine (31.3%, ceftriaxone (23.1%, and paracetamol (16.4%. Level of the DILI usage in patient with liver disease was relative high (96%. Further research is needed to determine the effect of the drug induced liver injury to liver injury.

  10. Gene expression profiling in a mouse model identifies fetal liver- and placenta-derived potential biomarkers for Down syndrome screening

    NARCIS (Netherlands)

    Pennings, J.L.A.; Rodenburg, W.; Imholz, S.; Koster, M.P.H.; van Oostrom, C.T.M.; Breit, T.M.; Schielen, P.C.J.I.; de Vries, A.

    2011-01-01

    Background: As a first step to identify novel potential biomarkers for prenatal Down Syndrome screening, we analyzed gene expression in embryos of wild type mice and the Down Syndrome model Ts1Cje. Since current Down Syndrome screening markers are derived from placenta and fetal liver, these tissues

  11. 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.

  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. 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.

  14. 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.

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

    Science.gov (United States)

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

    2000-06-01

    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 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 failed to engraft irradiated recipient mice. Moreover, absence of beta1 integrin resulted in sequestration of HSCs in the circulation and their reduced adhesion to endothelioma cells. These findings define beta1 integrin as an essential adhesion receptor for the homing of HSCs.

  16. 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

    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...... failed to engraft irradiated recipient mice. Moreover, absence of beta1 integrin resulted in sequestration of HSCs in the circulation and their reduced adhesion to endothelioma cells. These findings define beta1 integrin as an essential adhesion receptor for the homing of HSCs....... 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...

  17. Mechanisms of viral hepatitis induced liver injury.

    Science.gov (United States)

    Nakamoto, Yasunari; Kaneko, Shuichi

    2003-09-01

    Among seven human hepatitis viruses (A to E, G and TT virus), hepatitis B (HBV) and C (HCV) viruses are able to persist in the host for years and principally contribute to the establishment of chronic hepatitis. During the course of persistent infection, continuous intrahepatic inflammation maintains a cycle of liver cell destruction and regeneration that often terminates in hepatocellular carcinoma (HCC). While the expression and retention of viral proteins in hepatocytes may influence the severity and progression of liver disease, the mechanisms of liver injury in viral hepatistis are defined to be due not to the direct cytopathic effects of viruses, but to the host immune response to viral proteins expressed by infected hepatocytes. In the process of liver injury, hepatocellular death (apoptosis) induced by the proapoptotic molecules of T cells activated following antigen recognition triggers a cascade of antigen nonspecific effector systems and causes necroinflammatory disease. Accordingly, the regulation of the immune response, e.g., via the cell death pathways, in chronically infected patients should prevent the development of HCC.

  18. 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...... 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...

  19. 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

  20. [Fetal experimentation, transplantations, cosmetics and their connection with induced abortion].

    Science.gov (United States)

    Redondo Calderón, José Luis

    2012-01-01

    The increase in induced abortion produces large numbers of cells, tissues and organs, which are used in several fields of Medicine, either in research or in treatment. The main uses are in Cardiology, Hematology, Metabolism, Embryology, Neurology, Immunology, Ophthalmology, Dermatology and Transplantations. Flavor enhancers and cosmetics also benefit. Utilitarianism has led to an increase in abortion-originated cell and tissue banks. Abortion is justified through the manipulation of language. Vested interests give rise to complicity in researchers and society as a whole. Abortion and tissue 'donation' cannot be split; since fresh tissues are involved there is a symbiotic relationship between them. Valid consent is not possible. A contradiction emerges, the nasciturus is not desired or valued but fetal organs are. When someone is deprived of his rights it is because another wants to enslave them. Research must have a moral base. Knowledge should not be increased at any price. Something that is legal and well intentioned is not always morally acceptable. The duty of omission is applicable. Means to achieve a goal must be ethical means. Educational efforts to restore respect for the human embryo and fetus must be promoted. Technical advances are not always in accordance with human nature and dignity. Research and treatment that do not resort to cells, tissues and organs obtained from induced abortions should be promoted.

  1. Streptozotocin-Induced Diabetes Models: Pathophysiological Mechanisms and Fetal Outcomes

    Directory of Open Access Journals (Sweden)

    D. C. Damasceno

    2014-01-01

    Full Text Available Glucose homeostasis is controlled by endocrine pancreatic cells, and any pancreatic disturbance can result in diabetes. Because 8% to 12% of diabetic pregnant women present with malformed fetuses, there is great interest in understanding the etiology, pathophysiological mechanisms, and treatment of gestational diabetes. Hyperglycemia enhances the production of reactive oxygen species, leading to oxidative stress, which is involved in diabetic teratogenesis. It has also been suggested that maternal diabetes alters embryonic gene expression, which might cause malformations. Due to ethical issues involving human studies that sometimes have invasive aspects and the multiplicity of uncontrolled variables that can alter the uterine environment during clinical studies, it is necessary to use animal models to better understand diabetic pathophysiology. This review aimed to gather information about pathophysiological mechanisms and fetal outcomes in streptozotocin-induced diabetic rats. To understand the pathophysiological mechanisms and factors involved in diabetes, the use of pancreatic regeneration studies is increasing in an attempt to understand the behavior of pancreatic beta cells. In addition, these studies suggest a new preventive concept as a treatment basis for diabetes, introducing therapeutic efforts to minimize or prevent diabetes-induced oxidative stress, DNA damage, and teratogenesis.

  2. The transcription factor Gli3 promotes B cell development in fetal liver through repression of Shh.

    Science.gov (United States)

    Solanki, Anisha; Lau, Ching-In; Saldaña, José Ignacio; Ross, Susan; Crompton, Tessa

    2017-07-03

    Before birth, B cells develop in the fetal liver (FL). In this study, we show that Gli3 activity in the FL stroma is required for B cell development. In the Gli3-deficient FL, B cell development was reduced at multiple stages, whereas the Sonic hedgehog (Hh [Shh])-deficient FL showed increased B cell development, and Gli3 functioned to repress Shh transcription. Use of a transgenic Hh-reporter mouse showed that Shh signals directly to developing B cells and that Hh pathway activation was increased in developing B cells from Gli3-deficient FLs. RNA sequencing confirmed that Hh-mediated transcription is increased in B-lineage cells from Gli3-deficient FL and showed that these cells expressed reduced levels of B-lineage transcription factors and B cell receptor (BCR)/pre-BCR-signaling genes. Expression of the master regulators of B cell development Ebf1 and Pax5 was reduced in developing B cells from Gli3-deficient FL but increased in Shh-deficient FL, and in vitro Shh treatment or neutralization reduced or increased their expression, respectively. © 2017 Solanki et al.

  3. 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.

  4. 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.

  5. 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

  6. 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. 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.

  7. 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.

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

    Science.gov (United States)

    Rezai, Shadi; Faye, Justin; Hughes, Alexander; Cheung, Mon-Lai; Cohen, Joel R; Kaia, Judy A; Fuller, Paul N; Henderson, Cassandra E

    2017-01-01

    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.

  9. 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

    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......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...... 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...

  10. [Induced abortion because of fetal abnormality in Norway, 1996-7].

    Science.gov (United States)

    Eskild, A; Nesheim, B I; Berglund, T; Totlandsdal, J K; Andresen, J F

    2000-03-30

    The objective of this study was to estimate the national and regional rates of induced abortions after the 12th gestational week attributed to fetal maldevelopment in Norway during 1996 and 1997. In 1998, the National Board of Health requested from all hospitals copies of relevant documents in the medical records of women who had applied for induced abortion after 12th gestational week. There were 303 women in 1996 and 1997 who applied for induced abortion because of diagnosed fetal maldevelopment. For all of these women the application was accepted. One woman did not have an abortion. The national rate of induced abortion attributed to fetal maldevelopment was 2.5 per 1000 births. There were regional differences in the rate of abortion. In 53% of all applications for induced abortion the fetal diagnosis was not reported. Among the reported diagnoses, 28% were chromosomal abnormalities. There is a need for better knowledge of factors influencing the number of induced abortions attributed to fetal malformations. We also need a better understanding of the impact of such abortions on the observed perinatal mortality and occurrence of birth defects.

  11. 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)

  12. 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.

  13. 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

  14. Agentes indutores da síntese de hemoglobina fetal Fetal hemoglobin inducing factors

    Directory of Open Access Journals (Sweden)

    Maria Stella Figueiredo

    2007-09-01

    Full Text Available Anemia falciforme é uma doença heterogênea caracterizada por uma grande variabilidade clínica. Desde as primeiras observações desta doença, foi visto que aumento no nível de hemoglobina fetal (HbF estava associado com manifestações clínicas mais brandas, já que a HbF interfere na polimerização da HbS. A hidroxiuréia é um agente citotóxico que causa vários efeitos nos pacientes com anemia falciforme, tais como: aumento da produção de HbF, aumento do volume corpuscular médio, aumento da hidratação do glóbulo vermelho, melhora da hemoglobina, mielossupressão, produção de óxido nítrico e diminuição de moléculas de adesão. Até o momento, ela é considerada a terapia de maior sucesso para a anemia falciforme e seu uso nesta doença é descrito neste artigo.Sickle cell anemia is a heterogeneous disorder with variable severity. Initial observations showed that a high level of fetal hemoglobin (HbF was associated with minor clinical manifestations, as HbF interferes with HbS polymerization. Hydroxyurea, a cytotoxic agent, has several effects on sickle cell patients, such as: increased HbF production, increased mean corpuscular volume, improved red blood cell hydration, improved hemoglobin, myelosuppression, production of nitric oxide and decreases in adhesion molecules. Till now, hydroxyurea is considered the most successful drug therapy for sickle cell anemia and its use is described in this article.

  15. Kidney and Liver Function Parameters in Alloxan-Induced Diabetic ...

    African Journals Online (AJOL)

    Aloe barbadensis juice extract has been reported to possess hypoglycaemic property but the effects of its use on kidney and liver functions in diabetic animals have not been well investigated. This study investigated some biochemical parameters in the liver and kidney of alloxan-induced diabetic rats treated with Aloe ...

  16. 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.

  17. 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.

  18. Primate fetal hepatic responses to maternal obesity: epigenetic signalling pathways and lipid accumulation.

    Science.gov (United States)

    Puppala, Sobha; Li, Cun; Glenn, Jeremy P; Saxena, Romil; Gawrieh, Samer; Quinn, Amy; Palarczyk, Jennifer; Dick, Edward J; Nathanielsz, Peter W; Cox, Laura A

    2018-03-07

    Maternal obesity (MO) increases offspring cardiometabolic disease risk. Altered fetal liver development in response to the challenge of MO has metabolic consequences underlying adverse offspring life-course health outcomes. Little is known about molecular pathways and potential epigenetic changes regulating primate fetal liver responses to MO. We hypothesized that MO would induce fetal baboon liver epigenetic changes resulting in dysregulation of key metabolic pathways that impact lipid metabolism. MO was induced prior to pregnancy by a high fat, high sucrose diet. Unbiased gene and microRNA (miRNA; small RNA Seq) abundance analyses were performed on fetal baboon livers at 0.9 gestation (G) and subjected to pathway analyses to identify fetal liver molecular responses to MO. Fetal baboon liver lipid and glycogen content were quantified by Computer Assisted Stereology Toolbox. In response to MO, fetal livers revealed dysregulation of TCA cycle, proteasome, oxidative phosphorylation, glycolysis and Wnt/β-catenin signalling pathways together with marked lipid accumulation supporting our hypothesis that multiple pathway dysregulation detrimentally impacts lipid management. This is the first study of MO programming of the nonhuman primate fetal liver using unbiased transcriptome analysis to detect changes in hepatic gene expression levels and identify potential miRNA epigenetic regulators of metabolic disruption. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  19. 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.

  1. 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.

  2. Ex-Vivo Uterine Environment (EVE Therapy Induced Limited Fetal Inflammation in a Premature Lamb Model.

    Directory of Open Access Journals (Sweden)

    Yuichiro Miura

    Full Text Available Ex-vivo uterine environment (EVE therapy uses an artificial placenta to provide gas exchange and nutrient delivery to a fetus submerged in an amniotic fluid bath. Development of EVE may allow us to treat very premature neonates without mechanical ventilation. Meanwhile, elevations in fetal inflammation are associated with adverse neonatal outcomes. In the present study, we analysed fetal survival, inflammation and pulmonary maturation in preterm lambs maintained on EVE therapy using a parallelised umbilical circuit system with a low priming volume.Ewes underwent surgical delivery at 115 days of gestation (term is 150 days, and fetuses were transferred to EVE therapy (EVE group; n = 5. Physiological parameters were continuously monitored; fetal blood samples were intermittently obtained to assess wellbeing and targeted to reference range values for 2 days. Age-matched animals (Control group; n = 6 were surgically delivered at 117 days of gestation. Fetal blood and tissue samples were analysed and compared between the two groups.Fetal survival time in the EVE group was 27.0 ± 15.5 (group mean ± SD hours. Only one fetus completed the pre-determined study period with optimal physiological parameters, while the other 4 animals demonstrated physiological deterioration or death prior to the pre-determined study end point. Significant elevations (p0.05 in surfactant protein mRNA expression level between the two groups.In this study, we achieved limited fetal survival using EVE therapy. Despite this, EVE therapy only induced a modest fetal inflammatory response and did not promote lung maturation. These data provide additional insight into markers of treatment efficacy for the assessment of future studies.

  3. Arginine nutrition and fetal brown adipose tissue development in diet-induced obese sheep.

    Science.gov (United States)

    Carey Satterfield, M; Dunlap, Kathrin A; Keisler, Duane H; Bazer, Fuller W; Wu, Guoyao

    2012-10-01

    The global incidence of human obesity has more than doubled over the past three decades. An ovine model of obesity was developed to determine effects of maternal obesity and arginine supplementation on maternal, placental, and fetal parameters of growth, health, and well being. One-hundred-twenty days prior to embryo transfer, ewes were fed either ad libitum (n = 10) to induce obesity or 100% National Research Council-recommended nutrient requirements (n = 10) as controls. Embryos from superovulated ewes with normal body condition were transferred to the uterus of control-fed and obese ewes on day 5.5 post-estrus to generate genetically similar singleton pregnancies. Beginning on day 100 of gestation, obese ewes received intravenous administration of saline or L-arginine-HCl three times daily (81 mg arginine/kg body weight/day) to day 125, whereas control-fed ewes received saline. Fetal growth was assessed at necropsy on day 125. Maternal obesity increased (1) percentages of maternal and fetal carcass lipids and (2) concentrations of leptin, insulin, glucose, glutamate, leucine, lysine and threonine in maternal plasma while reducing (1) concentrations of progesterone, glycine and serine in maternal plasma and (2) amniotic and allantoic fluid volumes. Administration of L-arginine to obese ewes increased arginine and ornithine concentrations in maternal and fetal plasma, amniotic fluid volume, protein content in maternal carcass, and fetal brown adipose tissue (+60%), while reducing maternal lipid content and circulating leptin levels. Fetal or placental weight did not differ among treatments. Results indicate that arginine treatment beneficially reduces maternal adiposity and enhances fetal brown adipose tissue development in obese ewes.

  4. 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 ...

  5. 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

  6. Synthetic PreImplantation Factor (PIF prevents fetal loss by modulating LPS induced inflammatory response.

    Directory of Open Access Journals (Sweden)

    Nicoletta Di Simone

    Full Text Available Maternal control of inflammation is essential during pregnancy and an exaggerated response is one of the underlying causes of fetal loss. Inflammatory response is mediated by multiple factors and Toll-like receptors (TLRs are central. Activation of TLRs results in NALP-3 mediated assembly of apoptosis-associated speck-like protein containing a CARD (ASC and caspase-1 into the inflammasome and production of pro-inflammatory cytokines IL-1β and IL-18. Given that preventing measures are lacking, we investigated PreImplantation Factor (PIF as therapeutic option as PIF modulates Inflammation in pregnancy. Additionally, synthetic PIF (PIF analog protects against multiple immune disorders. We used a LPS induced murine model of fetal loss and synthetic PIF reduced this fetal loss and increased the embryo weight significantly. We detected increased PIF expression in the placentae after LPS insult. The LPS induced serum and placenta cytokines were abolished by synthetic PIF treatment and importantly synthetic PIF modulated key members of inflammasome complex NALP-3, ASC, and caspase-1 as well. In conclusion our results indicate that synthetic PIF protects against LPS induced fetal loss, likely through modulation of inflammatory response especially the inflammasome complex. Given that synthetic PIF is currently tested in autoimmune diseases of non-pregnant subjects (clinicaltrials.gov, NCT02239562, therapeutic approach during pregnancy can be envisioned.

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

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    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.

  8. Neonatally Induced Mild Diabetes in Rats and Its Effect on Maternal, Placental, and Fetal Parameters

    Directory of Open Access Journals (Sweden)

    Yuri Karen Sinzato

    2012-01-01

    Full Text Available The aim of this study was to assess placental changes and reproductive outcomes in neonatally induced mild diabetic dams and fetal development in their offspring. At birth, female rats were assigned either to control or diabetic group (100 mg of streptozotocin/Kg, subcutaneously. At adulthood, the female rats were mated. During pregnancy, the blood glucose levels and glucose and insulin tolerance tests were performed. At term, maternal reproductive outcomes, fetal and placental weight, and placental morphology were analyzed. Diabetic rats had smaller number of living fetuses, implantations and corpora lutea, and increased rate of embryonic loss. Placenta showed morphometric alterations in decidua area. Our results showed that mild diabetes was sufficient to trigger alterations in maternal organism leading to impaired decidua development contributing to failure in embryonic implantation and early embryonic losses. Regardless placental decidua alteration, the labyrinth, which is responsible for the maternal-fetal exchanges, showed no morphometric changes contributing to an appropriate fetal development, which was able to maintain normal fetal weight at term in mild diabetic rats. Thus, this experimental model of diabetes induction at the day of birth was more effective to reproduce the reproductive alterations of diabetic women.

  9. 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.

  10. Oroxylin A accelerates liver regeneration in CCl₄-induced acute liver injury mice.

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    Runzhi Zhu

    Full Text Available INTRODUCTION: Based on the previous research that oroxylin A can suppress inflammation, we investigated the hepatoprotective role of oroxylin A against CCl₄-induced liver damage in mice and then studied the possible alteration of the activities of cytokine signaling participating in liver regeneration. Wild type (WT mice were orally administrated with oroxylin A (60 mg/kg for 4 days after CCl₄ injection, the anti-inflammatory effects of oroxylin A were assessed directly by hepatic histology and indirectly by measuring serum levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT and Albumin. Proliferating cell nuclear antigen (PCNA staining was performed to evaluate the role of oroxylin A in promoting hepatocyte proliferation. Serum IL-1β, TNF-α, IL-6 and IL-1Ra levels were measured by enzyme-linked immunosorbent assay (ELISA and liver HGF, EGF, TNF-α, IL-6, IL-1Ra and IL-1β gene expression was determined by quantitative real-time PCR. The data indicated that the IL-6 and TNF-α mRNA of oroxylin A administered group significantly increased higher than the control within 12 hours after CCl4 treatment. Meanwhile, oroxylin A significantly enhanced the expression of IL-1Ra at the early phase, which indicated that oroxylin A could facilitate the initiating events in liver regeneration by increasing IL-1Ra which acts as an Acute-Phase Protein (APP. In addition, a lethal CCl₄-induced acute liver failure model offers a survival benefit in oroxylin A treated WT mice. However, oroxylin A could not significantly improve the percent survival of IL-1RI⁻/⁻ mice with a lethal CCl₄-induced acute liver failure. CONCLUSIONS: Our study confirmed that oroxylin A could strongly promote liver structural remodeling and functional recovery through IL-1Ra/IL-1RI signaling pathway. All these results support the possibility of oroxylin A being a therapeutic candidate for acute liver injury.

  11. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

    OpenAIRE

    Cotter, David G.; Ercal, Baris; Huang, Xiaojing; Leid, Jamison M.; d’Avignon, D. André; Graham, Mark J.; Dietzen, Dennis J.; Brunt, Elizabeth M.; Patti, Gary J.; Crawford, Peter A.

    2014-01-01

    Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohe...

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

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    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.

  13. 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

  14. 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. • Caffeine

  15. 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

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

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    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.

  17. 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

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

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    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.

  19. 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 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.

  20. Traditional Chinese Medicine Induced Liver Injury

    Science.gov (United States)

    2014-01-01

    Traditional Chinese Medicine (TCM) is popular around the world and encompasses many different practices with particular emphasis on herbal TCM. Using the PubMed database, a literature search was undertaken to assess the extent herbal TCM products exert rare hepatotoxicity. Analysis of reported cases revealed numerous specified herbal TCM products with potential hepatotoxicity. Among these were An Shu Ling, Bai Fang, Bai Xian Pi, Ban Tu Wan, Bo He, Bo Ye Qing Niu Dan, Bofu Tsu Sho San, Boh Gol Zhee, Cang Er Zi, Chai Hu, Chaso, Chi R Yun, Chuan Lian Zi, Ci Wu Jia, Da Chai Hu Tang, Da Huang, Du Huo, Gan Cao, Ge Gen, Ho Shou Wu, Hu Bohe You, Hu Zhang, Huang Qin, Huang Yao Zi, Hwang Geun Cho, Ji Gu Cao, Ji Ji, Ji Xue Cao, Jiguja, Jin Bu Huan, Jue Ming Zi, Kamishoyosan, Kudzu, Lei Gong Teng, Long Dan Xie Gan Tang, Lu Cha, Ma Huang, Mao Guo Tian Jie Cai, Onshido, Polygonum multiflorum, Qian Li Guang, Ren Shen, Sairei To, Shan Chi, Shen Min, Shi Can, Shi Liu Pi, Shou Wu Pian, Tian Hua Fen, White flood, Wu Bei Zi, Xi Shu, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, Zhen Chu Cao, and various unclassified Chinese herbal mixtures. Causality was firmly established for a number of herbal TCM products by a positive reexposure test result, the liver specific scale of CIOMS (Council for International Organizations of Medical Sciences), or both. Otherwise, the quality of case data was mixed, especially regarding analysis of the herb ingredients because of adulteration with synthetic drugs, contamination with heavy metals, and misidentification. In addition, non-herbal TCM elements derived from Agaricus blazei, Agkistrodon, Antelope, Bombyx, Carp, Fish gallbladder, Phellinus, Scolopendra, Scorpio, and Zaocys are also known or potential hepatotoxins. For some patients, the clinical course was severe, with risks for acute liver failure, liver transplantation requirement, and lethality. In conclusion, the use of few herbal TCM products may rarely be associated with hepatotoxicity in some

  1. Maternal choline modifies fetal liver copper, gene expression, DNA methylation, and neonatal growth in the tx-j mouse model of Wilson disease

    Science.gov (United States)

    Medici, Valentina; Shibata, Noreene M; Kharbanda, Kusum K; Islam, Mohammad S; Keen, Carl L; Kim, Kyoungmi; Tillman, Brittany; French, Samuel W; Halsted, Charles H; LaSalle, Janine M

    2014-01-01

    Maternal diet can affect fetal gene expression through epigenetic mechanisms. Wilson disease (WD), which is caused by autosomal recessive mutations in ATP7B encoding a biliary copper transporter, is characterized by excessive hepatic copper accumulation, but variability in disease severity. We tested the hypothesis that gestational supply of dietary methyl groups modifies fetal DNA methylation and expression of genes involved in methionine and lipid metabolism that are impaired prior to hepatic steatosis in the toxic milk (tx-j) mouse model of WD. Female C3H control and tx-j mice were fed control (choline 8 mmol/Kg of diet) or choline-supplemented (choline 36 mmol/Kg of diet) diets for 2 weeks throughout mating and pregnancy to gestation day 17. A second group of C3H females, half of which were used to cross foster tx-j pups, received the same diet treatments that extended during lactation to 21 d postpartum. Compared with C3H, fetal tx-j livers had significantly lower copper concentrations and significantly lower transcript levels of Cyclin D1 and genes related to methionine and lipid metabolism. Maternal choline supplementation prevented the transcriptional deficits in fetal tx-j liver for multiple genes related to cell growth and metabolism. Global DNA methylation was increased by 17% in tx-j fetal livers after maternal choline treatment (P < 0.05). Maternal dietary choline rescued the lower body weight of 21 d tx-j mice. Our results suggest that WD pathogenesis is modified by maternal in utero factors, including dietary choline. PMID:24220304

  2. Identification and Characterization of Cefazolin-Induced Liver Injury.

    Science.gov (United States)

    Alqahtani, Saleh A; Kleiner, David E; Ghabril, Marwan; Gu, Jiezhun; Hoofnagle, Jay H; Rockey, Don C

    2015-07-01

    Cephalosporin antibiotics are popular because they have a broad spectrum of activity and are generally well tolerated; however, cephalosporin-induced liver injury is considered rare. We describe a new syndrome associated with a single intravenous dose of cefazolin and the clinical features of cephalosporin-induced liver injury. The Drug-Induced Liver Injury (DILI) Network collected detailed clinical data on 1212 patients with DILI between 2004 and 2012. We analyzed data from 41 patients in whom cephalosporins were implicated as primary agents of liver disease; 33 formally were adjudicated as having cephalosporin-induced DILI. Nineteen patients developed clinically apparent DILI after a single intravenous dose of cefazolin. All patients developed self-limited liver injury 3 to 23 days after receiving cefazolin during surgery-often during a minor outpatient procedure. The latency period was 20 days. Clinical features included itching, jaundice, nausea, fever, and rash. Laboratory abnormalities included a mixed or cholestatic pattern of serum enzyme increases. We identified 14 more patients with DILI attributed to other cephalosporins (5 first-generation, 2 second-generation, 6 third-generation, and 1 fourth-generation agent). Although latency and injury patterns were similar for cefazolin and other cephalosporins, the other cephalosporins were associated with more severe courses of injury, including 2 deaths from liver failure. DILI can develop after a single dose of cefazolin. It is characterized by a latency period of 1 to 3 weeks after exposure, a cholestatic biochemical pattern, and a self-limited moderate to severe clinical course. Other cephalosporins can cause a similar but more severe injury. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

  3. Liver injury from ampicillin-induced intestinal microbiota distresses ...

    African Journals Online (AJOL)

    Serum hepatospecific markers (AST, ALT and ALP) were estimated. The antioxidant status of liver tissues was estimated for GSH, MDA, GST, LDH and vitamin C l, in addition to sodium and potassium. Results: Administration of orogastric dose of ampicillin for 3 weeks induced inhibition of E.coli, yeasts, total anaerobes, and ...

  4. Attenuation of sepsis-induced rat liver injury by epigallocatechin ...

    African Journals Online (AJOL)

    Green tea contains four major polyphenols, of which EGCG is the most active antioxidant component [10]. In the present study, the protective role of EGCG against oxidative stress and liver injury in rats subjected to CLP-induced sepsis was investigated. EXPERIMENTAL. Animals and reagents. Adult male Wistar rats (mean ...

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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....

  12. 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

  13. Moderate Exercise Attenuates Lipopolysaccharide-Induced Inflammation and Associated Maternal and Fetal Morbidities in Pregnant Rats.

    Directory of Open Access Journals (Sweden)

    Karina T Kasawara

    Full Text Available Fetal growth restriction (FGR and coagulopathies are often associated with aberrant maternal inflammation. Moderate-intensity exercise during pregnancy has been shown to increase utero-placental blood flow and to enhance fetal nutrition as well as fetal and placental growth. Furthermore, exercise is known to reduce inflammation. To evaluate the effect of moderate-intensity exercise on inflammation associated with the development of maternal coagulopathies and FGR, Wistar rats were subjected to an exercise regime before and during pregnancy. To model inflammation-induced FGR, pregnant rats were administered daily intraperitoneal injections of E. coli lipopolysaccharide (LPS on gestational days (GD 13.5-16.5 and sacrificed at GD 17.5. Control rats were injected with saline. Maternal hemostasis was assessed by thromboelastography. Moderate-intensity exercise prevented LPS-mediated increases in white blood cell counts measured on GD 17.5 and improved maternal hemostasis profiles. Importantly, our data reveal that exercise prevented LPS-induced FGR. Moderate-intensity exercise initiated before and maintained during pregnancy may decrease the severity of maternal and perinatal complications associated with abnormal maternal inflammation.

  14. Upregulated microRNA-92b regulates the differentiation and proliferation of EpCAM-positive fetal liver cells by targeting C/EBPß.

    Directory of Open Access Journals (Sweden)

    Nian-Song Qian

    Full Text Available microRNAs (miRNAs are short noncoding RNAs that negatively regulate gene expression. Although recent evidences have been indicated that their aberrant expression may play an important role in cancer stem cells, the mechanism of their deregulation in neoplastic transformation of liver cancer stem cells (LCSCs has not been explored. In our study, the HCC model was established in F344 rats by DEN induction. The EpCAM(+ cells were sorted out from unfractionated fetal liver cells and liver cancer cells using the FACS analysis and miRNA expression profiles of two groups were screened through microarray platform. Gain-of-function studies were performed in vitro and in vivo to determine the role of miR-92b on proliferation and differentiation of the hepatic progenitors. In addition, luciferase reporter system and gene function analysis were used to predict miR-92b target. we found that miR-92b was highly downregulated in EpCAM(+ fetal liver cells in expression profiling studies. RT-PCR analysis demonstrated reverse correlation between miR-92b expression and differentiation degree in human HCC samples. Overexpression of miR-92b in EpCAM(+ fetal liver cells significantly increased proliferation and inhibited differentiation as well as in vitro and in vivo studies. Moreover, we verified that C/EBPß is a direct target of miR-92b and contributes to its effects on proliferation and differentiation. We conclude that aberrant expression of miR-92b can result in proliferation increase and differentiation arrest of hepatic progenitors by targeting C/EBPß.

  15. 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

  16. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia.

    Science.gov (United States)

    Cotter, David G; Ercal, Baris; Huang, Xiaojing; Leid, Jamison M; d'Avignon, D André; Graham, Mark J; Dietzen, Dennis J; Brunt, Elizabeth M; Patti, Gary J; Crawford, Peter A

    2014-12-01

    Nonalcoholic fatty liver disease (NAFLD) spectrum disorders affect approximately 1 billion individuals worldwide. However, the drivers of progressive steatohepatitis remain incompletely defined. Ketogenesis can dispose of much of the fat that enters the liver, and dysfunction in this pathway could promote the development of NAFLD. Here, we evaluated mice lacking mitochondrial 3-hydroxymethylglutaryl CoA synthase (HMGCS2) to determine the role of ketogenesis in preventing diet-induced steatohepatitis. Antisense oligonucleotide-induced loss of HMGCS2 in chow-fed adult mice caused mild hyperglycemia, increased hepatic gluconeogenesis from pyruvate, and augmented production of hundreds of hepatic metabolites, a suite of which indicated activation of the de novo lipogenesis pathway. High-fat diet feeding of mice with insufficient ketogenesis resulted in extensive hepatocyte injury and inflammation, decreased glycemia, deranged hepatic TCA cycle intermediate concentrations, and impaired hepatic gluconeogenesis due to sequestration of free coenzyme A (CoASH). Supplementation of the CoASH precursors pantothenic acid and cysteine normalized TCA intermediates and gluconeogenesis in the livers of ketogenesis-insufficient animals. Together, these findings indicate that ketogenesis is a critical regulator of hepatic acyl-CoA metabolism, glucose metabolism, and TCA cycle function in the absorptive state and suggest that ketogenesis may modulate fatty liver disease.

  17. 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)

  18. Characterization of diethylnitrosamine-induced liver carcinogenesis in Syrian golden hamsters

    Science.gov (United States)

    CHEN, GUO; DAI, ZHI-KAI; LIANG, RONG-GAN; XIAO, SHENG-JUN; HE, SONG-QING; ZHAO, HAI-LU; XU, QING

    2012-01-01

    The aim of this study was to characterize hepatocarcinogenesis in diethylnitrosamine (DEN)-treated hamsters. Syrian golden hamsters (n=36) were administered DEN by hypodermic injection and addition to drinking water. Morphological analyses, including light microscopy and immunohistochemistry of α-fetal protein (AFP), were performed on liver and lung tissues. Primary cell culture and tumor transplantation were carried out to evaluate the potential application in hepatocellular carcinoma (HCC) research. From 25 to 50 weeks of treatment, liver tumors, including macronodular HCC and ascites, were found in one-third (4/12) of the animals treated with DEN. HCC was characterized by poor differentiation, frequent mitosis, AFP reaction, vessel invasion and potential application in primary cell culture and xenotransplantation. Pre-neoplastic lesions were hyperplastic nodules comprised of clear cells, bile duct proliferation, fatty metamorphosis and multilocular cysts. The DEN-treated hamsters also showed lung tumors consisting of AFP-negative, well-differentiated neoplastic cells. Characterization of DEN-induced HCC in hamsters provides insights into human hepatocarcinogenesis. This animal model has potential applications in HCC research. PMID:22969883

  19. Early bladder outlet obstruction in fetal lambs induces renal dysplasia and the prune-belly syndrome.

    Science.gov (United States)

    Gonzalez, R; Reinberg, Y; Burke, B; Wells, T; Vernier, R L

    1990-03-01

    A model of posterior urethral valves in fetal lambs was developed in order to evaluate the effect of intrauterine urinary obstruction on the developing kidney. Complete urethral obstruction was induced in five fetal lambs at 43 to 45 days of gestation. Two control fetal lambs underwent sham operations. At full term (140 days), two of the five experimental lambs and both control lambs were available for postmortem examination. Results of gross and histological examination of the control lambs were normal. In contrast, the kidneys of the experimental lambs were markedly asymmetrical in size. Histological examination of the kidneys in experimental lambs showed cystic dilatation of the collecting ducts and occasional cystic dilatation of Bowman's spaces, features compatible with obstruction. Also noted were peripheral cortical cysts and primitive tubules lined with cuboidal epithelium and surrounded by fibromuscular collarettes, characteristic of renal dysplasia. One of the infant lambs had many characteristics of the prune-belly syndrome, including a wrinkled, markedly distended abdomen, deficient abdominal wall musculature, flared chest wall, limb deformities, and undescended testes. These results suggest that early in utero urethral obstruction (at the beginning of the second third of gestation) causes renal dysplasia. The results also support the hypothesis that the prune-belly syndrome results from abdominal distention that occurs early in gestation.

  20. 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.

  1. Aluminium-induced Liver and Testicular Damage: Effects of ...

    African Journals Online (AJOL)

    Conclusion: Data of the study suggest that AlCl3 exposure particularly through oral route at a dose of (0.5mg/kg b.w) is toxic and capable of inducing liver damage and testicular dysfunction in animals and possibly humans. Interestingly, Piliostigma thoninngii extract (methanolic) at a dose of 250mg/kg b.wt) was effective in ...

  2. 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.

  3. 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

  4. Liver-specific microRNAs as biomarkers of nanomaterial-induced liver damage

    International Nuclear Information System (INIS)

    Nagano, Takashi; Higashisaka, Kazuma; Kunieda, Akiyoshi; Iwahara, Yuki; Tanaka, Kota; Yoshikawa, Tomoaki; Yoshioka, Yasuo; Tsutsumi, Yasuo; Nagano, Kazuya; Kamada, Haruhiko; Tsunoda, Shin-ichi; Abe, Yasuhiro; Nabeshi, Hiromi

    2013-01-01

    Although nanomaterials are being used in various fields, their safety is not yet sufficiently understood. We have been attempting to establish a nanomaterials safety-assessment system by using biomarkers to predict nanomaterial-induced adverse biological effects. Here, we focused on microRNAs (miRNAs) because of their tissue-specific expression and high degree of stability in the blood. We previously showed that high intravenous doses of silica nanoparticles of 70 nm diameter (nSP70) induced liver damage in mice. In this study, we compared the effectiveness of serum levels of liver-specific or -enriched miRNAs (miR-122, miR-192, and miR-194) with that of conventional hepatic biomarkers (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)) as biomarkers for nSP70. After mice had been treated with nSP70, their serum miRNAs levels were measured by using quantitative RT-PCR. Serum levels of miR-122 in nSP70-treated mice were the highest among the three miRNAs. The sensitivity of miR-122 for liver damage was at least as good as those of ALT and AST. Like ALT and AST, miR-122 may be a useful biomarker of nSP70. We believe that these findings will help in the establishment of a nanomaterials safety-assessment system. (paper)

  5. Inhibition of gingipains prevents Porphyromonas gingivalis-induced preterm birth and fetal death in pregnant mice.

    Science.gov (United States)

    Takii, Ryosuke; Kadowaki, Tomoko; Tsukuba, Takayuki; Yamamoto, Kenji

    2018-04-05

    Accumulating epidemiological evidence indicates that infection with Porphyromonas gingivalis which is a major periodontal pathogen, causes preterm birth and low birth weight. However, virulence factors of P. gingivalis responsible for preterm birth/low birth weight remain to be elucidated. In this study, using P. gingivalis-infected pregnant mice as an in vivo model, we investigated whether gingipains-cysteine proteinases produced by P. gingivalis-affect preterm birth and low birth weight. We found that intravenous infection of pregnant mice with P. gingivalis induced higher accumulation of the bacterium in the placenta than that in other organs. Compared to infection with P. gingivalis wild-type, infection with a gingipain-deficient P. gingivalis mutant KDP136 led to significant reduction in preterm birth and pregnancy loss. Although repetitive low-level infections of P. gingivalis failed to induce preterm birth and fetal death, it induced suppressive effects on IFN-γ production. Therapeutically, treatment with ginginpain inhibitors prevented fetal death and preterm birth caused by P. gingivalis infection and resulted in recovery of IFN-γ suppression caused by repetitive chronic P. gingivalis infection. These results indicate that gingipains are major virulence factors of P. gingivalis responsible for preterm birth/low birth, and gingipain inhibitors may be useful not only as a therapeutic agent for periodontal diseases, but also as a preventive medicine for preterm birth/low birth weight. Copyright © 2018 Elsevier B.V. All rights reserved.

  6. 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

  7. 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

  8. 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.

  9. 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

  10. 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

  11. Astaxanthin pretreatment attenuates acetaminophen-induced liver injury in mice.

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    Zhang, Jingyao; Zhang, Simin; Bi, Jianbin; Gu, Jingxian; Deng, Yan; Liu, Chang

    2017-04-01

    Acetaminophen (APAP) is a conventional drug widely used in the clinic because of its antipyretic-analgesic effects. However, accidental or intentional APAP overdoses induce liver injury and even acute liver failure (ALF). Astaxanthin (ASX) is the strongest antioxidant in nature that shows preventive and therapeutic properties, such as ocular protection, anti-tumor, anti-diabetes, anti-inflammatory, and immunomodulatory effects. The aim of present study was to determine whether ASX pretreatment provides protection against APAP-induced liver failure. Male C57BL/6 mice were randomly divided into 7 groups, including control, oil, ASX (30mg/kg or 60mg/kg), APAP and APAP+ASX (30mg/kg or 60mg/kg) groups. Saline, olive oil and ASX were administered for 14days. The APAP and APAP+ASX groups were given a peritoneal injection of 700mg/kg or 300mg/kg APAP to determine the 5-day survival rate and for further observation, respectively. Blood and liver samples were collected to detect alanine transaminase (ALT), aspartate transaminase (AST), inflammation, oxidative stress and antioxidant systems, and to observe histopathologic changes and key proteins in the mitogen-activated protein kinase (MAPK) family. ASX pretreatment before APAP increased the 5-day survival rate in a dose-dependent manner and reduced the ALT, AST, hepatic necrosis, reactive oxygen species (ROS) generation, lipid peroxidation (LPO), oxidative stress and pro-inflammatory factors. ASX protected against APAP toxicity by inhibiting the depletion of glutathione (GSH) and superoxide dismutase (SOD). Administration of ASX did not change the expression of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and P38. However, phosphorylation of JNK, ERK and P38 was reduced, consistent with the level of tumor necrosis factor alpha (TNF-α) and TNF receptor-associated factor 2 (TRAF2). ASX provided protection for the liver against APAP hepatotoxicity by alleviating hepatocyte necrosis, blocking ROS

  12. POLG determines the risk of sodium valproate induced liver toxicity

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    Stewart, Joanna D.; Horvath, Rita; Baruffini, Enrico; Ferrero, Iliana; Bulst, Stefanie; Watkins, Paul B.; Fontana, Robert J.; Day, Christopher P.; Chinnery, Patrick F.

    2013-01-01

    Sodium valproate (VPA) is widely used throughout the world to treat epilepsy, migraine, chronic headache, bipolar disorder, and as adjuvant chemotherapy. VPA toxicity is an uncommon but potentially fatal cause of idiosyncratic liver injury. Rare mutations in POLG, which codes for the mitochondrial DNA polymerase γ (polγ), cause the Alpers-Huttenlocher syndrome (AHS). AHS is a neurometabolic disorder associated with an increased risk of developing fatal VPA-hepatotoxicity. We therefore set out to determine whether common genetic variants in POLG explain why some otherwise healthy individuals develop VPA-hepatotoxicity. We carried out a prospective study of subjects enrolled in the Drug Induced Liver Injury Network (DILIN) from 2004 to 2008 through five US centres. POLG was sequenced and the functional consequences of VPA and novel POLG variants were evaluated in primary human cell lines and the yeast model system Saccharomyces cerevisiae. Heterozygous genetic variation in POLG was strongly associated with VPA-induced liver toxicity (odds ratio = 23.6, 95% CI = 8.4 – 65.8, P = 5.1 × 10−7). This was principally due to the p.Q1236H substitution which compromised polγ function in yeast. Therapeutic doses of VPA inhibited human cellular proliferation, and high doses caused non-apoptotic cell death which was not mediated through mitochondrial DNA depletion, mutation, or a defect of fatty acid metabolism. These findings implicate impaired liver regeneration in VPA toxicity, and show that prospective genetic testing of POLG will identify individuals at high risk of this potentially fatal consequence of treatment. PMID:21038416

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

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    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.

  14. Quercetin Reverses Rat Liver Preneoplastic Lesions Induced by Chemical Carcinogenesis

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    Gabriela Carrasco-Torres

    2017-01-01

    Full Text Available Quercetin is a flavonoid widely studied as a chemopreventive agent in different types of cancer. Previously, we reported that quercetin has a chemopreventive effect on the liver-induced preneoplastic lesions in rats. Here, we evaluated if quercetin was able not only to prevent but also to reverse rat liver preneoplastic lesions. We used the modified resistant hepatocyte model (MRHM to evaluate this possibility. Treatment with quercetin was used 15 days after the induction of preneoplastic lesions. We found that quercetin reverses the number of preneoplastic lesions and their areas. Our results showed that quercetin downregulates the expression of EGFR and modulates this signaling pathway in spite of the activated status of EGFR as detected by the upregulation of this receptor, with respect to that observed in control rats. Besides, quercetin affects the phosphorylation status of Src-1, STAT5, and Sp-1. The better status of the liver after the treatment with quercetin could also be confirmed by the recovery in the expression of IGF-1. In conclusion, we suggest that quercetin reversed preneoplastic lesions by EGFR modulation and the activation state of Src, STAT5, and Sp1, so as the basal IGF-1.

  15. Quercetin Reverses Rat Liver Preneoplastic Lesions Induced by Chemical Carcinogenesis

    Science.gov (United States)

    Monroy-Ramírez, Hugo Christian; Martínez-Guerra, Arturo Axayacatl; Baltiérrez-Hoyos, Rafael; Romero-Tlalolini, María de los Ángeles; Villa-Treviño, Saúl; Sánchez-Chino, Xariss

    2017-01-01

    Quercetin is a flavonoid widely studied as a chemopreventive agent in different types of cancer. Previously, we reported that quercetin has a chemopreventive effect on the liver-induced preneoplastic lesions in rats. Here, we evaluated if quercetin was able not only to prevent but also to reverse rat liver preneoplastic lesions. We used the modified resistant hepatocyte model (MRHM) to evaluate this possibility. Treatment with quercetin was used 15 days after the induction of preneoplastic lesions. We found that quercetin reverses the number of preneoplastic lesions and their areas. Our results showed that quercetin downregulates the expression of EGFR and modulates this signaling pathway in spite of the activated status of EGFR as detected by the upregulation of this receptor, with respect to that observed in control rats. Besides, quercetin affects the phosphorylation status of Src-1, STAT5, and Sp-1. The better status of the liver after the treatment with quercetin could also be confirmed by the recovery in the expression of IGF-1. In conclusion, we suggest that quercetin reversed preneoplastic lesions by EGFR modulation and the activation state of Src, STAT5, and Sp1, so as the basal IGF-1. PMID:28740570

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

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    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.

  17. Interleukin-6 and C-Reactive Protein Are Overexpressed in the Liver of Perinatal Deaths Diagnosed with Fetal Inflammatory Response Syndrome

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    Lívia Helena M. Pereira

    2014-01-01

    Full Text Available Anatomopathologic studies have failed to define the fetal inflammatory response syndrome (FIRS as a cause of fetal death. Here, liver fragments of perinatal autopsies were collected at a university hospital from 1990 to 2009 and classified according to the cause of death, perinatal stress, and gestational age (GA of the fetus. IL-6, TNF-α, and C-reactive protein (CRP expression were immunostained, respectively, with primary antibody. Cases with congenital malformation, ascending infection, and perinatal anoxia showed increased IL-6, CRP, and TNF-α, respectively. Prematures presented higher expression of IL-6 whereas term births showed higher expression of CRP. Cases classified as acute stress presented higher expression of IL-6 and TNF-α and cases with chronic stress presented higher expression of CRP. GA correlated negatively with IL-6 and positively with CRP and TNF-α. Body weight correlated negatively with IL-6 and positively with CRP and TNF-α. Despite the diagnosis of FIRS being clinical and based on serum parameters, the findings in the current study allow the inference of FIRS diagnosis in the autopsied infants, based on an in situ liver analysis of these markers.

  18. Portal vein embolization induces more liver regeneration than portal vein ligation in a standardized rabbit model

    NARCIS (Netherlands)

    van den Esschert, Jacomina W.; van Lienden, Krijn P.; de Graaf, Wilmar; Maas, Martinus A. W.; Roelofs, Joris J. T. H.; Heger, Michal; van Gulik, Thomas M.

    2011-01-01

    Background. Portal vein ligation (PVL) and portal vein embolization (PVE) are used to induce hypertrophy of the future remnant liver before major liver resection. The aim of our study was to compare the hypertrophy response of the liver after PVL versus PVE in a rabbit model. Methods. Twenty rabbits

  19. Drug-induced and postnatal hypothyroidism impairs the accumulation of diacylglycerol in liver and liver cell plasma membranes

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    Kavok Nataliya S

    2002-08-01

    sharply differed from PL. DAG was relatively enriched in [14C]oleic acid whereas PL were enriched in [3H]arachidonic acid. Conclusions The above data have indicated that thyroid hormones are important physiological modulators of DAG level in rat liver and cell plasma membranes. Age- and drug-induced malfunction of thyroid gland resulted in a prominent decrease of glycerolipid synthesis which may promote DAG accumulation in liver.

  20. 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, Rosalinde; 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

  1. Mechanisms of hepatoprotection of Terminalia catappa L. extract on D-Galactosamine-induced liver damage.

    Science.gov (United States)

    Tang, Xin-Hui; Gao, Ling; Gao, Jing; Fan, Yi-Mei; Xu, Li-Zhi; Zhao, Xiao-Ning; Xu, Qiang

    2004-01-01

    The hepatoprotective effects of the extract of Terminalia catappa L. leaves (TCE) against D-Galactosamine (D-GalN)-induced liver injury and the mechanisms underlying its protection were studied. In acute hepatic injury test, it was found that serum ALT activity was remarkably increased (3.35-fold) after injection of D-GalN in mice. But with oral pretreatment of TCE (20, 50 and 100 mg/kg/d) for 7days, change in serum ALT was notably reversed. In primary cultured hepatocytes from fetal mice, it was found that cell viability was decreased by 45.0% after addition of D-GalN, while incubation with TCE (0.1, 0.5 and 1.0 mg/ml) for 36 hours could prevent the decrease in a dose-dependent manner. Meanwhile, D-GalN-induced both the increase of AST level (1.9-fold) and the decrease of SOD activity (48.0%) in supernatant of primary cultured hepatocytes could also be inhibited by pretreatment with TCE. In order to study the possible mechanisms underlying its hepatoprotective effects, one effective component separated from TCE, 2alpha, 3beta, 23-trihydroxyursane-12-en-28-oic acid (DHUA), was used to determine anti-mitochondrial swelling activity and superoxide radicals scavenging activity in vitro. It was found that at the concentration range of 50-500 micromol/L DHUA, Ca2+ -induced mitochondrial swelling was dose-dependently inhibited, and superoxide radicals scavenging activity was also shown in a dose-dependent manner. It was concluded that TCE has hepatoprotective activity and the mechanisms underlying its protective effects may be related to the direct mitochondrion protection and strong scavenging activity on reactive oxygen species (ROS).

  2. Hepatoprotective Effects of Vitamin E Against Malathion-Induced Mitochondrial Dysfunction in Rat Liver

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    Ranjbar

    2014-09-01

    Full Text Available Background Malathion is an insecticide of the grouping of organophosphate pesticides (OPs, which shows strong insecticidal effects. In addition, vitamin E reacting to cell membrane site may prevent OP-induced oxidative injury. Objectives The aim of this study was to examine the protective function of vitamin E on toxicity of malathion, by measuring the activities of liver and liver mitochondrial superoxide dismutase (SOD, catalase (CAT,lipid peroxidation (LPO,and glutathione peroxidase (GPx in rats. Materials and Methods The mitochondrial viability was determined in liver. ‎Effective doses of malathion(200 mg/kg/day and vitamin E (alpha-tocopherylacetate [AT]; 15 mg/kg/day were administered alone or in combination for 14 days. At the end of the experiment, the liver tissue and liver mitochondria of the animals were harvested and examined. Results In liver tissue, the activity of LPO and CAT was higher in the malathion group in comparison to controls. AT reduced malathion-induced LPO, SOD, CAT, and GPx in rat liver. Coadministration of AT with malathion improved LPO, SOD, and CAT levels in liver as well as CAT and GPx in liver mitochondria. Malathion-induced mitochondria toxicity was recovered by AT. Conclusions In conclusion, AT measurement can be beneficial for the safety or recovery of malathion-induced toxic injury in liver tissue and liver mitochondria.

  3. Peptidome profiling of umbilical cord plasma associated with gestational diabetes-induced fetal macrosomia.

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    Liu, Fei; Zhao, Chun; Liu, Lan; Ding, Hongjuan; Huo, Ran; Shi, Zhonghua

    2016-04-29

    Fetal macrosomia, defined as a birth weight ≥4000g, may affect 15-45% of newborns of women with gestational diabetes mellitus (GDM). The associations between endogenous peptides and gestational diabetes-induced macrosomia have not been investigated extensively by peptidome analysis. Here, we analyzed the umbilical cord plasma by combining ultrafiltration using molecular weight cut-off filters and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to investigate potential associations of GDM with macrosomia. As macrosomic babies have increased susceptibility to obesity, diabetes and cardiovascular diseases in later life, we also aimed to identify specific biomarkers to detect these future diseases. Thirty pairs of GDM mothers and controls were randomly divided into three subgroups. We identified 235 peptides of around 1000-3000Da, originating from 115 proteins. Analyzing the cleavage sites revealed that these peptides were cleaved in regulation, which may reflect the protease activity and distribution in umbilical cord plasma. Four identified peptides, of 2471.7, 1077.2, 1446.5 and 2372.7Da, were significantly differentially expressed in the GDM macrosomia groups compared with controls, whose precursors may play a critical role in developing GDM macrosomia. We provide for the first time a validated GDM macrosomia peptidome profile and identify potential biomarkers linking the effects of macrosomia to later-life diseases. Fetal macrosomia is the predominant adverse outcome of gestational diabetes mellitus (GDM), which is a frequent medical condition during pregnancy. Till now, the detailed molecular mechanisms underlying gestational diabetes-induced macrosomia are still not elucidated. With high detection sensitivity and high throughput of peptidome technology, it is now possible to systemically identify peptides possibly involved in the umbilical cord plasma of GDM induced macrosomia cases. With LC-MS/MS based quantification, totally, we identified 235

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

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    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.

  5. 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

  6. 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

  7. 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.

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

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    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.

  9. Temozolomide-induced liver damage. A case report

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    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.)

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

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    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

  11. 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

  12. 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.

  13. 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)

  14. Intra-Amniotic LPS Induced Region-Specific Changes in Presynaptic Bouton Densities in the Ovine Fetal Brain

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    Eveline Strackx

    2015-01-01

    Full Text Available Rationale. Chorioamnionitis has been associated with increased risk for fetal brain damage. Although, it is now accepted that synaptic dysfunction might be responsible for functional deficits, synaptic densities/numbers after a fetal inflammatory challenge have not been studied in different regions yet. Therefore, we tested in this study the hypothesis that LPS-induced chorioamnionitis caused profound changes in synaptic densities in different regions of the fetal sheep brain. Material and Methods. Chorioamnionitis was induced by a 10 mg intra-amniotic LPS injection at two different exposure intervals. The fetal brain was studied at 125 days of gestation (term = 150 days either 2 (LPS2D group or 14 days (LPS14D group after LPS or saline injection (control group. Synaptophysin immunohistochemistry was used to quantify the presynaptic density in layers 2-3 and 5-6 of the motor cortex, somatosensory cortex, entorhinal cortex, and piriforme cortex, in the nucleus caudatus and putamen and in CA1/2, CA3, and dentate gyrus of the hippocampus. Results. There was a significant reduction in presynaptic bouton densities in layers 2-3 and 5-6 of the motor cortex and in layers 2-3 of the entorhinal and the somatosensory cortex, in the nucleus caudate and putamen and the CA1/2 and CA3 of the hippocampus in the LPS2D compared to control animals. Only in the motor cortex and putamen, the presynaptic density was significantly decreased in the LPS14 D compared to the control group. No changes were found in the dentate gyrus of the hippocampus and the piriforme cortex. Conclusion. We demonstrated that LPS-induced chorioamnionitis caused a decreased density in presynaptic boutons in different areas in the fetal brain. These synaptic changes seemed to be region-specific, with some regions being more affected than others, and seemed to be transient in some regions.

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

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    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.

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

    Science.gov (United States)

    Shearstone, Jeffrey R; Golonzhka, Olga; Chonkar, Apurva; Tamang, David; van Duzer, John H; Jones, Simon S; Jarpe, Matthew B

    2016-01-01

    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.

  17. 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.

  18. Quantification of fetal organ volume and fat deposition following in utero exposure to maternal Western Diet using MRI.

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    Kevin J Sinclair

    Full Text Available To examine the feasibility of using MRI to identify differences in liver size and fat deposition in fetal guinea pigs exposed to an in utero environment influenced by maternal consumption of a Western diet.Female guinea pigs fed either an energy-dense Western Diet (WD, comprised of increased saturated fats and simple sugars, or a Control Diet (CD from weaning through pregnancy, underwent MR scanning near term (~ 60 days; term ~ 69 days. Maternal weights were collected at mating and at MR scanning. T1-weighted, T2-weighted, and IDEAL water-fat images were acquired at 3 Tesla. The images were used to segment maternal adipose tissue, fetal liver, fetal brain, fetal adipose tissue, and total fetal volumes and to measure maternal and fetal hepatic fat fractions.Weights of WD sows were lower prior to pregnancy (P = .04, however their weight gain over pregnancy did not differ from the CD group (P = .98. The WD sows had less total adipose tissue (TAT at MR scanning (P = .04, while hepatic fat content was significantly elevated (P = .04. When controlling for litter size, WD fetuses had larger livers (P = .02, smaller brains (P = .01, and increased total adipose tissue volume (P = .01 when normalized by fetal volume. The WD fetuses also had increased hepatic fat fractions compared to CD fetal livers (P < .001.Maternal Western Diet consumption prior to and during pregnancy induces differences in maternal liver fat content, fetal liver volume and liver fat storage, as well as changes in fetal adipose tissue deposition that can be measured in utero using MRI.

  19. 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.

  20. Protective effect of oligomeric proanthocyanidins against alcohol-induced liver steatosis and injury in mice.

    Science.gov (United States)

    Wang, Zhiguo; Su, Bo; Fan, Sumei; Fei, Haixia; Zhao, Wei

    2015-03-20

    The long-term consumption of alcohol has been associated with multiple pathologies at all levels, such as alcoholism, chronic pancreatitis, malnutrition, alcoholic liver disease (ALD) and cancer. In the current study, we investigated the protective effect of oligomeric proanthocyanidins (OPC) against alcohol-induced liver steatosis and injury and the possible mechanisms using ethanol-induced chronic liver damage mouse models. The results showed that OPC significantly improved alcohol-induced dyslipidemia and alleviated liver steatosis by reducing levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total triglyceride (TG), total cholesterol (TC), low-density cholesterol (LDL-c) and liver malondialdehyde (MDA), and increasing levels of serum high-density lipoprotein (HDL-c), liver superoxide dismutase (SOD). Further investigation indicated that OPC markedly decreased the expressions of lipid synthesis genes and inflammation genes such as sterol regulatory element-binding protein-1c (Srebp-1c), protein-2 (Srebp2), interleukin IL-1β, IL-6 and TNF-α. Furthermore, AML-12 cells line was used to investigate the possible mechanisms which indicated that OPC might alleviate liver steatosis and damage through AMP-activated protein kinase (AMPK) activation involving oxidative stress. In conclusion, our study demonstrated excellent protective effect of OPC against alcohol-induced liver steatosis and injury, which could a potential drug for the treatment of alcohol-induced liver injury in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

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

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    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.

  2. 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

  3. A fetal human heart cardiac-inducing RNA (CIR) promotes the differentiation of stem cells into cardiomyocytes.

    Science.gov (United States)

    Kochegarov, Andrei; Moses-Arms, Ashley; Lemanski, Larry F

    2015-08-01

    A specific human fetal heart RNA has been discovered, which has the ability to induce myocardial cell formation from mouse embryonic and human-induced pluripotent stem cells in culture. In this study, commercially obtained RNA from human fetal heart was cloned, sequenced, and synthesized using standard laboratory approaches. Molecular analyses of the specific fetal cardiac-inducing RNA (CIR), revealed that it is a fragment of N-sulfoglucosaminesulfohydrolase and the caspase recruitment domain family member 14 precursor. Stem cells transfected with CIRs often form into spindle-shaped cells characteristic of cardiomyocytes,and express the cardiac-specific contractile protein marker, troponin-T, in addition to tropomyosin and α-actinin as detected by immunohistochemical staining. Expression of these contractile proteins showed organization into sarcomeric myofibrils characteristic of striated cardiac muscle cells. Computer analyses of the RNA secondary structures of the active CIR show significant similarities to a RNA from salamander or myofibril-inducing RNA (MIR), which also promotes non-muscle cells to differentiate into cardiac muscle. Thus, these two RNAs, salamander MIR and the newly discovered human-cloned CIR reported here, appear to have evolutionarily conserved secondary structures suggesting that both play major roles in vertebrate heart development and, particularly, in the differentiation of cardiomyocytes from non-muscle cells during development.

  4. Calcium spirulan as an inducer of tissue-type plasminogen activator in human fetal lung fibroblasts.

    Science.gov (United States)

    Hayakawa, Y; Hayashi, T; Hayashi, K; Ozawa, T; Niiya, K; Sakuragawa, N

    1997-03-01

    Calcium spirulan (Ca-SP), a novel sulfated polysaccharide isolated from the blue-green alga Spirulina platensis, has been found to have antiviral and heparin cofactor II-dependent antithrombin activities. We have obtained evidence that Ca-SP is a potent inducer of tissue-type plasminogen activator (t-PA) production. The addition of Ca-SP to a culture of IMR-90 human fetal lung fibroblasts increased t-PA concentrations in the conditioned medium, in a dose- and time-dependent manner, but in the cell lysate, t-PA concentrations were unchanged, suggesting that t-PA induced by Ca-SP is easily secreted into the conditioned medium. The amount of newly synthesized t-PA in IMR-90 cells, as measured by labeling with [35S]methionine and subsequent immunoprecipitation of t-PA from conditioned medium, was significantly increased by Ca-SP-stimulation. However, Ca-SP did not increase the t-PA mRNA levels. As previously reported, thrombin stimulated t-PA gene transcription in IMR-90 cells, and the simultaneous treatment with Ca-SP and thrombin caused further enhancement of t-PA production, in a synergistic manner. It would thus appear that Ca-SP increases t-PA production through post-transcriptional processes. IMR-90 cells also produce plasminogen activator inhibitor type-1 (PAI-1), but Ca-SP showed little effect on the PAI-1 production. H-SP, which was obtained by removing the calcium from Ca-SP, had no effect on the t-PA production. Na-SP, which was prepared by replacement of the calcium with sodium, stimulated the t-PA production similarly to Ca-SP. Thus, Ca-SP specifically induces t-PA production, and the molecular conformation of Ca-SP maintained by Ca or Na may be essential for the stimulation of t-PA synthesis.

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

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    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.

  6. 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

  7. 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

  8. 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

  9. 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

  10. Smoking-Induced Changes in the Maternal Immune, Endocrine, and Metabolic Pathways and Their Impact on Fetal Growth: A Topical Review.

    Science.gov (United States)

    Sabra, Sally; Gratacós, Eduard; Gómez Roig, Maria Dolores

    2017-01-01

    Perinatal maternal smoking exposure (PMSE) is one of the major environmental risk factors encountered by the fetus. PMSE is usually associated with adverse pregnancy outcomes that may manifest at different stages of life. Nevertheless, fetal growth restriction is the most common smoking-induced side effect. PMSE induces changes in the maternal multiple organ systems. These alterations may affect placentation, which subsequently affects fetal growth. It is worthy to note, however, that the extent of maternal smoking-induced changes depends mainly on the maternal level of susceptibility. Hence, the perinatal pregnancy outcomes vary depending on the interaction between the triad: the maternal, fetal, and placental modifications, making it more complex. In this review, we try to unveil the effect of smoking-induced maternal changes on the maternal immune, endocrine, and metabolic pathways and their impact on fetal growth. © 2017 S. Karger AG, Basel.

  11. 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.

  12. 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.

  13. 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.

  14. Connecting liver and gut: murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid.

    Science.gov (United States)

    Neumann, Katrin; Kruse, Nils; Szilagyi, Balint; Erben, Ulrike; Rudolph, Christine; Flach, Anne; Zeitz, Martin; Hamann, Alf; Klugewitz, Katja

    2012-06-01

    Gut-activated T cells migrating into the liver can cause extraintestinal manifestations of inflammatory bowel disease. T cells acquire a gut-homing phenotype dependent on retinoic acid (RA) provided by intestinal dendritic cells (DC). We investigated whether liver antigen-presenting cells can induce gut tropism supporting an enterohepatic lymphocyte circulation. Priming of CD4(+) T cells by liver sinusoidal endothelial cells (LSEC) supported migration into gut and gut-associated lymphoid tissue. As observed for T cells primed by intestinal DCs, this gut tropism depended on α(4) β(7) integrin and CC chemokine receptor 9 (CCR9) expression by LSEC-primed CD4(+) T cells. The induction of gut-homing molecules was mediated by RA, a derivate of vitamin A that is stored in large amounts within the liver. LSECs expressed functional retinal dehydrogenases and could convert vitamin A to RA. Conversely, the lack of signaling via the RA receptor prevented the expression of α(4) β(7) integrin and CCR9 on LSEC-primed CD4(+) T cells, consequently reducing their in vivo migration to the intestine. Other liver antigen-presenting cells failed to support high expression of α(4) β(7) integrin on CD4(+) T cells, thus, the potential to induce gut homing is restricted to LSECs. The capacity to promote gut tropism via vitamin A use is not unique for intestinal DCs but is also a feature of LSECs. Our data support the assumption that CD4(+) T cells can migrate from the liver to the gut as one branch of a postulated enterohepatic lymphocyte circulation. Copyright © 2011 American Association for the Study of Liver Diseases.

  15. 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.

  16. 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

  17. 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.

  18. A Rare Case of Propofol-Induced Acute Liver Failure and Literature Review

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    G. Kneiseler

    2010-02-01

    Full Text Available The incidence of drug-induced acute liver failure is increasing. A number of drugs can inhibit mitochondrial functions, alter β-oxidation and cause accumulation of free fatty acids within the hepatocytes. This may result in hepatic steatosis, cell death and liver injury. In our case, propofol, an anesthetic drug commonly used in adults and children, is suspected to have induced disturbance of the mitochondrial respiratory chain, which in consequence led to insufficient energy supply and finally liver failure. We report the case of a 35-year-old Caucasian woman with acute liver failure after anesthesia for stripping of varicose veins. Liver histology, imaging and laboratory data indicate drug-induced acute liver failure, presumably due to propofol. Hepatocyte death and microvesicular fatty degeneration of 90% of the liver parenchyma were observed before treatment with steroids. Six months later, a second biopsy was performed, which revealed only minimal steatosis and minimal periportal hepatitis. We suggest that propofol led to impaired fatty acid oxidation possibly due to a genetic susceptibility. This caused free fatty acid accumulation within hepatocytes, which presented as hepatocellular fatty degeneration and cell death. Large scale hepatocyte death was followed by impaired liver function and, consecutively, progressed to acute liver failure.

  19. 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...

  20. 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

  1. 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

  2. Massive Liver Cell Necrosis Induced in the Pig with Carbon ...

    African Journals Online (AJOL)

    P450 or electron microscopy was made (see Discussion). Biochemical tests of liver damage were chosen to align with clinical practice and sera were analysed for aspartate transaminase, bilirubin and alkaline phos- phatase. Histological sections of the liver, kidneys and lungs were taken at death or sacrifice in all animals.

  3. Evaluation of vaccination with Neospora caninum protein for prevention of fetal loss associated with experimentally induced neosporosis in sheep.

    Science.gov (United States)

    Jenkins, Mark C; Tuo, Wenbin; Dubey, J P

    2004-10-01

    To evaluate the immunologic response of a killed tachyzoite vaccine against Neospora caninum and its effectiveness in preventing fetal loss associated with experimentally induced neosporosis in sheep. 30 Dorset ewes. Ewes were randomly allocated to receive vaccination on days 1 and 60 of the study with a killed N caninum tachyzoite preparation in a commercially available adjuvant or a saline-adjuvant mixture. A ram was placed on pasture with the ewes from days 15 to 60. Blood was collected from ewes before primary and booster vaccinations and prior to experimental challenge with N caninum tachyzoite performed on day 90; sera were assessed via Neospora agglutination (NA) and immunofluorescence antibody (IFA) assays. Blood was collected from lambs before they suckled, and sera were tested for antibodies against N caninum. Of the 14 vaccinated ewes that became pregnant, 12 gave birth to live-born lambs; in contrast, 5 of 11 pregnant control ewes gave birth to live-born lambs. Whereas vaccination improved fetal survival in pregnant ewes challenged with N caninum tachyzoites, it did not appear to have any appreciable effect on transmission of N caninum to offspring, as indicated by results of NA and IFA assays. The N caninum tachyzoite vaccine used in this study appeared to provide protection against fetal loss associated with experimentally induced neosporosis in a high proportion of pregnant ewes.

  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. 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.

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

    OpenAIRE

    Gonz?lez-Ponce, Herson Antonio; Mart?nez-Salda?a, Mar?a Consolaci?n; Rinc?n-S?nchez, Ana Rosa; Sumaya-Mart?nez, Mar?a Teresa; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Ju?rez, 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 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 agai...

  8. 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.

  9. 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.

  10. 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

  11. A case of amoxicillin-induced hepatocellular liver injury with bile-duct damage

    Science.gov (United States)

    Kim, Ju Seung; Jang, Young Rock; Lee, Ji Won; Kim, Jin Yong; Chung, Dong Hae; Kwon, Oh Sang; Kim, Yun Soo; Choi, Duck Joo; Kim, Ju Hyun

    2011-01-01

    Amoxicillin, an antibiotic that is widely prescribed for various infections, is associated with a very low rate of drug-induced liver injury; hepatitis and cholestasis are rare complications. Here we present a case of a 39-year-old woman who was diagnosed with abdominal actinomycosis and received amoxicillin treatment. The patient displayed hepatocellular and bile-duct injury, in addition to elevated levels of liver enzymes. The patient was diagnosed with amoxicillin-induced cholestatic hepatitis. When amoxicillin was discontinued, the patient's symptoms improved and her liver enzyme levels reduced to near to the normal range. PMID:22102391

  12. Hepatoprotective effect of vitamin C on lithocholic acid-induced cholestatic liver injury in Gulo(-/-) mice.

    Science.gov (United States)

    Yu, Su Jong; Bae, Seyeon; Kang, Jae Seung; Yoon, Jung-Hwan; Cho, Eun Ju; Lee, Jeong-Hoon; Kim, Yoon Jun; Lee, Wang Jae; Kim, Chung Yong; Lee, Hyo-Suk

    2015-09-05

    Prevention and restoration of hepatic fibrosis from chronic liver injury is essential for the treatment of patients with chronic liver diseases. Vitamin C is known to have hepatoprotective effects, but their underlying mechanisms are unclear, especially those associated with hepatic fibrosis. Here, we analyzed the impact of vitamin C on bile acid induced hepatocyte apoptosis in vitro and lithocholic acid (LCA)-induced liver injury in vitamin C-insufficient Gulo(-/-) mice, which cannot synthesize vitamin C similarly to humans. When Huh-BAT cells were treated with bile acid, apoptosis was induced by endoplasmic reticulum stress-related JNK activation but vitamin C attenuated bile acid-induced hepatocyte apoptosis in vitro. In our in vivo experiments, LCA feeding increased plasma marker of cholestasis and resulted in more extensive liver damage and hepatic fibrosis by more prominent apoptotic cell death and recruiting more intrahepatic inflammatory CD11b(+) cells in the liver of vitamin C-insufficient Gulo(-/-) mice compared to wild type mice which have minimal hepatic fibrosis. However, when vitamin C was supplemented to vitamin C-insufficient Gulo(-/-) mice, hepatic fibrosis was significantly attenuated in the liver of vitamin C-sufficient Gulo(-/-) mice like in wild type mice and this hepatoprotective effect of vitamin C was thought to be associated with both decreased hepatic apoptosis and necrosis. These results suggested that vitamin C had hepatoprotective effect against cholestatic liver injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. 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

  14. Nasogastric tube induced refractory epistaxis during liver transplantation

    Directory of Open Access Journals (Sweden)

    Yun Hee Kim

    2016-10-01

    Full Text Available Cirrhosis has many possible manifestations. These signs and symptoms may be either the direct results of liver cell failure or secondary to the resultant portal hypertension. Portal hypertension can decrease the number of platelets, which increases the risk of bleeding.  Additionally, the liver plays a central role in hemostasis, because it is the site of clotting factors synthesis, coagulation inhibitors, and fibrinolytic proteins. Low platelet count and prolonged clotting times may increase the risk of epistaxis arising from minimal trauma, which can cause sometimes serious and occasionally fatal results. We experienced an intraoperative refractory epistaxis in a 60-year-old man with end-stage liver disease (ESLD due to hepatitis B virus-related hepatocellular carcinoma during liver transplantation. The patient started severe epistaxis after we attempted to place a nasogastric (NG tube. We describe successful management of massive epistaxis in an operating room under appropriate anesthesia and close hemodynamic monitoring.   Keywords: End-stage liver disease; Epistaxis; Liver transplantation; Nasogastric tube

  15. Effects of pharmaceutical formulations containing thyme on carbon tetrachloride-induced liver injury in rats.

    Science.gov (United States)

    Rašković, Aleksandar; Pavlović, Nebojša; Kvrgić, Maja; Sudji, Jan; Mitić, Gorana; Čapo, Ivan; Mikov, Momir

    2015-12-18

    Herbal supplements are widely used in the treatment of various liver disases, but some of them may also induce liver injuries. Regarding the infuence of thyme and its constituents on the liver, conflicting results have been reported in the literature. The objective of this study was to examine the influence of two commonly used pharmaceutical formulations containing thyme (Thymus vulgaris L.), tincture and syrup, on carbon tetrachloride-induced acute liver injury in rats. Chemical composition of investigated formulations of thyme was determined by gas chromatography and mass spectrometry. Activities of enzyme markers of hepatocellular damage in serum and antioxidant enzymes in the liver homogenates were measured using the kinetic spectrophotometric methods. Liver morphology was characterized by light microscopy using routine hematoxylin and eosin staining. Thymol was found to be predominant active constituent in both tincture and syrup. Investigated thyme preparations exerted antioxidant effects in liver by preventing carbon tetrachloride-induced increase of lipid peroxidation. Furthermore, co-treatment with thyme preparations reversed the activities of oxidative stress-related enzymes xanthine oxidase, catalase, peroxidase, glutathione peroxidase and glutathione reductase, towards normal values in the liver. Hepatotoxicity induced by carbon tetrachloride was reflected by a marked elevation of AST and ALT activities, and histopathologic alterations. Co-administration of thyme tincture resulted in unexpected exacerbation of AST and ALT values in serum, while thyme syrup managed to reduce activites of aminotransferases, in comparison to carbon tetrachloride-treated animals. Despite demonstrated antioxidant activity, mediated through both direct free radical scavenging and activation of antioxidant defense mechanisms, thyme preparations could not ameliorate liver injury in rats. Molecular mechanisms of diverse effects of thyme preparations on chemical-induced

  16. 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)

  17. 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.

  18. 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...

  19. 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

  20. 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

  1. 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.

  2. CYP1A2 polymorphism in Chinese patients with acute liver injury induced by Polygonum multiflorum.

    Science.gov (United States)

    Ma, K F; Zhang, X G; Jia, H Y

    2014-07-25

    The objective of this study was to evaluate the genotype and allelic frequencies of CYP1A2 in Chinese patients with acute liver injury induced by Polygonum multiflorum. We examined the clinical mechanism of acute liver injury induced by P. multiflorum. According to the diagnostic criteria for drug-induced liver injury (DILI), 43 cases of P. multiflorum-induced liver injury admitted to the First Affiliated Hospital, Zhejiang University were identified between January 2008 and December 2012. An additional 43 control subjects were also chosen. Several alleles, including 1C, 1F, 2, 7, 9, and 11 of CYP1A2 were amplified from genomic DNA and sequenced. We used the chi-square test to determine whether CYP1A2 allele polymorphisms are associated with acute liver injury induced by P. multiflorum. The frequency of the CYP1A2 1C allele was 46.5% in P. multiflorum-induced DILI patients, which was significantly different from the frequency of 27.9% observed in healthy subjects. The frequency of the CYP1A2 1F allele was 63.9% in P. multiflorum-induced DILI patients, compared to 57.0% in healthy controls; the difference was not significant. The allelic frequencies of CYP1A2 2, CYP1A2 7, CYP1A2 9, and CYP1A2 11 were too low to be detected. The frequency of the CYP1A2 1C mutation in Chinese patients with P. multiflorum-induced acute liver injury differed from that in healthy Chinese people, indicating that CYP1A2 1C is probably related to metabolism of P. multiflorum, which is followed by acute liver injury.

  3. 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.

  4. A metabolomic perspective of griseofulvin-induced liver injury in mice.

    Science.gov (United States)

    Liu, Ke; Yan, Jiong; Sachar, Madhav; Zhang, Xinju; Guan, Ming; Xie, Wen; Ma, Xiaochao

    2015-12-01

    Griseofulvin (GSF) causes hepatic porphyria in mice, which mimics the liver injury associated with erythropoietic protoporphyria (EPP) in humans. The current study investigated the biochemical basis of GSF-induced liver injury in mice using a metabolimic approach. GSF treatment in mice resulted in significant accumulations of protoporphyrin IX (PPIX), N-methyl PPIX, bile acids, and glutathione (GSH) in the liver. Metabolomic analysis also revealed bioactivation pathways of GSF that contributed to the formation of GSF-PPIX, GSF-GSH and GSF-proline adducts. GSF-PPIX is the precursor of N-methyl PPIX. A six-fold increase of N-methyl PPIX was observed in the liver of mice after GSF treatment. N-methyl PPIX strongly inhibits ferrochelatase, the enzyme that converts PPIX to heme, and leads to PPIX accumulation. Excessive PPIX in the liver results in bile duct blockage and disturbs bile acid homeostasis. The accumulation of GSH in the liver was likely due to Nrf2-mediated upregulation of GSH synthesis. In summary, this study provides the biochemical basis of GSF-induced liver injury that can be used to understand the pathophysiology of EPP-associated liver injury in humans. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Protective effects of ursodeoxycholic acid on chenodeoxycholic acid-induced liver injury in hamsters.

    Science.gov (United States)

    Iwaki, Tomomichi; Ishizaki, Kaoru; Kinoshita, Shuji; Tanaka, Hideki; Fukunari, Atsushi; Tsurufuji, Makoto; Imada, Teruaki

    2007-10-07

    To investigate the effects of ursodeoxycholic acid (UDCA) on chenodeoxycholic acid (CDCA)-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver. Liver injury was induced in hamsters by administration of 0.5% (w/w) CDCA in their feed for 7 d. UDCA (50 mg/kg and 150 mg/kg) was administered for the last 3 d of the experiment. At the end of the experiment, serum alanine aminotransferase (ALT) increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid (LCA). UDCA (50 mg/kg and 150 mg/kg) improved liver histology, with a significant decrease (679.3 +/- 77.5 U/L vs 333.6 +/- 50.4 U/L and 254.3 +/- 35.5 U/L, respectively, P LCA, which accumulate and show the cytotoxicity in the liver.

  6. 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.

  7. Inhibition of hepatic cells pyroptosis attenuates CLP-induced acute liver injury.

    Science.gov (United States)

    Chen, Yuan-Li; Xu, Guo; Liang, Xiao; Wei, Juan; Luo, Jing; Chen, Guan-Nan; Yan, Xiao-Di; Wen, Xue-Ping; Zhong, Ming; Lv, Xin

    2016-01-01

    Pyroptosis is a programmed cell death associated with caspase-1 and accompanied by the secretion of a large number of pro-inflammatory cytokines. In the acute stage of sepsis, the release of several pro-inflammatory cytokines aggravates hepatic cell death, and acute liver injury is aggravated with the progress of the disease, resulting in acute liver failure with a very high mortality rate. The present study investigated the effect of inhibiting hepatic cell pyroptosis on the septic acute liver injury. Septic acute liver injury mice model was established by cecal ligation and puncture (CLP model). The liver tissues were assessed for inflammatory infiltration by HE, serum concentrations of ALT, AST, IL-1β, and IL-18 were examined by ELISA, hepatic cell pyroptosis was determined by flow cytometry, and expressions of caspase-1 and NLRP3 were assessed by Western blot. CLP-induced acute liver injury was distinct at 24 h post-operation, with the highest hepatic cell pyroptosis rate. The pyroptosis rate and liver injury indexes were positively correlated. Western blot showed that the expressions of pyroptosis-related proteins, caspase-1, and NLRP3, were increased. Normal mouse hepatic cells were cultured in vitro and LPS+ATP introduced to establish the cell model of septic acute liver injury. The expressions of caspase-1, NLRP3, IL-1β, and IL-18 in LPS+ATP group were significantly higher than the control group by Western blot and ELISA. The inhibitors of NLRP3 (Glyburide) and caspase-1 (AC-YVAD-CMK) alone or in combination were used to pre-treat the hepatic cells, which revealed that the pyroptosis rate was decreased and the cell damage alleviated. The in vivo assay in rats showed that post inhibitor treatment, the 10-days survival was significantly improved and the liver damage reduced. Therefore, inhibiting the hepatic cell pyroptosis could alleviate CLP-induced acute liver injury, providing a novel treatment target for septic acute liver injury.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. 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

    Directory of Open Access Journals (Sweden)

    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.

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

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    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  15. 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.

  16. 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

  17. Betanin attenuates paraquat-induced liver toxicity through a mitochondrial pathway.

    Science.gov (United States)

    Han, Junyan; Zhang, Zongju; Yang, Shaobin; Wang, Jun; Yang, Xuelian; Tan, Dehong

    2014-08-01

    We attempted to determine whether betanin (from natural pigments) that has anti-oxidant properties would be protective against paraquat-induced liver injury in Sprague-Dawley rats. Paraquat was injected intraperitoneally into rats to induce liver toxicity. The rats were randomly divided into four groups: a control group, a paraquat group, and two groups that received betanin at doses of 25 and 100mg/kg/day three days before and two days after they were administered paraquat. We evaluated liver histopathology, serum liver enzymatic activities, oxidative stress, cytochrome P450 (CYP) 3A2 mRNA expression, and mitochondrial damage. The rats that were injected with paraquat incurred liver injury, evidenced by histological changes and elevated serum aspartate aminotransferase and alanine aminotransferase levels; paraquat also led to oxidative stress, an increase of cytochrome P450 3A2 mRNA expression, and mitochondrial damage, indicated by mitochondrial membrane swelling, reduced mitochondrial cytochrome C, and apoptosis-inducing factor protein levels. Pathological damage and all of the above mentioned markers were lesser in the animals treated with betanin than in those who received paraquat alone. Betanin had a protective effect against paraquat-induced liver damage in rats. The mechanism of the protection appears to be the inhibition of CYP 3A2 expression and protection of mitochondria. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Protection against acetaminophen-induced liver injury by allopurinol is dependent on aldehyde oxidase-mediated liver preconditioning

    Energy Technology Data Exchange (ETDEWEB)

    Williams, C. David; McGill, Mitchell R.; Lebofsky, Margitta; Bajt, Mary Lynn; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu

    2014-02-01

    Acetaminophen (APAP) overdose causes severe and occasionally fatal liver injury. Numerous drugs that attenuate APAP toxicity have been described. However these compounds frequently protect by cytochrome P450 inhibition, thereby preventing the initiating step of toxicity. We have previously shown that pretreatment with allopurinol can effectively protect against APAP toxicity, but the mechanism remains unclear. In the current study, C3HeB/FeJ mice were administered allopurinol 18 h or 1 h prior to an APAP overdose. Administration of allopurinol 18 h prior to APAP overdose resulted in an 88% reduction in liver injury (serum ALT) 6 h after APAP; however, 1 h pretreatment offered no protection. APAP-cysteine adducts and glutathione depletion kinetics were similar with or without allopurinol pretreatment. The phosphorylation and mitochondrial translocation of c-jun-N-terminal-kinase (JNK) have been implicated in the progression of APAP toxicity. In our study we showed equivalent early JNK activation (2 h) however late JNK activation (6 h) was attenuated in allopurinol treated mice, which suggests that later JNK activation is more critical for the toxicity. Additional mice were administered oxypurinol (primary metabolite of allopurinol) 18 h or 1 h pre-APAP, but neither treatment protected. This finding implicated an aldehyde oxidase (AO)-mediated metabolism of allopurinol, so mice were treated with hydralazine to inhibit AO prior to allopurinol/APAP administration, which eliminated the protective effects of allopurinol. We evaluated potential targets of AO-mediated preconditioning and found increased hepatic metallothionein 18 h post-allopurinol. These data show metabolism of allopurinol occurring independent of P450 isoenzymes preconditions the liver and renders the animal less susceptible to an APAP overdose. - Highlights: • 18 h allopurinol pretreatment protects against acetaminophen-induced liver injury. • 1 h allopurinol pretreatment does not protect from APAP-induced

  1. Endotoxin-induced liver damage in rats is minimized by beta 2-adrenoceptor stimulation.

    NARCIS (Netherlands)

    Izeboud, C.A.; Hoebe, K.H.; Grootendorst, A.F.; Nijmeijer, S.M.; Miert, A.S. van; Witkamp, R.R.; Rodenburg, R.J.T.

    2004-01-01

    OBJECTIVE AND DESIGN: To investigate the effects of beta(2)-adrenoceptor (beta(2)-AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats. SUBJECTS: Standard male Wistar rats. TREATMENT: A disease-model of lipopolysaccharide (LPS)-induced acute systemic inflammation

  2. Endotoxin-induced liver damage in rats is minimized by β2- adrenoceptor stimulation

    NARCIS (Netherlands)

    Izeboud, C.A.; Hoebe, K.H.N.; Grootendorst, A.F.; Nijmeijer, S.M.; Miert, A.S. van; Witkamp, R.F.; Rodenburg, R.J.T.

    2004-01-01

    Objective and Design: To investigate the effects of β2- adrenoceptor (β2-AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats. Subjects: Standard male Wistar rats. Treatment: A disease-model of lipolysaccharide (LPS)-induced acute systemic inflammation was used. The

  3. Liver injury from ampicillin-induced intestinal microbiota distresses ...

    African Journals Online (AJOL)

    Purpose: To investigate the effect of ampicillin on rat intestinal microflora and liver in the presence of high carbohydrate and protein diets. Methods: Male Wistar albino rats were divided into four groups. The first group served as the control, the second group was treated with ampicillin (50 mg/kg for 3 weeks) and fed with a ...

  4. Liver function of Streptozotocin- Induced Diabetic Rats Orally ...

    African Journals Online (AJOL)

    Klinische Chemie (Rec. GSCC DGKC) (1972) and the. Szasz (1969) methods respectively. Serum and liver protein concentrations were measured by Biuret method (Gornall et al., 1949), serum albumins concentration was measured by Doumas and Biggs. (1972) method while the amount of globulins was calculated as a ...

  5. 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

  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. 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.

  8. Protective effects of Centella asiatica leaf extract on dimethylnitrosamine-induced liver injury in rats

    Science.gov (United States)

    Choi, Myung-Joo; Zheng, Hong-Mei; Kim, Jae Min; Lee, Kye Wan; Park, Yu Hwa; Lee, Don Haeng

    2016-01-01

    Oxidative stress in liver injury is a major pathogenetic factor in the progression of liver damage. Centella asiatica (L.) Urban, known in the United States as Gotu kola, is widely used as a traditional herbal medicine in Chinese or Indian Pennywort. The efficacy of Centella asiatica is comprehensive and is used as an anti-inflammatory agent, for memory improvement, for its antitumor activity and for treatment of gastric ulcers. The present study investigated the protective effects of Centella asiatica on dimethylnitrosamine (DMN)-induced liver injury in rats. The rats in the treatment groups were treated with Centella asiatica at either 100 or 200 mg/kg in distilled water (D.W) or with silymarin (200 mg/kg in D.W) by oral administration for 5 days daily following intraperitoneal injections of 30 mg/kg DMN. Centella asiatica significantly decreased the relative liver weights in the DMN-induced liver injury group, compared with the control. The assessment of liver histology showed that Centella asiatica significantly alleviated mass periportal ± bridging necrosis, intralobular degeneration and focal necrosis, with fibrosis of liver tissues. Additionally, Centella asiatica significantly decreased the level of malondialdehyde, significantly increased the levels of antioxidant enzymes, including superoxide dismutase, glutathione peroxidase and catalase, and may have provided protection against the deleterious effects of reactive oxygen species. In addition, Centella asiatica significantly decreased inflammatory mediators, including interleukin (IL)-1β, IL-2, IL-6, IL-10, IL-12, tumor necrosis factor-α, interferon-γ and granulocyte/macrophage colony-stimulating factor. These results suggested that Centella asiatica had hepatoprotective effects through increasing the levels of antioxidant enzymes and reducing the levels of inflammatory mediators in rats with DMN-induced liver injury. Therefore, Centella asiatica may be useful in preventing liver damage. PMID:27748812

  9. 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.

  10. Hepatoprotective Potential of Caesalpinia crista against Iron-Overload-Induced Liver Toxicity in Mice

    Directory of Open Access Journals (Sweden)

    Rhitajit Sarkar

    2012-01-01

    Full Text Available The present study was carried out to evaluate the ameliorating effect of Caesalpinia crista Linn. (CCME extract on iron-overload-induced liver injury. Iron overload was induced by intraperitoneal administration of iron dextran into mice. CCME attenuated the percentage increase in liver iron and serum ferritin levels when compared to control group. CCME also showed a dose-dependent inhibition of lipid peroxidation, protein oxidation, and liver fibrosis. The serum enzyme markers were found to be less, whereas enhanced levels of liver antioxidant enzymes were detected in CCME-treated group. In presence of CCME, the reductive release of ferritin iron was increased significantly. Furthermore, CCME exhibited DPPH radical scavenging and protection against Fe2+-mediated oxidative DNA damage. The current study confirmed the hepatoprotective effect of CCME against the model hepatotoxicant iron overload and the activity is likely related to its potent antioxidant and iron-chelating property.

  11. 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

    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...... normalised ratio (INR), and cardiovascular failure were used to derive an initial predictive model, with a second (day 2) model including additional changes in INR and lactate. FINDINGS: We developed and validated new high-performance statistical models to support decision making in patients with paracetamol...

  12. Inulin-type fructan and infusion of Artemisia vulgaris protect the liver against carbon tetrachloride-induced liver injury.

    Science.gov (United States)

    Corrêa-Ferreira, Marília Locatelli; Verdan, Maria Helena; Dos Reis Lívero, Francislaine Aparecida; Galuppo, Larissa Favaretto; Telles, José Ederaldo Queiroz; Alves Stefanello, Maria Élida; Acco, Alexandra; Petkowicz, Carmen Lúcia de Oliveira

    2017-01-15

    Infusions of aerial parts of Artemisia vulgaris L. (Asteraceae) are used in herbal medicine to treat several disorders, including hepatosis. Evaluation of in vivo hepatoprotective effects of A. vulgaris infusion (VI) and inulin (VPI; i.e., the major polysaccharide of VI). The hepatoprotective effect of A. vulgaris extracts on carbon tetrachloride (CCl 4 )-induced hepatotoxicity and the probable mechanism involved in this protection were investigated in mice. A. vulgaris infusion (VI) was prepared according to folk medicine using the aerial parts of the plant. Carbohydrate, protein, and total phenolic content was determined in VI, and its phenolic profile was determined by high-performance liquid chromatography (HPLC). Male Swiss mice were orally pretreated for 7 days with VI or VPI (once per day). On days 6 and 7 of treatment, the mice were intraperitoneally challenged with CCl 4 . Liver and blood were collected and markers of hepatic damage in plasma and oxidative stress in the liver were analyzed. Hepatic histology and inflammatory parameters were also studied in the liver. The scavenging activity of VI and VPI were evaluated in vitro using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. VI contained 40% carbohydrates, 2.9% proteins and 9.8% phenolic compounds. The HPLC fingerprint analysis of VI revealed chlorogenic, caffeic and dicaffeoylquinic acids as major low-molar-mass constituents. Oral pretreatment with VI and VPI significantly attenuated CCl 4 -induced liver damage, reduced the activity of alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP) in plasma, and prevented reactive oxygen species accumulation and lipid peroxidation in the liver. Comparisons with the CCl 4 -treated group showed that VI and VPI completely prevented necrosis, increased the levels of reduced glutathione (GSH), and reduced tumor necrosis factor alpha (TNF-α) level in the liver. VI and VPI also exhibited high radical scavenging activity in vitro

  13. TLR4 Deficiency Protects against Hepatic Fibrosis and Diethylnitrosamine-Induced Pre-Carcinogenic Liver Injury in Fibrotic Liver.

    Directory of Open Access Journals (Sweden)

    Susanne Nicole Weber

    Full Text Available The development of hepatocellular carcinoma (HCC is a common consequence of advanced liver fibrosis but the interactions between fibrogenesis and carcinogenesis are still poorly understood. Recently it has been shown that HCC promotion depends on Toll-like receptor (TLR 4. Pre-cancerogenous events can be modelled in mice by the administration of a single dose of diethylnitrosamine (DEN, with HCC formation depending amongst others on interleukin (IL 6 production. Mice lacking the hepatocanalicular phosphatidylcholine transporter ABCB4 develop liver fibrosis spontaneously, resemble patients with sclerosing cholangitis due to mutations of the orthologous human gene, and represent a valid model to study tumour formation in pre-injured cholestatic liver. The aim of this study was to investigate DEN-induced liver injury in TLR4-deficient mice with biliary fibrosis.ABCB4-deficient mice on the FVB/NJ genetic background were crossed to two distinct genetic backgrounds (TLR4-sufficient C3H/HeN and TLR4-deficient C3H/HeJ for more than 10 generations. The two congenic knockout and the two corresponding wild-type mouse lines were treated with a single dose of DEN for 48 hours. Phenotypic differences were assessed by measuring hepatic collagen contents, inflammatory markers (ALT, CRP, IL6 as well as hepatic apoptosis (TUNEL and proliferation (Ki67 rates.Hepatic collagen accumulation is significantly reduced in ABCB4-/-:TLR4-/-double-deficient mice. After DEN challenge, apoptosis, proliferation and inflammatory markers are decreased in TLR4-deficient in comparison to TLR4-sufficient mice. When combining ABCB4 and TLR4 deficiency with DEN treatment, hepatic IL6 expression and proliferation rates are lowest in fibrotic livers from the double-deficient line. Consistent with these effects, selective digestive tract decontamination in ABCB4-/- mice also led to reduced tumor size and number after DEN.This study demonstrates that liver injury upon DEN challenge

  14. 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

  15. 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.)

  16. Apocynin reduced doxycycline-induced acute liver injury in ovariectomized mice

    Directory of Open Access Journals (Sweden)

    Satoru Mitazaki

    2016-01-01

    Full Text Available To determine the physiological role of estrogen in the development of liver injury, we examined the sensitivities of sham and ovariectomy (ovx mice against doxycycline (DOXY-induced acute liver injury. Ovx or sham operation was performed in C57BL/6J wild-type female mice of eight weeks of age. Sham mice and ovx mice were treated with DOXY (240 mg/kg ip 8 weeks after the operation, 30 min after apocynin (5 mg/kg or saline administration. Blood and liver samples were obtained at 3 and 6 h after DOXY administration. Liver dysfunction occurred soon after DOXY administration and became more severe in ovx mice than in sham mice. At early phase after DOXY injection, TNF-α and iNOS inductions upregulated almost the same levels in sham and ovx mice. On the other hand, expression levels of IL-6, IL-10, c-fos, cox-2 and HO-1, downstream genes of TNF-α, were significantly increased in ovx mice compared to those in sham mice, correlated with liver dysfunction. In addition, apocynin, a NADPH oxidase (Nox inhibitor, totally improved DOXY-induced liver injury in both sham and ovx mice, indicating that reactive oxygen species generated through Nox activation by DOXY are responsible for development of acute liver injury.

  17. A Patient with Nafcillin-Associated Drug-Induced Liver Failure.

    Science.gov (United States)

    Rao, Qin; Schuster, Isaiah; Seoud, Talal; Zarrabi, Kevin; Goolsarran, Nirvani

    2017-01-01

    Nafcillin-induced acute liver injury is a rare and potentially fatal complication that has been known since the 1960s but inadequately studied. At this time, the only proven treatment is early discontinuation of the drug. Because of the high prevalence of nafcillin class antibiotic use in the United States, it is important for clinicians to have a high clinical suspicion for this diagnosis. We present a case of liver failure attributable to nafcillin use in a 68-year-old male with a history methicillin-sensitive Staphylococcus and L3/L4 osteomyelitis. After starting long-term antibiotic therapy, he presented with painless jaundice which necessitated discontinuation of the drug. At the time of presentation, the patient's lab work exhibited a bilirubin/direct bilirubin of 9.4/8.2 mg/dL, alkaline phosphatase of 311 IU/L, and aspartate transaminase/alanine transaminase of 109/127 IU/L. The patient was switched to i.v. vancomycin given the concern for drug-induced liver injury. Imaging did not show obstruction of the hepatobiliary or pancreaticobiliary trees. Serology was unremarkable for viral etiology, autoimmune processes, Wilson disease, and hemochromatosis. A liver biopsy showed findings consistent with drug-induced liver injury. The patient's liver function tests peaked at day 7 of admission and trended towards normal levels with cessation of nafcillin therapy. The patient was discharged with a diagnosis of nafcillin-induced acute liver injury. Our case highlights the importance of early recognition of the diagnosis and careful monitoring of liver function when nafcillin is employed in the clinical setting.

  18. A Patient with Nafcillin-Associated Drug-Induced Liver Failure

    Directory of Open Access Journals (Sweden)

    Qin Rao

    2017-09-01

    Full Text Available Nafcillin-induced acute liver injury is a rare and potentially fatal complication that has been known since the 1960s but inadequately studied. At this time, the only proven treatment is early discontinuation of the drug. Because of the high prevalence of nafcillin class antibiotic use in the United States, it is important for clinicians to have a high clinical suspicion for this diagnosis. We present a case of liver failure attributable to nafcillin use in a 68-year-old male with a history methicillin-sensitive Staphylococcus and L3/L4 osteomyelitis. After starting long-term antibiotic therapy, he presented with painless jaundice which necessitated discontinuation of the drug. At the time of presentation, the patient’s lab work exhibited a bilirubin/direct bilirubin of 9.4/8.2 mg/dL, alkaline phosphatase of 311 IU/L, and aspartate transaminase/alanine transaminase of 109/127 IU/L. The patient was switched to i.v. vancomycin given the concern for drug-induced liver injury. Imaging did not show obstruction of the hepatobiliary or pancreaticobiliary trees. Serology was unremarkable for viral etiology, autoimmune processes, Wilson disease, and hemochromatosis. A liver biopsy showed findings consistent with drug-induced liver injury. The patient’s liver function tests peaked at day 7 of admission and trended towards normal levels with cessation of nafcillin therapy. The patient was discharged with a diagnosis of nafcillin-induced acute liver injury. Our case highlights the importance of early recognition of the diagnosis and careful monitoring of liver function when nafcillin is employed in the clinical setting.

  19. 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

  20. Alleviation of Carbon-Tetrachloride-Induced Liver Injury and Fibrosis by Betaine Supplementation in Chickens

    OpenAIRE

    Tsai, Meng-Tsz; Chen, Ching-Yi; Pan, Yu-Hui; Wang, Siou-Huei; Mersmann, Harry J.; Ding, Shih-Torng

    2015-01-01

    Betaine is a food component with well-reported hepatoprotection effects. However, the effects and mechanisms of betaine on liver fibrosis development are still insufficient. Because metabolic functions of chicken and human liver is similar, we established a chicken model with carbon Tetrachloride- (CCl4-) induced fibrosis for studying antifibrotic effect of betaine in vivo and in vitro. Two-week-old male chicks were supplemented with betaine (1%, w/v) in drinking water for 2 weeks prior to th...

  1. Combined effects of high-fat diet and ethanol induce oxidative stress in rat liver.

    Science.gov (United States)

    Demori, Ilaria; Voci, Adriana; Fugassa, Emilia; Burlando, Bruno

    2006-11-01

    Individuals affected by liver steatosis seldom have symptoms of liver injury, but may be particularly vulnerable to oxidative insults. In this study, we evaluated liver redox alterations produced by acute ethanol administration to rats that were fed a high-fat diet (HFD). Adult male Wistar rats were fed HFD or standard diet (controls) for 1 month; a group of animals from each condition were gavaged with 35% (vol/vol) ethanol every 12h for the last 3 days of the experiment. Total lipid content determined in liver showed lipid accumulation after HFD or HFD combined with ethanol. HFD alone induced a significant rise of seric alanine aminotransferase levels and a marked reduction of antioxidant enzyme activities (catalase, superoxide dismutase, glutathione transferase). Ethanol alone caused a significant rise of seric cholesterol levels and enhanced mitochondrial H2O2 production, but without apparent oxidative stress as evaluated by thiobarbituric acid-reactive substances (TBARS) assay. The combination of HFD and acute ethanol caused an increase of TBARS, indicating lipid peroxidation, most likely as a consequence of a decrease in antioxidant defenses induced by HFD and of an increase in reactive oxygen species production induced by ethanol. Principal component analysis, based on all the measured parameters, that is, serum liver function tests, antioxidant enzyme activities, mitochondrial H2O2 release, and TBARS, indicated that HFD and ethanol act as two independent factors. In conclusion, our results show that HFD or acute ethanol alone produce, at the most, mild liver injury, whereas their combination triggers oxidative stress, possibly inducing a progression toward liver disease. Hence, our data indicate that a diet too rich in fat is a serious risk factor for the occurrence of liver injury deriving from acute ethanol consumption.

  2. 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.

  3. 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

  4. 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...

  5. FOXA2 alleviates CCl4-induced liver fibrosis by protecting hepatocytes in mice.

    Science.gov (United States)

    Wang, Wei; Yao, Li-Jia; Shen, Weifeng; Ding, Kai; Shi, Pei-Mei; Chen, Fei; He, Jin; Ding, Jin; Zhang, Xin; Xie, Wei-Fen

    2017-11-14

    The liver-enriched transcription factor Forkhead Box A2 (FOXA2) has been reported to be involved in bile acid homeostasis and bile duct development. However, the role of FOXA2 in liver fibrogenesis remains undefined. In this study, we found that the abundance of FOXA2 was significantly lower in fibrotic livers of patients and mice treated with CCl 4 than in controls. Interestingly, the expression level of FOXA2 decreased in hepatocytes, whereas FOXA2 was elevated in hepatic stellate cells (HSCs) of mouse fibrotic livers. Hepatocyte-specific ablation of FOXA2 in adult mice exacerbated liver fibrosis induced by CCl 4 . Either lentivirus LV-CMV-FOXA2 mediated FOXA2 overexpression in the liver or adeno-associated virus AAV8-TBG-FOXA2-mediated hepatocyte-specific upregulation of FOXA2 alleviated hepatic fibrosis. Overexpression of FOXA2 in HSCs did not obviously affect hepatic fibrogenesis. Additionally, FOXA2 knockout in hepatocytes resulted in aberrant transcription of metabolic genes. Furthermore, hepatocyte-specific knockout of FOXA2 enhanced endoplasmic reticulum stress (ER stress) and the apoptosis of hepatocytes, whereas FOXA2 overexpression in hepatocytes suppressed ER stress and hepatocyte apoptosis in mouse fibrotic livers. In conclusion, our findings suggested that FOXA2-mediated hepatocyte protection has a therapeutic role in hepatic fibrosis, and thus may be a new, promising anti-fibrotic option for treating chronic liver diseases.

  6. SRC-2-mediated coactivation of anti-tumorigenic target genes suppresses MYC-induced liver cancer

    Science.gov (United States)

    Zhou, Xiaorong; Comerford, Sarah A.; York, Brian; O’Donnell, Kathryn A.

    2017-01-01

    Hepatocellular carcinoma (HCC) is the fifth most common solid tumor in the world and the third leading cause of cancer-associated deaths. A Sleeping Beauty-mediated transposon mutagenesis screen previously identified mutations that cooperate with MYC to accelerate liver tumorigenesis. This revealed a tumor suppressor role for Steroid Receptor Coactivator 2/Nuclear Receptor Coactivator 2 (Src-2/Ncoa2) in liver cancer. In contrast, SRC-2 promotes survival and metastasis in prostate cancer cells, suggesting a tissue-specific and context-dependent role for SRC-2 in tumorigenesis. To determine if genetic loss of SRC-2 is sufficient to accelerate MYC-mediated liver tumorigenesis, we bred Src-2-/- mice with a MYC-induced liver tumor model and observed a significant increase in liver tumor burden. RNA sequencing of liver tumors and in vivo chromatin immunoprecipitation assays revealed a set of direct target genes that are bound by SRC-2 and exhibit downregulated expression in Src-2-/- liver tumors. We demonstrate that activation of SHP (Small Heterodimer Partner), DKK4 (Dickkopf-4), and CADM4 (Cell Adhesion Molecule 4) by SRC-2 suppresses tumorigenesis in vitro and in vivo. These studies suggest that SRC-2 may exhibit oncogenic or tumor suppressor activity depending on the target genes and nuclear receptors that are expressed in distinct tissues and illuminate the mechanisms of tumor suppression by SRC-2 in liver. PMID:28273073

  7. 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.

  8. Ganoderma applanatum terpenes protect mouse liver against benzo(α)pyren-induced oxidative stress and inflammation.

    Science.gov (United States)

    Ma, Jie-Qiong; Liu, Chan-Min; Qin, Zhi-Hong; Jiang, Ji-Hong; Sun, Yun-Zhi

    2011-05-01

    Ganoderma applanatum terpenes (GAT) have been reported to have many benefits and medicinal properties. In this study, we evaluated the protective effect of GAT against benzo(a)pyrene (BaP) induced oxidative stress and inflammation in mouse liver, and explored the potential mechanism of its action. Our data showed that GAT significantly decreased levels of ALT and AST in serum and the liver histological injury in BaP-treated mice. GAT markedly decreased the levels of ROS, MDA and lowered the GSH/GSSG ratio in the liver of BaP-treated mice. Furthermore, GAT markedly inhibited the BaP-induced increase of Cu/Zn-SOD, CAT, GPx and GST activities in the mouse liver. Western blot analysis showed that GAT significantly inhibited inflammation by pressing the expression of IL-1β and COX-2 and inhibiting NF-κB translocation in the liver of BaP-treated mice. In conclusion, these results suggested that GAT could protect the mouse liver against BaP-induced injury by improving hepatic function, attenuating histopathologic changes, decreasing levels of ROS and MDA, renewing the activities of antioxidant enzymes and suppressing inflammatory response. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. The Role of Mitochondrial Oxidation in Endotoxin-Induced Liver-Dependent Swine Pulmonary Edema

    Science.gov (United States)

    Siore, Amsel M.; Parker, Richard E.; Cuppels, Chris; Thorn, Natalie; Hansen, Jason M.; Stecenko, Arlene A.; Brigham, Kenneth L.

    2012-01-01

    We reported previously studies in an in situ perfused swine preparation demonstrating that endotoxemia induced lung injury required the presence of the liver and that the response was accompanied by oxidative stress. To determine whether lung and liver mitochondrial oxidative stress was important to the response, we compared the effects of equimolar amounts of two antioxidants, n-acetylcysteine, which does not replenish mitochondrial glutathione, and procysteine which does, on endotoxemia induced lung injury in the swine preparation. In a swine perfused liver-lung preparation, we measured physiologic, biochemical and cellular responses of liver and lung to endotoxemia with and without the drugs. Endotoxemia caused oxidation of the mitochondria-specific protein, thioredoxin-2, in both the lungs and the liver. Procysteine reduced thioredoxin-2 oxidation, attenuated hemodynamic, gas exchange, hepatocellular dysfunction, and cytokine responses and prevented lung edema. n-acetylcysteine had more modest effects and did not prevent lung edema. Conclusions: We conclude that mitochondrial oxidation may be critical to the pathogenesis of endotoxemia-induced liver-dependent lung injury and that choices of antioxidant therapy for such conditions must consider the desired subcellular target in order to be optimally effective. PMID:22925572

  10. The role of osteopontin in D-galactosamine-induced liver injury in genetically obese mice

    International Nuclear Information System (INIS)

    Kwon, Hyo-Jung; Won, Young-Suk; Yoon, Won-Kee; Nam, Ki-Hoan; Kim, Dae-Yong; Kim, Hyoung-Chin

    2010-01-01

    Various epidemiological studies have shown that obesity increases the risk of liver disease, but the precise mechanisms through which this occurs are poorly understood. In the present study, we hypothesized that osteopontin (OPN), an extracellular matrix and proinflammatory cytokine, has an important role in making obese mice more susceptible to inflammatory liver injury. After exposure of genetically obese ob/ob and db/db mice to a single dose of D-galactosamine (GalN), the plasma liver enzyme levels, histology and expression levels of cytokines and OPN were evaluated. The ob/ob and db/db mice, which were more sensitive to GalN-induced inflammatory liver injury compared with wild-type mice, had significantly higher plasma and hepatic OPN expression levels. Increased OPN expression was mainly found in hepatocytes and inflammatory cells and was correlated with markedly up-regulated interleukin (IL)-12 and IL-18 levels. Furthermore, pretreatment with a neutralizing OPN (nOPN) antibody attenuated the GalN-induced inflammatory liver injury in ob/ob and db/db mice, which was accompanied by significantly reduced macrophages recruitment and IL-12 and IL-18 productions. Taken together, these results suggest that up-regulated OPN expression is a contributing factor to increased susceptibility of genetically obese mice to GalN-induced liver injury by promoting inflammation and modulating immune response.

  11. Efficacy of grape seed and skin extract against doxorubicin-induced oxidative stress in rat liver.

    Science.gov (United States)

    Mokni, Meherzia; Hamlaoui, Sonia; Kadri, Safouen; Limam, Ferid; Amri, Mohamed; Marzouki, Lamjed; Aouani, Ezzedine

    2015-11-01

    Doxorubicin (Dox) is an anthracycline used in chemotherapy, although it causes toxicity and oxidative stress. Grape seed and skin extract (GSSE) is a mixture of polyphenolic compounds with antioxidant properties. To evaluate the hepato-toxicity of Dox on healthy rats as well as the protective effect of GSSE, rats were treated with GSSE (500mg/kg bw) during 8 days. At the 4th day of treatment, they received a single dose of Dox (20 mg/kg bw). After the treatment (9th day), livers were collected and processed for oxidative stress status. Dox increased MDA (+ 900%), decreased catalase (-60%) and increased peroxidase (+90%) and superoxide dismutase (+100%) activities. In this latter case Dox mainly increased the iron isoform. Furthermore Dox altered intracellular mediators as catalytic free iron (-75%), H₂O₂(-75%) and calcium (+30%). Dox also affected liver function by elevating plasma triacylglycerol and transaminases and liver morphology by altering its typical architecture. Importantly all Dox-induced liver disturbances were alleviated upon GSSE treatment. Dox induced liver toxicity and an oxidative stress mainly characterized by increased lipoperoxidation but not protein carbonylation. GSSE efficiently protected the liver from Dox-induced toxicity and appeared as a safe adjuvant that could be incorporated into chemotherapy protocols.

  12. Hepatoprotective effect of ghrelin on carbon tetrachloride-induced acute liver injury in rats.

    Science.gov (United States)

    Cetin, Ebru; Kanbur, Murat; Cetin, Nazmi; Eraslan, Gökhan; Atasever, Ayhan

    2011-11-10

    Recent studies have revealed that ghrelin may be an antioxidant and antiinflammatory agent. Oxidative stress are considered to play a prominent causative role in the development of various hepatic disorders. We investigated whether ghrelin plays a protective role against carbon tetrachloride (CCl(4))-induced acute liver injury in rats. Forty adult male Sprague-Dawley rats were randomly divided into four equal groups as; control, ghrelin, CCl(4) and ghrelin plus CCl(4). Evaluations were made for lipid peroxidation, enzyme activities and biochemical parameters. Pathological histology was also performed. CCl(4) treatment increased plasma and liver tissue malondialdehyde (MDA) content and plasma nitric oxide (NO) level, and decreased erythrocyte and liver tissue superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities when compared to control group. At the same time, CCl(4) treatment increased the serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alcaline phosphatase (ALP) activities. By contrast, ghrelin pretreatment reduced plasma and liver MDA content and plasma NO level, and increased erythrocyte and liver tissue SOD, CAT and GPx activities when compared with CCl(4)-treated group. Moreover, both ghrelin alone and ghrelin plus CCl(4) treatment elevated serum glucose level. The CCl(4)-induced histopathological changes were also reduced by the ghrelin pretreatment. Our results show that ghrelin can be proposed to protect the liver against CCl(4)-induced oxidative damage in rats, and the hepatoprotective effect may be correlated with its antioxidant and free radical scavenger effects. Copyright © 2011 Elsevier B.V. All rights reserved.

  13. 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.

  14. Production of embryonic and fetal-like red blood cells from human induced pluripotent stem cells.

    Directory of Open Access Journals (Sweden)

    Chan-Jung Chang

    Full Text Available We have previously shown that human embryonic stem cells can be differentiated into embryonic and fetal type of red blood cells that sequentially express three types of hemoglobins recapitulating early human erythropoiesis. We report here that we have produced iPS from three somatic cell types: adult skin fibroblasts as well as embryonic and fetal mesenchymal stem cells. We show that regardless of the age of the donor cells, the iPS produced are fully reprogrammed into a pluripotent state that is undistinguishable from that of hESCs by low and high-throughput expression and detailed analysis of globin expression patterns by HPLC. This suggests that reprogramming with the four original Yamanaka pluripotency factors leads to complete erasure of all functionally important epigenetic marks associated with erythroid differentiation regardless of the age or the tissue type of the donor cells, at least as detected in these assays. The ability to produce large number of erythroid cells with embryonic and fetal-like characteristics is likely to have many translational applications.

  15. An increase in liver PPARγ2 is an initial event to induce fatty liver in response to a diet high in butter: PPARγ2 knockdown improves fatty liver induced by high-saturated fat.

    Science.gov (United States)

    Yamazaki, Tomomi; Shiraishi, Sayaka; Kishimoto, Kyoko; Miura, Shinji; Ezaki, Osamu

    2011-06-01

    The effects of a diet rich in saturated fat on fatty liver formation and the related mechanisms that induce fatty liver were examined. C57BL/6J mice were fed butter or safflower oil as a high-fat (HF) diet (40% fat calories) for 2, 4, 10, or 17 weeks. Although both HF diets induced similar levels of obesity, HF butter-fed mice showed a two to threefold increase in liver triacylglycerol (TG) concentration compared to HF safflower oil-fed mice at 4 or 10 weeks without hyperinsulinemia. At 4 weeks, increases in peroxisome proliferator-activated receptor γ2 (PPARγ2), CD36, and adipose differentiation-related protein (ADRP) mRNAs were observed in HF butter-fed mice; at 10 weeks, an increase in sterol regulatory element-binding protein-1c (SREBP-1c) was observed; at 17 weeks, these increases were attenuated. At 4 weeks, a single injection of adenoviral vector-based short hairpin interfering RNA against PPARγ2 in HF butter-fed mice reduced PPARγ protein and mRNA of its target genes (CD36 and ADRP) by 43%, 43%, and 39%, respectively, with a reduction in liver TG concentration by 38% in 5 days. PPARγ2 knockdown also reduced mRNAs in lipogenic genes (fatty-acid-synthase, stearoyl-CoA desaturase 1, acetyl-CoA carboxylase 1) without alteration of SREBP-1c mRNA. PPARγ2 knockdown reduced mRNAs in genes related to inflammation (CD68, interleukin-1β, tumor necrosis factor-α, and monocyte chemoattractant protein-1). In conclusion, saturated fatty acid-rich oil induced fatty liver in mice, and this was triggered initially by an increase in PPARγ2 protein in the liver, which led to increased expression of lipogenic genes. Inactivation of PPARγ2 may improve fatty liver induced by HF saturated fat. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. Use of serial assessment of disease severity and liver biopsy for indication for liver transplantation in pediatric Epstein-Barr virus-induced fulminant hepatic failure.

    Science.gov (United States)

    Nakazawa, Atsuko; Nakano, Natsuko; Fukuda, Akinari; Sakamoto, Seisuke; Imadome, Ken-Ichi; Kudo, Toyoichiro; Matsuoka, Kentaro; Kasahara, Mureo

    2015-03-01

    The decision to perform liver transplantation (LT) in patients with Epstein-Barr virus (EBV)-induced fulminant hepatic failure (FHF) relies on a precise assessment of laboratory and pathological findings. In this study, we analyzed clinical and laboratory data as well as the pathological features of the liver in order to evaluate the pathogenesis and the need for LT in 5 patients with EBV-induced FHF. According to the King's College criteria, the Acute Liver Failure Early Dynamic (ALFED) model, and the Japanese criteria (from the Acute Liver Failure Study Group of Japan), only 1 patient was considered to be a candidate for LT. However, explanted liver tissues in 3 cases exhibited massive hepatocellular necrosis together with diffuse CD8-positive T cell infiltration in both the portal area and the sinusoid. EBV was detected in the liver, plasma, and peripheral blood mononuclear cells (PBMNCs). In 2 cases indicated to be at moderate risk by the ALFED model, liver biopsy showed CD8-positive and EBV-encoded RNA signal-positive lymphocytic infiltration predominantly in the portal area, but massive hepatocellular necrosis was not observed. These patients were treated with immunosuppressants and etoposide under the diagnosis of EBV-induced hemophagocytic lymphohistiocytosis or systemic EBV-positive T cell lymphoproliferative disease of childhood. EBV DNA was detected at a high level in PBMNCs, although it was negative in plasma. On the basis of the pathological analysis of the explanted liver tissues, LT was proposed for the restoration of liver function and the removal of the EBV-infected lymphocytes concentrated in the liver. Detecting EBV DNA by a quantitative polymerase chain reaction in plasma and PBMNCs was informative. An accurate evaluation of the underlying pathogenesis is essential for developing a treatment strategy in patients with EBV-induced FHF. © 2015 American Association for the Study of Liver Diseases.

  17. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Hepatocyte Turnover in Chronic HCV-Induced Liver Injury and Cirrhosis.

    Science.gov (United States)

    Karidis, Nikolaos P; Delladetsima, Ioanna; Theocharis, Stamatios

    2015-01-01

    Chronic hepatitis C virus (HCV) infection may eventually lead to progressive liver fibrosis and cirrhosis through a complex, multistep process involving hepatocyte death and regeneration. Despite common pathogenetic pathways present in all forms of liver cirrhosis irrespective of etiology, hepatocyte turnover and related molecular events in HCV-induced cirrhosis are increasingly being distinguished from even "similar" causes, such as hepatitis B virus- (HBV-) related cirrhosis. New insights in HCV-induced hepatocellular injury, differential gene expression, and regenerative pathways have recently revealed a different pattern of progression to irreversible parenchymal liver damage. A shift to the significant role of the host immune response rather than the direct effect of HCV on hepatocytes and the imbalance between antiapoptotic and proapoptotic signals have been investigated in several studies but need to be further elucidated. The present review aims to comprehensively summarize the current evidence on HCV-induced hepatocellular turnover with a view to outline the significant trends of ongoing research.

  20. 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.

  1. 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

  2. Hepatoprotective effect of Taraxacum officinale leaf extract on sodium dichromate-induced liver injury in rats.

    Science.gov (United States)

    Hfaiedh, Mbarka; Brahmi, Dalel; Zourgui, Lazhar

    2016-03-01

    Taraxacum officinale (L.) Weber, commonly known as Dandelion, has been widely used as a folkloric medicine for the treatment of liver and kidney disorders and some women diseases such as breast and uterus cancers. The main objective of the present study was to assess the efficiency of T. officinale leaf extract (TOE) in treating sodium dichromate hazards; it is a major environmental pollutant known for its wide toxic manifestations witch induced liver injury. TOE at a dose of 500 mg/kg b.w was orally administered once per day for 30 days consecutively, followed by 10 mg/kg b.w sodium dichromate was injected (intraperitoneal) for 10 days. Our results using Wistar rats showed that sodium dichromate significantly increased serum biochemical parameters. In the liver, it was found to induce an oxidative stress, evidenced from increase in lipid peroxidation and changes in antioxidative activities. In addition, histopathological observation revealed that sodium dichromate causes acute liver damage, necrosis of hepatocytes, as well as DNA fragmentation. Interestingly, animals that were pretreated with TOE, prior to sodium dichromate administration, showed a significant hepatoprotection, revealed by a significant reduction of sodium dichromate-induced oxidative damage for all tested markers. These finding powerfully supports that TOE was effective in the protection against sodium dichromate-induced hepatotoxicity and genotoxicity and, therefore, suggest a potential therapeutic use of this plant as an alternative medicine for patients with acute liver diseases. © 2014 Wiley Periodicals, Inc.

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

    Directory of Open Access Journals (Sweden)

    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.

  4. Antifibrotic Effect of Lactulose on a Methotrexate-Induced Liver Injury Model

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    Banu Taskin

    2017-01-01

    Full Text Available The most severe side effect of prolonged MTX treatment is hepatotoxicity. The aim of this study is to investigate the effect of lactulose treatment on MTX-induced hepatotoxicity in a rat model. Twenty-four male rats were included in the study. Sixteen rats were given a single dose of 20 mg/kg MTX to induce liver injury. Eight rats were given no drugs. 16 MTX-given rats were divided into two equal groups. Group 1 subjects were given lactulose 5 g/kg/day, and group 2 subjects were given saline 1 ml/kg/day for 10 days. The rats were then sacrificed to harvest blood and liver tissue samples in order to determine blood and tissue MDA, serum ALT, plasma TNF-α, TGF-β, and PTX3 levels. Histological specimens were examined via light microscopy. Exposure to MTX caused structural and functional hepatotoxicity, as evidenced by relatively worse histopathological scores and increased biochemical marker levels. Lactulose treatment significantly reduced the liver enzyme ALT, plasma TNF-α, TGF-β, PTX3, and MDA levels and also decreased histological changes in the liver tissue with MTX-induced hepatotoxicity in the rat model. We suggest that lactulose has anti-inflammatory and antifibrotic effects on an MTX-induced liver injury model. These effects can be due to the impact of intestinal microbiome.

  5. Protective effect of andrographolide against concanavalin A-induced liver injury.

    Science.gov (United States)

    Shi, Guojun; Zhang, Zhijian; Zhang, Rong; Zhang, Xiaofang; Lu, Yan; Yang, Jian; Zhang, Di; Zhang, Zhiguo; Li, Xiaoying; Ning, Guang

    2012-01-01

    This study was designed to investigate the hepatic protective effect and the molecular mechanisms of andrographolide in concanavalin A-induced liver injury model. Results showed that andrographolide (Ag) attenuated concanavalin A (Con-A)-induced liver injury and inhibited hepatocyte apoptosis. Further results showed that oxidative stress response genes were significantly elevated during the pathogenesis induced by Con-A. Meanwhile, gadolinium chloride and N-acetyl-L-cysteine (NAC) treatment, which inactivates Kupffer cells or reduces reactive oxygen species, respectively, prevented the liver injury. So the messenger RNA levels of the oxidative response genes mentioned above were detected, and the following results showed that Ag treatment reduced their expression. Besides, serum lactate dehydrogenase and myeloperoxidase activity was significantly reduced by Ag. Finally, Ag treatment did not further reduce serum tumor necrosis factor-α production compared with NAC treatment alone. Thus, our results indicate that Ag prevents Con-A-induced liver injury and reduced the hepatic oxidative stress response. The hepatic protective effect of Ag indicates that Ag supplementation may be beneficial in the treatment of immune-mediated liver injury.

  6. 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.

  7. Protective Effects of Hydrolyzed Nucleoproteins from Salmon Milt against Ethanol-Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Akiko Kojima-Yuasa

    2016-12-01

    Full Text Available Dietary nucleotides play a role in maintaining the immune responses of both animals and humans. Oral administration of nucleic acids from salmon milt have physiological functions in the cellular metabolism, proliferation, differentiation, and apoptosis of human small intestinal epithelial cells. In this study, we examined the effects of DNA-rich nucleic acids prepared from salmon milt (DNSM on the development of liver fibrosis in an in vivo ethanol-carbon tetrachloride cirrhosis model. Plasma aspartate transaminase and alanine transaminase were significantly less active in the DNSM-treated group than in the ethanol plus carbon tetrachloride (CCl4-treated group. Collagen accumulation in the liver and hepatic necrosis were observed histologically in ethanol plus CCl4-treated rats; however, DNSM-treatment fully protected rats against ethanol plus CCl4-induced liver fibrosis and necrosis. Furthermore, we examined whether DNSM had a preventive effect against alcohol-induced liver injury by regulating the cytochrome p450 2E1 (CYP2E1-mediated oxidative stress pathway in an in vivo model. In this model, CYP2E1 activity in ethanol plus CCl4-treated rats increased significantly, but DNSM-treatment suppressed the enzyme’s activity and reduced intracellular thiobarbituric acid reactive substances (TBARS levels. Furthermore, the hepatocytes treated with 100 mM ethanol induced an increase in cell death and were not restored to the control levels when treated with DNSM, suggesting that digestive products of DNSM are effective for the prevention of alcohol-induced liver injury. Deoxyadenosine suppressed the ethanol-induced increase in cell death and increased the activity of alcohol dehydrogenase. These results suggest that DNSM treatment represents a novel tool for the prevention of alcohol-induced liver injury.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. mTOR Overactivation in Mesenchymal cells Aggravates CCl4- Induced liver Fibrosis.

    Science.gov (United States)

    Shan, Lanlan; Ding, Yan; Fu, You; Zhou, Ling; Dong, Xiaoying; Chen, Shunzhi; Wu, Hongyuan; Nai, Wenqing; Zheng, Hang; Xu, Wanfu; Bai, Xiaochun; Jia, Chunhong; Dai, Meng

    2016-11-07

    Hepatic stellate cells are of mesenchymal cell type located in the space of Disse. Upon liver injury, HSCs transactivate into myofibroblasts with increase in expression of fibrillar collagen, especially collagen I and III, leading to liver fibrosis. Previous studies have shown mTOR signaling is activated during liver fibrosis. However, there is no direct evidence in vivo. The aim of this study is to examine the effects of conditional deletion of TSC1 in mesenchymal on pathogenesis of liver fibrosis. Crossing mice bearing the floxed TSC1 gene with mice harboring Col1α2-Cre-ER(T) successfully generated progeny with a conditional knockout of TSC1 (TSC1 CKO) in collagen I expressing mesenchymal cells. TSC1 CKO and WT mice were subjected to CCl 4 , oil or CCl 4 + rapamycin treatment for 8 weeks. TSC1 CKO mice developed pronounced liver fibrosis relative to WT mice, as examined by ALT, hydroxyproline, histopathology, and profibrogenic gene. Absence of TSC1 in mesenchymal cells induced proliferation and prevented apoptosis in activated HSCs. However, there were no significant differences in oil-treated TSC1 CKO and WT mice. Rapamycin, restored these phenotypic changes by preventing myofibroblasts proliferation and enhancing their apoptosis. These findings revealed mTOR overactivation in mesenchymal cells aggravates CCl 4 - induced liver fibrosis and the rapamycin prevent its occurance.

  14. Anti-apoptotic effects of tamarind leaves against ethanol-induced rat liver injury.

    Science.gov (United States)

    Ghoneim, Asser I; Eldahshan, Omayma A

    2012-03-01

    The leaf decoctions of Tamarindus indica (TI) have long been traditionally used in liver ailments. The aim of this study was to investigate the anti-apoptotic activity of TI leaf extract against acute ethanol (EtOH)-induced liver injury. The major constituents of the extract were also examined for standardization purposes. Rats (n = 5-7) were orally pretreated with TI leaf extract (25, 50 and 100 mg/kg) for seven days. Silymarin was used as a positive control. Liver tissue biochemical assays included key markers of apoptosis and its redox signalling. Serum enzyme levels were also determined. All graded doses of TI leaf extract mitigated the EtOH-induced liver caspase-3 activation (42, 57 and 64%) as well as DNA fragmentation (32, 47 and 50%), respectively. The highest dose of the extract demonstrated membrane-stabilizing (38%) in addition to glutathione-replenishing (88%) effects. Also, the leaves improved the liver histopathological alterations. Moreover, major plant bioactive polyphenolics, that might be responsible for the extract's observed effects, were isolated and identified. TI leaf extract demonstrated promising anti-apoptotic hepatoprotective effects in rats. The use of TI leaves in different liver diseases, having apoptosis as the underlying pathology, hence warrants further clinical investigation. © 2011 The Authors. JPP © 2011 Royal Pharmaceutical Society.

  15. Polyol Pathway Exacerbated Ischemia/Reperfusion-Induced Injury in Steatotic Liver

    Science.gov (United States)

    Zhang, Changhe; Huang, Changjun; Tian, Yuan

    2014-01-01

    Background. The polyol pathway, a bypass pathway of glucose metabolism initiated by aldose reductase (AR), has been shown to play an important role in mediating tissue ischemia/reperfusion (I/R) impairment recently. Here, we investigated how and why this pathway might affect the fatty liver following I/R. Methods. Two opposite models were created: mice with high-fat-diet-induced liver steatosis were treated with aldose reductase inhibition (ARI) and subsequent I/R; and AR-overexpressing L02 hepatocytes were sequentially subjected to steatosis and hypoxia/reoxygenation. We next investigated (a) the hepatic injuries, including liver function, histology, and hepatocytes apoptosis/necrosis; (b) the NAD(P)(H) contents, redox status, and mitochondrial function; and (c) the flux through the caspase-dependent apoptosis pathway. Results. AR-inhibition in vivo markedly attenuated the I/R-induced liver injuries, maintained the homeostasis of NAD(P)(H) contents and redox status, and suppressed the caspase-dependent apoptosis pathway. Correspondingly, AR overexpression in vitro presented the opposite effects. Conclusion. The flux through the polyol pathway may render steatotic liver greater vulnerability to I/R. Interventions targeting this pathway might provide a novel adjunctive approach to protect fatty liver from ischemia. PMID:24967007

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

  18. ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

    DEFF Research Database (Denmark)

    DeZwaan-McCabe, Diane; Sheldon, Ryan D; Gorecki, Michelle C

    2017-01-01

    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......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...

  19. 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 ) ...

  20. 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.

  1. 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

    and a lower birth weight. The weight of the lungs was particularly low in the offspring of EGF-immunized rats, and morphologically the lungs from the surviving pups seemed atelectatic and had alveolar duct dilatation, which indicates mild respiratory distress syndrome. Judged from immunohistochemical studies......, 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...... was lower in pups from EGF-immunized rats. This difference was, however, not significant (p = 0.07), but flow cytometric analyses showed a significantly lower proportion of the liver cells from newborn EGF-deficient pups to be in S-phase and indicated that these cells were larger than liver cells from...

  2. 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.

  3. Rat liver arginase system under acetaminophen-induced toxic injury and protein deprivation

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    H. P. Kopylchuk

    2017-04-01

    Full Text Available Arginase activity and L-arginine content in both cytosolic and mitochondrial fractions of rat liver cells under the conditions of toxic injury on the background of protein deprivation was studied. The most significant reduction of arginase activity in liver cells and depletion of L-arginine pool was found in rats with toxic acetaminophen-induced liver injury maintained on the ration balanced by all nutrients as well as in protein deficiency rats. It was concluded that reduction of the arginase activity in the cytosolic fraction of rat liver cells, combined with simultaneous decrease of L-arginine content, may be considered as one of the mechanisms of ornithine cycle disturbance. The decline of activity of mitochondrial isoform of arginase II, for certain, is related with activation of NO-synthase system.

  4. Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy.

    Science.gov (United States)

    Yang, Lili; Rozenfeld, Raphael; Wu, Defeng; Devi, Lakshmi A; Zhang, Zhenfeng; Cederbaum, Arthur

    2014-03-01

    Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prevent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol. In conclusion, these results show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy. Published by Elsevier Inc.

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

    Science.gov (United States)

    González-Ponce, Herson Antonio; Martínez-Saldaña, María Consolación; Rincón-Sánchez, Ana Rosa; Sumaya-Martínez, María Teresa; Buist-Homan, Manon; Faber, Klaas Nico; Moshage, Han; Jaramillo-Juárez, Fernando

    2016-10-04

    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.

  6. 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)

  7. 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.

  8. Hepatoprotective effect of Woodfordia fruticosa Kurz flowers on diclofenac sodium induced liver toxicity in rats.

    Science.gov (United States)

    Baravalia, Yogesh; Vaghasiya, Yogeshkumar; Chanda, Sumitra

    2011-05-01

    To evaluate the protective effect of Woodfordia fruticosa Kurz flowers against experimentally induced liver toxicity in rats. Two different doses of methanol extract of Woodfordia fruticosa (WFM) were evaluated for the hepatoprotective activity against diclofenac sodium induced hepatotoxicity in rats. Various biochemical parameters like alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total protein (TP), albumin (ALB), blood urea nitrogen (BUN) from serum; total protein (TP), glutathione (GSH) levels, catalase (CAT) and glutathione peroxidase (GPx) activities from liver were studied; histopathologic changes of liver were also evaluated. WFM effectively reduced the elevated levels of serum ALT, AST, ALP and BUN, enhanced the reduced TP, ALB and hepatic GSH, CAT, GPx activity. The histopathological analysis suggested that WFM decreased the degree of liver fibrosis induced by diclofenac. This study demonstrates the hepatoprotective activity of WFM and thus scientifically support the use of this plant in traditional medicine for the treatment of liver disorders. Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

  9. 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

  10. Definition and risk factors for chronicity following acute idiosyncratic drug-induced liver injury.

    Science.gov (United States)

    Medina-Caliz, Inmaculada; Robles-Diaz, Mercedes; Garcia-Muñoz, Beatriz; Stephens, Camilla; Ortega-Alonso, Aida; Garcia-Cortes, Miren; González-Jimenez, Andres; Sanabria-Cabrera, Judith A; Moreno, Inmaculada; Fernandez, M Carmen; Romero-Gomez, Manuel; Navarro, Jose M; Barriocanal, Ana M; Montane, Eva; Hallal, Hacibe; Blanco, Sonia; Soriano, German; Roman, Eva M; Gómez-Dominguez, Elena; Castiella, Agustin; Zapata, Eva M; Jimenez-Perez, Miguel; Moreno, Jose M; Aldea-Perona, Ana; Hernández-Guerra, Manuel; Prieto, Martin; Zoubek, Miguel E; Kaplowitz, Neil; Lucena, M Isabel; Andrade, Raul J

    2016-09-01

    Chronic outcome following acute idiosyncratic drug-induced liver injury (DILI) is not yet defined. This prospective, long-term follow-up study aimed to analyze time to liver enzyme resolutions to establish the best definition and risk factors of DILI chronicity. 298 out of 850 patients in the Spanish DILI registry with no pre-existing disease affecting the liver and follow-up to resolution or ⩾1year were analyzed. Chronicity was defined as abnormal liver biochemistry, imaging test or histology one year after DILI recognition. Out of 298 patients enrolled 273 (92%) resolved ⩽1year from DILI recognition and 25 patients (8%) were chronic. Independent risk factors for chronicity were older age [OR: 1.06, p=0.011], dyslipidemia [OR: 4.26, p=0.04] and severe DILI [OR: 14.22, p=0.005]. Alanine aminotransferase (ALT), alkaline phosphatase (ALP) and total bilirubin (TB) median values were higher in the chronic group during follow-up. Values of ALP and TB >1.1 x upper limit of normal (xULN) and 2.8 xULN respectively, in the second month from DILI onset, were found to predict chronic DILI (prisk factors being older age, dyslipidemia and severity of the acute episode. Statins are distinctly related to chronicity. ALP and TB values in the second month could help predict chronicity or very prolonged recovery. Drug-induced liver injury (DILI) patients who do not resolve their liver damage during the first year should be considered chronic DILI patients. Risk factors for DILI chronicity are older age, dyslipidemia and severity of the acute episode. Chronic DILI is not a very common condition; normally featuring mild liver profile abnormalities and not being an important clinical problem, with the exception of a small number of cases of early onset cirrhosis. Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  11. [Effect of cordyceps polysaccharide on lipid peroxidation of rats with dimethylnitrosamine-induced liver fibrosis].

    Science.gov (United States)

    Peng, Jing-Hua; Li, Xue-Mei; Hu, Yi-Yang; Feng, Qin

    2013-02-01

    To observe the pharmacological effect of Cordyceps polysaccharide on dimethylnitrosamine (DMN)-induced liver fibrosis in rats. DMN rat liver fibrosis model was established and divided into the normal group (N, n = 6), the model group (M, n = 11), the Cordyceps polysaccharide group (C, n = 8) and the colchicine group (Q, n = 9). During the modeling for four weeks, Cordyceps polysaccharide (60 mg x kg(-1)) and colchicine (0.1 mg x kg(-1)) were orally administered for three weeks, while the model and normal groups were given disinfected water of the same amount. serum ALT, AST, GGT and Alb, TBil content; content of hydroxyproline (Hyp) in liver tissues; liver pathology and collagen staining; SOD activity and MDA, GSH, GSH-Px in liver tissues; protein expression of proliferating cell nuclear antigen (PCNA) in liver tissues. Serum ALT, AST, GGT, TBil significantly increased, and A1b decreased significantly in the model group. Hepatic Hyp significantly increased in the model group, whereas the index remarkably decreased in the Cordyceps polysaccharide group and the colchicine group. HE staining: the structure of normal hepatic lobules was damaged, with hepatocytes tumefaction and proliferation of connective tissues in portal tracts in the model group, while the Cordyceps polysaccharide group and the colchicine group recorded notable reduction in above pathological changes. Collagen staining: the model group showed hepatic lobule fibrous septum and many intact pseudolobules; while the Cordyceps polysaccharide group and the colchicine group witnessed decrease in collagen deposition. The model group showed significant decrease in SOD, GSH-Px and GSH and increase in MDA, whereas the Cordyceps polysaccharide group and the colchicine group recorded notable growth in GSH and GSH-Px. The model group showed significant decrease in protein expression of PCNA in liver tissues, while the Cordyceps polysaccharide group and the colchicine group showed significant reduction. Cordyceps

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Maternal obesity induced by a high fat diet causes altered cellular development in fetal brains suggestive of a predisposition of offspring to neurological disorders in later life.

    Science.gov (United States)

    Stachowiak, Ewa K; Srinivasan, Malathi; Stachowiak, Michal K; Patel, Mulchand S

    2013-12-01

    Fetal development in an obese maternal intrauterine environment has been shown to predispose the offspring for a number of metabolic disorders in later life. The observation that a large percentage of women of child-bearing age in the US are overweight/obese during pregnancy is therefore a source of concern. A high fat (HF) diet-induced obesity in female rats has been used as a model for maternal obesity. The objective of this study was to determine cellular development in brains of term fetuses of obese rats fed a HF diet from the time of weaning. Fetal brains were dissected out on gestational day 21 and processed for immunohistochemical analysis in the hypothalamic as well as extra-hypothalamic regions. The major observation of this study is that fetal development in the obese HF female rat induced several alterations in the HF fetal brain. Marked increases were observed in orexigenic signaling and a significant decrease was observed for anorexigenic signaling in the vicinity of the 3rd ventricle in HF brains. Additionally, our results indicated diminished migration and maturation of stem-like cells in the 3rd ventricular region as well as in the brain cortex. The results from the present study indicate developmental alterations in the hypothalamic and extra-hypothalamic regions in the HF fetal brain suggestive of a predisposition for the development of obesity and possibly neurodevelopmental abnormalities in the offspring.

  14. Broccoli sprout extract induces detoxification-related gene expression and attenuates acute liver injury.

    Science.gov (United States)

    Yoshida, Kazutaka; Ushida, Yusuke; Ishijima, Tomoko; Suganuma, Hiroyuki; Inakuma, Takahiro; Yajima, Nobuhiro; Abe, Keiko; Nakai, Yuji

    2015-09-21

    To investigate the effects of broccoli sprout extract (BSEx) on liver gene expression and acute liver injury in the rat. First, the effects of BSEx on liver gene expression were examined. Male rats were divided into two groups. The Control group was fed the AIN-76 diet, and the BSEx group was fed the AIN-76 diet containing BSEx. After a 10-d feeding period, rats were sacrificed and their livers were used for DNA microarray and real-time reverse transcription-polymerase chain reaction (RT-PCR) analyses. Next, the effects of BSEx on acute liver injury were examined. In experiments using acute liver injury models, 1000 mg/kg acetaminophen (APAP) or 350 mg/kg D-galactosamine (D-GalN) was used to induce injury. These male rats were divided into four groups: Control, BSEx, Inducer (APAP or D-GalN), and Inducer+BSEx. The feeding regimens were identical for the two analyses. Twenty-four hours following APAP administration via p.o. or D-GalN administration via i.p., rats were sacrificed to determine serum aspartate transaminase (AST) and alanine transaminase (ALT) levels, hepatic glutathione (GSH) and thiobarbituric acid-reactive substances accumulation and glutathione-S-transferase (GST) activity. Microarray and real-time RT-PCR analyses revealed that BSEx upregulated the expression of genes related to detoxification and glutathione synthesis in normal rat liver. The levels of AST (70.91 ± 15.74 IU/mL vs 5614.41 ± 1997.83 IU/mL, P detoxification enzymes and glutathione synthesis.

  15. Regenerative medicine and spina bifida: Recent developments in induced fetal regeneration.

    Science.gov (United States)

    Fauza, Dario O

    2017-12-11

    Regenerative medicine as it applies to spina bifida is a multi-pronged endeavor involving spinal cord repair, tissue engineering and fetal regeneration, all of which can mutually overlap to variable extents. The efforts involving spinal cord repair, whether they be cell-based or not, are virtually indistinguishable from the enormous body of work related to spinal cord recovery after traumatic injury. Tissue engineering, on the other hand, can involve a variety of structures besides constructs used for covering the spina bifida defect, for example the urinary bladder, bone, muscle and skin. This brief review will not delve into any of these two main areas, which actually can also involve fetal interventions within their respective realms, but rather be devoted to a very recent development making use of the uniquely enhanced ability of the fetus to repair, or regenerate areas of tissue damage, coined transamniotic stem cell therapy, or TRASCET. TRASCET is a still experimental therapeutic paradigm for the treatment of not only spina bifida, but also other birth defects, based on the principle of harnessing/enhancing the normal biological role of a select population of stem cells that naturally occur in the amniotic fluid, specifically amniotic fluid-derived mesenchymal stem cells (afMSCs), for therapeutic benefit.

  16. 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®.

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

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    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.

  19. 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

  20. Differential effects of nitric oxide synthase inhibitors on endotoxin-induced liver damage in rats

    NARCIS (Netherlands)

    Vos, TA; Gouw, ASH; Klok, PA; Havinga, R; vanGoor, H; Roelofsen, H; Kuipers, F; Jansen, PLM; Moshage, H

    1997-01-01

    Background & Aims: During endotoxemia, expression of inducible nitric oxide synthase (iNOS) and nitric oxide production in the liver is increased, NO has been suggested to have a hepatoprotective function. The aim of this study was to investigate the distribution of iNOS and the effect of different

  1. Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

    NARCIS (Netherlands)

    Kuijper, I.A.; Yang, H.; Water, van de B.; Beltman, J.B.

    2017-01-01

    Introduction: Drug-induced liver injury (DILI) is a significant threat to human health and a major problem in drug development. It is hard to predict due to its idiosyncratic nature and which does not show up in animal trials. Hepatic adaptive stress response pathway activation is generally observed

  2. Glucose turnover during insulin-induced hypoglycemia in liver-denervated rats

    DEFF Research Database (Denmark)

    Mikines, K J; Sonne, B; Richter, Erik

    1985-01-01

    The role of hepatic autonomic nerves in glucose production during hypoglycemia was studied. Selective, surgical denervation of the liver was performed in rats, which reduced hepatic norepinephrine concentrations by 96%. Hypoglycemia was induced by 250 mU of insulin intra-arterially in anesthetize...

  3. Effects of renal denervation on tubular sodium handling in rats with CBL-induced liver cirrhosis

    DEFF Research Database (Denmark)

    Jonassen, T.E.N.; Brønd, 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 of...

  4. 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.

  5. 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)

  6. The hepatoprotective effect of putrescine against cadmium-induced acute liver injury

    Energy Technology Data Exchange (ETDEWEB)

    Tzirogiannis, Konstantinos N.; Panoutsopoulos, Georgios I.; Papadimas, George K.; Kondyli, Vasiliki G.; Kourentzi, Kalliopi T.; Hereti, Rosa I.; Mykoniatis, Michael G. [Department of Experimental Pharmacology, Medical School, Athens University, 75 Mikras Asias St., 115 27, Athens (Greece); Demonakou, Maria D. [Histopathology Laboratory, Sismanoglion G.D. Hospital, Sismanogliou 1, Marousi 151 27, Attiki (Greece)

    2004-06-01

    The hepatoprotective effect of putrescine against cadmium liver injury was investigated. Male Wistar rats were injected with a dose of cadmium (6.5 mg CdCl{sub 2}/kg bodyweight, intraperitoneally). Normal saline (group I) or putrescine (300 {mu}mol/kg bodyweight; group II) were injected 2, 5 and 8 h later. A number of animals of both groups were killed 0, 12, 16, 24, 48 or 60 h after cadmium intoxication. Liver tissue was histologically assessed for necrosis, apoptosis, peliosis, mitoses, and inflammatory infiltration. Apoptosis was also quantified by the TUNEL assay for hepatocytes and nonparenchymal liver cells. The discrimination between hepatic cell subpopulations was achieved histochemically. The mitotic index in hematoxylin-eosin-stained sections and by the immunochemical detection of Ki67 nuclear antigen, {sup 3}H-thymidine incorporation into hepatic DNA, and hepatic thymidine kinase activity were all used as indices of liver regeneration. Both hepatocyte apoptosis and liver necrosis evolved in a biphasic temporal pattern. Nonparenchymal cell apoptosis and peliosis hepatis evolved in a monophasic pattern and were correlated closely. Putrescine administration totally reversed liver necrosis and hepatocyte apoptosis. The time profile of nonparenchymal apoptosis was altered and peliosis hepatis was also totally attenuated. In conclusion, putrescine protected hepatocytes and modulated the mechanism of cadmium-induced acute hepatotoxicity. (orig.)

  7. Metabonomics study on Polygonum multiflorum induced liver toxicity in rats by GC-MS.

    Science.gov (United States)

    Zhang, Yuan; Wang, Nannan; Zhang, Meiling; Diao, Tingting; Tang, Jingyue; Dai, Mingzhu; Chen, Suhong; Lin, Guanyang

    2015-01-01

    Polygonum multiflorum, a traditional Chinese medicinal herb, is widely used in liver and liver nourishing. Recent years, drug regulatory departments reported that Polygonum multiflorum caused serious adverse reaction in clinic, especially liver injury. In this study, we detected the changes in rat serum and liver tissue metabolites through gas chromatography-mass spectrometry (GC-MS). Mass spectrometry, partial least squares-discriminate analysis (PLS-DA) and other diversified techniques were used to analyze the differences among their metabolites. Compared to the control group, the serum concentrations of L-threonine and serine in water extraction groups increased. The serum concentrations of 9,12-octadecadienoic acid, hexadecanoic acid, oleic acid, D-glucose and octadecanoic acid in alcohol extraction groups increased, while lactic acid decreased to a great extent. For liver tissue, compared to the control group, the concentrations of myo-inositol, oleic acid and cholesterol in water extraction groups increased, while those of hexadecanoic acid, octadecanoic acid, ribitol and butanedioic acid decreased to a great extent. The concentrations of myo-inositol, phosphoric acid, uridine, oleic acid, cholesterol and butanoic acid in alcohol extraction groups increased to a great extent, while those of hexadecanoic acid, octadecanoic acid, ribitol and butanedioic acid decreased. The results indicate that Polygonum multiflorum induces the metabolic disorders of energy metabolism, amino acid and lipid metabolism. What's more, liver injury of alcohol extraction group was more serious than group of water extraction.

  8. Chlorogenic and Caftaric Acids in Liver Toxicity and Oxidative Stress Induced by Methamphetamine

    Science.gov (United States)

    Koriem, Khaled M. M.; Soliman, Rowan E.

    2014-01-01

    Methamphetamine intoxication can cause acute hepatic failure. Chlorogenic and caftaric acids are the major dietary polyphenols present in various foods. The aim of this study was to evaluate the protective role of chlorogenic and caftaric acids in liver toxicity and oxidative stress induced by methamphetamine in rats. Thirty-two male albino rats were divided into 4 equal groups. Group 1, which was control group, was injected (i.p) with saline (1 mL/kg) twice a day over seven-day period. Groups 2, 3, and 4 were injected (i.p) with methamphetamine (10 mg/kg) twice a day over seven-day period, where groups 3 and 4 were injected (i.p) with 60 mg/kg chlorogenic acid and 40 mg/kg caftaric acid, respectively, one day before methamphetamine injections. Methamphetamine increased serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, cholesterol, low-density lipoprotein, and triglycerides. Also, malondialdehyde in serum, liver, and brain and plasma and liver nitric oxide levels were increased while methamphetamine induced a significant decrease in serum total protein, albumin, globulin, albumin/globulin ratio, brain serotonin, norepinephrine and dopamine, blood and liver superoxide dismutase, and glutathione peroxidase levels. Chlorogenic and caftaric acids prior to methamphetamine injections restored all the above parameters to normal values. In conclusion, chlorogenic and caftaric acids before methamphetamine injections prevented liver toxicity and oxidative stress where chlorogenic acid was more effective. PMID:25136360

  9. Prolonged feeding with green tea polyphenols exacerbates cholesterol-induced fatty liver disease in mice.

    Science.gov (United States)

    Hirsch, Nina; Konstantinov, Anya; Anavi, Sarit; Aronis, Anna; Hagay, Zion; Madar, Zecharia; Tirosh, Oren

    2016-12-01

    This study investigated the potential deleterious impact of dietary supplementation with green tea extract (GTE) on the progression of fatty liver disease, in a mouse model of cholesterol-induced steatohepatitis that represents chronic liver injury. Male C57BL mice (n = 32, 8-wk-old) were fed for 6 wk with one of the following diets: normal control diet (ND, Con), Con + 1% w/w polyphenols from GTE (Con + GTE); high cholesterol diet, Con + 1% cholesterol + 0.5% cholate w/w (HCD); HCD + 1% green tea polyphenols w/w (HCD + GTE). Hepatic steatosis, oxidative, and inflammatory markers and bile acid synthesis pathways were measured. HCD supplementation resulted in hepatic steatosis and liver damage. In animals supplemented with the HCD + GTE an exacerbated hepatic steatosis, oxidative stress, and inflammatory response were observed compared to HCD supplemented animals. HCD + GTE supplementation elevated blood levels of liver enzymes and serum bile acids compared HCD-treated animals. HCD + GTE supplementation altered bile acid synthesis in the cholesterol clearance pathway, inducing a shift from the classically regulated CYP7A1 pathway to the alternative acidic pathway. Prolonged GTE supplementation dramatically increased hepatic oxidative stress, inflammation and liver injury, and altered the bile acid synthesis pathway in mice fed a HCD. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  10. 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.

  11. Quantitative optical imaging of paracetamol-induced metabolism changes in the liver

    Science.gov (United States)

    Liang, Xiaowen; Wang, Haolu; Liu, Xin; Roberts, Michael

    2016-12-01

    Paracetamol is the most readily available and widely used painkiller. However, its toxicity remains the most common cause of liver injury. The toxicity of paracetamol has been attributing to its toxic metabolite, which depletes cellular glutathione (GSH) stores and reacts within cells to increase oxidative stress, leading to mitochondrial dysfunction and cell necrosis. Multiphoton microscopy (MPM) and fluorescence lifetime imaging (FLIM) can provide quantitative imaging of biological tissues and organs in vivo and allow direct visualization of cellular events, which were used to monitor cellular metabolism in paracetamol-induced toxicity in this study. To better understand mechanisms of paracetamol induced liver injury, the redox ratio of NADH/FAD in liver cells were detected and quantified by MPM imaging to represent the relative rates of glycolysis and oxidative phosphorylation within cells. Compared to normal liver, average fluorescence lifetime of NADH and redox ratio of NADH/FAD in hepatocytes was significantly decreased after paracetamol overdose for 12 and 24 hrs, reflecting impaired metabolic activity. GSH levels of treatment groups were significantly lower than those of normal livers, with gradually decreasing from periportal to centrilobular zonation. This imaging technique has significant implications for investigating metabolic mechanisms of paracetamol toxicity.

  12. 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.

  13. 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.

  14. 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.

  15. 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, E-mail: rkpark@wku.ac.kr [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.

  16. 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

  17. 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

  18. Attenuating Effect of Ginkgo biloba Leaves Extract on Liver Fibrosis Induced by Thioacetamide in Mice

    Science.gov (United States)

    Al-Attar, Atef M.

    2012-01-01

    The purpose of this study is to investigate the effect of Ginkgo biloba leaves extract on experimental liver fibrosis induced by thioacetamide (TAA) in male albino mice. The experimental mice were divided into four groups. The mice of the first group were served as control. The experimental animals of the second group were given 150 mg/kg body weight of TAA by intraperitoneal injection, twice weekly, for 9 weeks. The mice of the third group were exposed to TAA and supplemented with G. biloba leaves extract. The animals of the fourth group were supplemented with G. biloba leaves extract. The levels of plasma alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, triglycerides, cholesterol, and low-density lipoprotein cholesterol were statistically increased while the levels of plasma total protein, albumin, glucose, and high-density lipoprotein cholesterol were significantly decreased. The levels of liver superoxide dismutase, glutathione, glycogen and total protein were notably declined, whereas the level of total lipid was increased in mice of the second group. Furthermore, microscopic examination of liver sections from mice treated with TAA showed an abnormal morphology characterized by nodular transformations in liver parenchyma which surrounded by fibrous septa. Administration of G. biloba leaves extract reduced extent and development of fibrous septa, liver cells change, and biochemical alterations in mice exposed to TAA. This study showed that G. biloba leaves extract has a potential activity against TAA-induced liver fibrosis and suggested that the chemical constituents of G. biloba are effective in modulation of oxidative stress induced by TAA. PMID:23091357

  19. 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.

  20. Resolution of inflammation in obesity-induced liver disease

    Directory of Open Access Journals (Sweden)

    Bibiana eRius

    2012-08-01

    Full Text Available Low-grade inflammation in adipose tissue is recognized as a critical event in the development of obesity-related co-morbidities. This chronic inflammation is powerfully augmented through the infiltration of macrophages, which together with adipocytes, perpetuate a vicious cycle of inflammatory cell recruitment and secretion of free fatty acids and deleterious adipokines that predispose to greater incidence of metabolic complications. In the last decade, many factors have been identified to contribute to mounting unresolved inflammation in obese adipose tissue. Among them, pro-inflammatory lipid mediators (i.e. leukotrienes derived from the omega-6 polyunsaturated arachidonic acid have been shown to play a prominent role. Of note, the same lipid mediators that initially trigger the inflammatory response also signal its termination by stimulating the formation of anti-inflammatory signals. Resolvins and protectins derived from the omega-3 polyunsaturated docosahexaenoic and eicosapentaenoic acids have emerged as a representative family of this novel class of autacoids with dual anti-inflammatory and pro-resolving properties that act as stop signals of the inflammatory response. This review discusses the participation of these endogenous autacoids in the resolution of adipose tissue inflammation, with a special emphasis in the amelioration of obesity-related metabolic dysfunctions, namely insulin resistance and non-alcoholic fatty liver disease.

  1. 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.

  2. Radiation-induced liver disease after radiotherapy for hepatocellular carcinoma: clinical manifestation and dosimetric description

    International Nuclear Information System (INIS)

    Cheng, Jason Chia-Hsien; Wu, Jian-Kuen; Huang, Chao-Ming; Huang, David Y.; Cheng, Skye H.; Lin, Yu-Mong; Jian, James J.; Yang, Po-Sheng; Chuang, Vincent P.; Huang, Andrew T.

    2002-01-01

    Twelve patients with hepatocellular carcinoma and chronic hepatitis developed radiation-induced liver disease (RILD) after three-dimensional conformal radiotherapy. Six patients died of RILD and six recovered. Mean prescribed dose was 50.6±4.3 Gy, in a daily fraction of 1.8-2.0 Gy. Commonly used dosimetric parameters, such as fraction volume of normal liver with radiation dose >30 Gy, prediction score, and normal tissue complication probability, failed to differentiate the fatality and clinical types of this complication. Elevated transaminases are more frequently seen than ascites and elevated alkaline phosphamide are seen in patients with RILD

  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. Effective protection of Terminalia catappa L. leaves from damage induced by carbon tetrachloride in liver mitochondria.

    Science.gov (United States)

    Tang, Xinhui; Gao, Jing; Wang, Yanping; Fan, Yi-Mei; Xu, Li-Zhi; Zhao, Xiao-Ning; Xu, Qiang; Qian, Zhong Ming

    2006-03-01

    The protective effects of chloroform extracts of Terminalia catappa L. leaves (TCCE) on carbon tetrachloride (CCl4)-induced liver damage and the possible mechanisms involved in the protection were investigated in mice. We found that increases in the activity of serum aspartate aminotransferase and alanine aminotransferase and the level of liver lipid peroxidation (2.0-fold, 5.7-fold and 2.8-fold) induced by CCl4 were significantly inhibited by oral pretreatment with 20, 50 or 100 mg/kg of TCCE. Morphological observation further confirmed the hepatoprotective effects of TCCE. In addition, the disruption of mitochondrial membrane potential (14.8%), intramitochondrial Ca2+ overload (2.1-fold) and suppression of mitochondrial Ca2+-ATPase activity (42.0%) in the liver of CCl4-insulted mice were effectively prevented by pretreatment with TCCE. It can be concluded that TCCE have protective activities against liver mitochondrial damage induced by CCl4, which suggests a new mechanism of the hepatoprotective effects of TCCE.

  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. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    Pepe, G.J.; Waddell, B.J.; Albrecht, E.D. (Eastern Virginia Medical School, Norfolk (USA))

    1990-12-01

    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.

  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. [Clinical Analysis of Drug-induced Liver Injury Caused by Polygonum multiflorum and its Preparations].

    Science.gov (United States)

    Zhu, Yun; Liu, Shu-hong; Wang, Jia-bo; Song, Hai-bo; Li, Yong-gang; He, Ting-ting; Ma, Xiao; Wang, Zhong-xia; Wang-Li-ping; Zhou, Kun; Bai, Yun-feng; Zou, Zheng-sheng; Xiao, Xiao-he

    2015-12-01

    To analyze hepatotoxicity of Polygonum multiflorum and clinical character- istics of drug-induced liver injury (DILI) caused by Polygonum multiflorum and its preparations. A retrospective study was performed in 158 patients treated at 302 Military Hospital between January 2009 and January 2014. All of them had used Polygonum multiflorum and its preparations before the onset of DILI, and their clinical characteristics and prognoses were analyzed. Of the 158 DILI patients who used Polygonum multiflorum or its preparations, 92 (58.2%) combined with Western medicine or Chinese herbal preparations without Polygonum multiflorum; 66 patients (41.8%) used Polygonum mult florum and its preparations alone. In 66 DILI patients induced by Polygonum multiflorum or its preparations alone, 51 cases (77.3%) were induced by Polygonum multiflorum compounds and 22.7% by single Po- lygonum multiflorum; 4 cases (6.1%) were caused by crude Polygonum multiflorum and 62 (93.9%) by processed Polygonum multiflorum and its preparations. Clinical injury patterns were hepatocellular 92.4% (61 cases), cholestatic 1.5% (1 case), and mixed 6.1% (4 cases). Pathological examination was per- formed by liver biopsy in 32 cases (48.15%), manifested as hepatocellular degeneration and necrosis, fibroplasia, Kupffer cells with pigment granule, and a large number of eosinophil infiltration, were ob- served. Four patients were developed into liver failure, 4 into cirrhosis, and 1 died. Polygo- num multiflorum and its preparations could induce DILI, but clinical diagnosis of Polygonum multiflorum induced hepatotoxicity should be cautious.

  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. Screening for biomarkers of liver injury induced by Polygonum multiflorum: a targeted metabolomic study

    Science.gov (United States)

    Dong, Qin; Li, Na; Li, Qi; Zhang, Cong-En; Feng, Wu-Wen; Li, Guang-Quan; Li, Rui-Yu; Tu, Can; Han, Xue; Bai, Zhao-Fang; Zhang, Ya-Ming; Niu, Ming; Ma, Zhi-Jie; Xiao, Xiao-He; Wang, Jia-Bo

    2015-01-01

    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. PMID:26483689

  12. Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice

    International Nuclear Information System (INIS)

    Yin Huquan; Kim, Mingoo; Kim, Ju-Han; Kong, Gu; Kang, Kyung-Sun; Kim, Hyung-Lae; Yoon, Byung-IL; Lee, Mi-Ock; Lee, Byung-Hoon

    2007-01-01

    Ethanol induces cumulative liver damage including steatosis, steatohepatitis and cirrhosis. The aim of this study is to investigate the global intrahepatic gene expression profile in the mouse liver treated with ethanol. A single oral dose of 0.5 or 5 g/kg ethanol was administered to male ICR mice, and liver samples were obtained after 6, 24 and 72 h. Histopathological evaluation showed typical fatty livers in the high-dose group at 24 h. Microarray analysis identified 28 genes as being ethanol responsive (two-way ANOVA; p < 0.05), after adjustment by the Benjamini-Hochberg multiple testing correction; these genes displayed ≥ 2-fold induction or repression. The expression of genes that are known to be involved in fatty acid synthesis was examined. The transcript for lipogenic transcription factor, sterol regulatory element (SRE)-binding factor 1 (Srebf1), was upregulated by acute ethanol exposure. Of the genes known to contain SRE or SRE-like sequences and to be regulated by SRE-binding protein 1 (SREBP1), those encoding malic enzyme (Mod1), ATP-citrate lyase (Acly), fatty acid synthase (Fasn) and stearyl-CoA desaturase (Scd1) were induced by ethanol. Quantitative real-time PCR confirmed the changes in the expression levels of the selected genes. The change in the Srebf1 mRNA level correlates well with that of the SREBP1 protein expression as well as its binding to the promoters of the target genes. The present study identifies differentially expressed genes that can be applied to the biomarkers for alcohol-binge-induced fatty liver. These results support the hypothesis by which ethanol-induced steatosis in mice is mediated by the fatty acid synthetic pathway regulated by SREBP1

  13. Luteolin alleviates alcoholic liver disease induced by chronic and binge ethanol feeding in mice.

    Science.gov (United States)

    Liu, Gaigai; Zhang, Yuxue; Liu, Chunchun; Xu, Daqian; Zhang, Rui; Cheng, Yuan; Pan, Yi; Huang, Cheng; Chen, Yan

    2014-07-01

    Ethanol consumption can lead to hepatic steatosis that contributes to late-stage liver diseases such as cirrhosis and hepatocellular carcinoma. In this study, we investigated the potential protective effect of a flavonoid, luteolin, on ethanol-induced fatty liver development and liver injury. Six-wk-old male C57BL/6 mice were divided into 3 groups: a control group; a group exposed to alcohol by using a chronic and binge ethanol feeding protocol (EtOH); and a group that was administered daily 50 mg/kg of luteolin in addition to ethanol exposure (EtOH + Lut). A chronic and binge ethanol feeding protocol was used, including chronic ethanol consumption (1%, 2%, and 4% for 3 d, and 5% for 9 d) and a binge (30% ethanol) on the last day. Compared with the control group, the EtOH group had a significant elevation in serum concentrations of alanine aminotransferase (ALT) (561%), triglyceride (TG) (47%), and LDL cholesterol (95%), together with lipid accumulation in the liver. Compared with the EtOH group, the EtOH + Lut group had significant reductions in serum concentrations of ALT (43%), TG (22%), LDL cholesterol (52%), and lipid accumulation in the liver. Ethanol elevated liver expression of lipogenic genes including sterol regulatory element-binding protein 1c (Srebp1c) (560%), fatty acid synthase (Fasn) (190%), acetyl-CoA carboxylase (Acc) (48%), and stearoyl-CoA desaturase 1 (Scd1) (286%). Luteolin reduced ethanol-induced expression of these genes in the liver: Srebp1c (79%), Fasn (80%), Acc (60%), and Scd1 (89%). In cultured hepatocytes, luteolin prevented alcohol-induced lipid accumulation and increase in the expression of lipogenic genes. The transcriptional activity of the master regulator of lipid synthesis, sterol regulatory element-binding protein (SREBP), was enhanced by ethanol treatment (160%) and reduced by luteolin administration (67%). In addition, ethanol-induced reduction of AMP-activated protein kinase and SREBP-1c phosphorylation was abrogated by

  14. 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)

  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. 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...... 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...... carboxylase (PC) remained unchanged after fasting in WT mice, but was upregulated in PGC-1a KO mice. In response to a single exercise bout G6Pase mRNA was upregulated in both genotypes, whereas no significant changes were detected in PEPCK or PC mRNA. While G6Pase and PC protein remained unchanged, liver...

  17. Hypoxia and Fetal Heart Development

    OpenAIRE

    Patterson, A.J.; Zhang, L

    2010-01-01

    Fetal hearts show a remarkable ability to develop under hypoxic conditions. The metabolic flexibility of fetal hearts allows sustained development under low oxygen conditions. In fact, hypoxia is critical for proper myocardial formation. Particularly, hypoxia inducible factor 1 (HIF-1) and vascular endothelial growth factor play central roles in hypoxia-dependent signaling in fetal heart formation, impacting embryonic outflow track remodeling and coronary vessel growth. Although HIF is not th...

  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. TGF-β signaling alters the pattern of liver tumorigenesis induced by Pten inactivation

    Science.gov (United States)

    Morris, Shelli M.; Carter, Kelly T.; Baek, Ji Yeon; Koszarek, Amanda; Yeh, Matthew M.; Knoblaugh, Sue E.; Grady, William M.

    2014-01-01

    Hepatocarcinogenesis results from the accumulation of genetic and epigenetic changes in liver cells. A common mechanism through which these alterations induce liver cancer is by deregulating signaling pathways. A number of signaling pathways, including the PI3K/PTEN/AKT and transforming growth factor β (TGF-β) pathways have been implicated in normal liver development as well as in cancer formation. In this study, we assessed the effect of the TGF-β signaling pathway on liver tumors induced by Pten (phosphatase and tensin homologue) loss. Inactivation of only the TGF-β receptor type II, Tgfbr2, in the mouse liver (Tgfbr2LKO) had no overt phenotype, while inactivation of Pten alone (PtenLKO), resulted in the formation of both hepatocellular carcinomas (HCC) and cholangiocarcinomas (CC). Interestingly, deletion of both Pten and Tgfbr2 (PtenLKO;Tgfbr2LKO) in the mouse liver resulted in a dramatic shift in tumor type to predominantly CC. Assessment of the PI3K/PTEN/AKT pathway revealed increased phosphorylation of AKT and GSK-3β in both the PtenLKO and PtenLKO;Tgfbr2LKO mice, suggesting that this pathway is constitutively active regardless of the status of the TGF-β signaling pathway. However, phosphorylation of p70 S6 kinase was observed in the liver of all three phenotypes (Tgfbr2LKO, PtenLKO, PtenLKO;Tgfbr2LKO) indicating that the loss of Tgfbr2 and/or Pten leads to an increase in this signaling pathway. Analysis of markers of liver progenitor/stem cells revealed that the loss of TGF-β signaling resulted in increased expression of c-Kit and CD133. Furthermore, in addition to increased c-Kit and CD133, Scf and EpCam expression were also increased in the double knock-out mice. These results suggest that the alteration in tumor types between the PtenLKO mice and PtenLKO;Tgfbr2LKO mice is secondary to the altered regulation of stem cell features induced by the loss of TGF-β signaling. PMID:25132272

  1. Males are from Mars, and females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity.

    Science.gov (United States)

    Edlow, Andrea G; Guedj, Faycal; Pennings, Jeroen L A; Sverdlov, Deanna; Neri, Caterina; Bianchi, Diana W

    2016-05-01

    Maternal obesity is associated with adverse neurodevelopmental outcomes in children, including autism spectrum disorders, developmental delay, and attention-deficit hyperactivity disorder. The underlying mechanisms remain unclear. We previously identified second-trimester amniotic fluid and term cord blood gene expression patterns suggesting dysregulated brain development in fetuses of obese compared with lean women. We sought to investigate the biological significance of these findings in a mouse model of maternal diet-induced obesity. We evaluated sex-specific differences in fetal growth, brain gene expression signatures, and associated pathways. Female C57BL/6J mice were fed a 60% high-fat diet or 10% fat control diet for 12-14 weeks prior to mating. During pregnancy, obese dams continued on the high-fat diet or transitioned to the control diet. Lean dams stayed on the control diet. On embryonic day 17.5, embryos were weighed and fetal brains were snap frozen. RNA was extracted from male and female forebrains (10 per diet group per sex) and hybridized to whole-genome expression arrays. Significantly differentially expressed genes were identified using a Welch's t test with the Benjamini-Hochberg correction. Functional analyses were performed using ingenuity pathways analysis and gene set enrichment analysis. Embryos of dams on the high-fat diet were significantly smaller than controls, with males more severely affected than females (P = .01). Maternal obesity and maternal obesity with dietary change in pregnancy resulted in significantly more dysregulated genes in male vs female fetal brains (386 vs 66, P Maternal obesity with and without dietary change in pregnancy was associated with unique brain gene expression signatures for each sex, with an overlap of only 1 gene. Changing obese dams to a control diet in pregnancy resulted in more differentially expressed genes in the fetal brain than maternal obesity alone. Functional analyses identified common

  2. Males are from Mars, females are from Venus: sex-specific fetal brain gene expression signatures in a mouse model of maternal diet-induced obesity

    Science.gov (United States)

    EDLOW, Andrea G.; GUEDJ, Faycal; PENNINGS, Jeroen L.A.; SVERDLOV, Deanna; NERI, Caterina; BIANCHI, Diana W.

    2016-01-01

    BACKGROUND Maternal obesity is associated with adverse neurodevelopmental outcomes in children, including autism spectrum disorders, developmental delay, and attention deficit hyperactivity disorder. The underlying mechanisms remain unclear. We previously identified second trimester amniotic fluid and term cord blood gene expression patterns suggesting dysregulated brain development in fetuses of obese compared to lean women. OBJECTIVES We sought to investigate the biological significance of these findings in a mouse model of maternal diet-induced obesity. We evaluated sex-specific differences in fetal growth, brain gene expression signatures and associated pathways. STUDY DESIGN Female C57BL/6J mice were fed a 60% high-fat diet or 10% fat control diet for 12–14 weeks prior to mating. During pregnancy, obese dams continued on the high-fat diet (HFD/HFD), or transitioned to the CD (HFD/CD). Lean dams stayed on the control diet. On embryonic day 17.5, embryos were weighed and fetal brains were snap frozen. RNA was extracted from male and female forebrains (10/diet group/sex) and hybridized to whole genome expression arrays. Significantly differentially expressed genes were identified using Welch’s t-test with the Benjamini-Hochberg correction. Functional analyses were performed using Ingenuity Pathways Analysis and Gene Set Enrichment Analysis. RESULTS Embryos of HFD/HFD dams were significantly smaller than controls, with males more severely affected than females (p=0.01). Maternal obesity and maternal obesity with dietary change in pregnancy resulted in significantly more dysregulated genes in male versus female fetal brains (386 vs 66, pMaternal obesity with and without dietary change in pregnancy was associated with unique brain gene expression signatures for each sex, with overlap of only one gene. Changing obese dams to a control diet in pregnancy resulted in more differentially expressed genes in the fetal brain than maternal obesity alone. Functional

  3. Dietary Supplementation with Lactobacillus casei Alleviates Lipopolysaccharide-Induced Liver Injury in a Porcine Model

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    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.

  4. Streptozotocin-induced diabetes mellitus affects lysosomal enzymes in rat liver

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    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.

  5. Streptozotocin-induced diabetes mellitus affects lysosomal enzymes in rat liver

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    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.

  6. Arsenite induced oxidative damage in mouse liver is associated with increased cytokeratin 18 expression

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    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.)

  7. Dietary Egg Yolk Supplementation Improves Low-Protein-Diet-Induced Fatty Liver in Rats.

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    Erami, Kazuo; Tanaka, Yasutake; Kawamura, Sayaka; Miyago, Motonori; Sawazaki, Ai; Imaizumi, Katsumi; Sato, Masao

    2016-01-01

    Egg yolk is an important source of nutrients and contains different bioactive substances. In the present study, we studied the benefits of egg yolk in preventing low-protein-diet-induced fatty liver in rats. Rats were fed the following diets, which were based on the AIN-76 formula, for 2 wk: an adequate-protein diet containing 20% casein (C), a low-protein diet containing 5% casein (LP-C), a low-protein diet supplemented with 12.5% egg yolk (LP-EY), and a low-protein diet supplemented with 4.1% egg yolk oil (LP-EYO). The low-protein diets were adjusted to contain 4.13% protein and 4.7% lipids. The LP-C diet resulted in a greater increase in the liver trigriceride (TG) and the vacuolation and a greater decrease in the serum TG and free fatty acid (FFA) than did the C diet. These deviations in the serum and liver TG, serum FFA levels and the liver histopathology were corrected in rats fed the LP-EY diet but not in those fed the LP-EYO diet. Compared to rats fed the LP-C diet, although the activities of lipogenesis-related enzymes (fatty acid synthase, glucose-6-phosphate dehydrogenase, and malic enzyme) decreased in rats fed both of the LP-EY and LP-EYO diets, the level of the microsomal TG transfer protein (MTP) increased only in rats fed the LP-EY diet. Collectively, these results suggest that dietary egg yolk supplementation decreases the LP diet-induced accumulation of TG in the liver by increasing transport of TG in the liver, and egg yolk oil alone is not sufficient enough to bring about these benefits.

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

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    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.

  9. Paradoxical increase in liver ketogenesis during long-term insulin-induced hypoglycemia in diabetic rats.

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    Schiavon, Fabiana P M; Gazola, Vilma A F G; Furlan, Maria M D P; Barrena, Helenton C; Bazotte, Roberto B

    2011-02-01

    It is well established that insulin inhibits liver ketogenesis. However, during insulin-induced hypoglycemia (IIH) the release of counterregulatory hormones could overcome the insulin effect on ketogenesis. To clarify this question the ketogenic activity in livers from alloxan-diabetic rats submitted to long-term IIH was investigated. Moreover, liver glycogenolysis, gluconeogensis, ureagenesis and the production of L-lactate were measured, and its correlation with blood levels of ketone bodies (KB), L-lactate, glucose, urea and ammonia was investigated. For this purpose, overnight fasted alloxan-diabetic rats (DBT group) were compared with control non-diabetic rats (NDBT group). Long-term IIH was obtained with an intraperitoneal injection of Detemir insulin (1 U/kg), and KB, glucose, L-lactate, ammonia and urea were evaluated at 0, 2, 4, 6, 8 or 10 h after insulin injection. Because IIH was well established two hours after insulin injection this time was used for liver perfusion experiments. The administration of Detemir insulin decreased (P < 0.05) blood KB and glucose levels, but there was an increase in the blood L-lactate levels and a rebound increase in blood KB during the glucose recovery phase of IIH. In agreement with these results, the capacity to produce KB from octanoate was increased in the livers of DBT rats. Moreover, the elevated blood L-lactate levels in DBT rats could be attributed to the higher (P < 0.05) glycogenolysis when part of glucose from glycogenolysis enters glycolysis, producing L-lactate. In contrast, except glycerol, gluconeogenesis was negligible in the livers of DBT rats. Therefore, during long-term IIH the higher liver ketogenic capacity of DBT rats increased the risk of hyperketonemia. In addition, in spite of the fact that the insulin injection decreased blood KB, there was a risk of worsening lactic acidosis.

  10. Protective effects of vitamin D3 against d-galactosamine-induced liver injury in rats.

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    Colakoglu, Neriman; Kuloglu, Tuncay; Ozan, Enver; Kocaman, Nevin; Dabak, Durrin Ozlem; Parlak, Gozde

    2016-08-01

    In this study, we examined liver damage induced by d-galactosamine (d-GaIN) and the protective effects of vitamin D3 in relation to d-GaIN toxicity. Twenty Wistar albino rats were used in this study. The rats were divided into four groups. Group I rats were used as the control group. Group II rats were given a single intraperitoneal injection of d-GaIN. Group III rats were given a single intraperitoneal injection of d-GaIN, intramuscular vitamin D3 for five days. Group IV rats were given intramuscular vitamin D3 for five days. All of rats were euthanized by cervical decapitation on the fifth day of experiment. Upon completion of the experiment, a midsaggital incision was performed, and the livers of all rats were removed and fixed. The livers were processed to perform TUNEL technique and histochemical staining. During the microscope examination, we observed inflamatory cell infiltration, sinusoidal dilatation, and apoptotic bodies due to d-GaIN exposure. In addition, glycogen content of the group II hepatocytes was significantly decreased. Vitamin D3 treatment provided better structural apperance of the livers in group III. TUNEL positive cells were extremly pervasive in the group II livers. The study found group III TUNEL positive cells at a reduced rate in relation to group II due to vitamin D3 treatment. This findings indicate that d-GaIN causes inflamation in the liver. This inflamation triggers the apoptotic process gradually. Vitamin D3 has potency to decrease the severity of d-GaIN-caused structural liver damage. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Protective effect of pretreatment with thymoquinone against Aflatoxin B1 induced liver toxicity in mice

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    A Nili-Ahmadabadi

    2011-10-01

    Full Text Available "n  Background and the purpose of the study: Thymoquinone (TQ is one of the active components of Nigella sativa. The plant has been used in herbal medicine for treatment of many diseases including liver complications. The present study aimed to investigate protective effects of TQ on Aflatoxin B1 (AFB1 induced liver toxicity in mice. "n  Methods: Animals were divided into six groups and treated intraperitoneally. Group 1 (blank served as vehicle, group 2 (positive control received AFB1, Group 3 was treated with 9 mg/kg of TQ, Groups 4, 5 and 6 were treated with 4.5, 9 and 18 mg/kg of TQ, respectively. After three consecutive days, except for groups 1 and 3, animals were administered with a single dose of AFB1 (2 mg/kg. All the animals were killed 24 hrs following the AFB1 administration under ether anesthesia. Biochemical parameters including AST, ALT and ALP in serum samples and glutathione (GSH and malondialdehyde (MDA contents in liver homogenates were determined. Liver sections were collected for histopathological examination. "n  Results: Findings of this study showed that AST, ALT, ALP and MDA levels were significantly lower in the TQ treated animals as compared to AFB1 group (group 2. Furthermore, TQ was able to recover glutathione content (GSH of liver tissue. The best response, however, was observed with the dose of 9 mg/kg. Liver sections of AFB1 intoxicated mice showed inflammation, necrosis, hyperplasia of kupffer and infiltration of mononuclear cells, dilation of sinusoids and disruption of hepatocytes, while treatment with TQ helped to normalize liver architecture in accordance to biochemical findings. "n  Conclusion: Taken collectively, TQ has a protective role with optimum dose of 9 mg/kg in AFB1 hepatotoxicity.

  12. Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a

    Science.gov (United States)

    Wang, Shuxia; Song, Kangxing; Srivastava, Roshni; Dong, Chao; Go, Gwang-Woong; Li, Na; Iwakiri, Yasuko; Mani, Arya

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease, which begins with isolated steatosis and advances to nonalcoholic steatohepatitis (NASH), steatofibrosis, and cirrhosis. The pathways involved in disease progression are not understood. Loss-of-function mutations in Wnt coreceptor LDL receptor-related protein 6 (LRP6) underlie early-onset atherosclerosis, metabolic risk factors, and NAFLD in humans by unknown mechanisms. We generated mice with the human disease-associated LRP6R611C mutation and phenotypically characterized their liver. Homozygote LRP6R611C (LRP6mut/mut) mice exhibited both steatohepatitis and steatofibrosis. These traits were associated with increased activity of the noncanonical Wnt/Ras homolog family member A, Rho-associated protein kinase 2, and PKC-α/-μ pathways. Accordingly, there was increased TGF-β1 activity, coupled with enhanced expression of smooth muscle α-actin and vimentin that colocalized with albumin in LRP6mut/mut mouse liver. LRP6 knockdown reprogramed HepG2 cells to express both these markers, linking impaired Wnt signaling with hepatocyte transdifferentiation. The causal link between altered Wnt signaling and NASH was established by normalization of the disease pathways and rescue of the liver traits by Wnt3a administration to LRP6mut/mut mice. Thus, this study identifies diverse disease pathways that underlie a spectrum of NASH-related liver diseases and are linked by a single human genetic variant. LRP6 and noncanonical Wnt pathways are important potential therapeutic targets against NASH.—Wang, S., Song, K., Srivastava, R., Dong, C., Go, G.-W., Li, N., Iwakiri, Y., Mani, A. Nonalcoholic fatty liver disease induced by noncanonical Wnt and its rescue by Wnt3a. PMID:25917329

  13. 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.

  14. 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.

  15. Propolis reduces Leishmania amazonensis-induced inflammation in the liver of BALB/c mice.

    Science.gov (United States)

    da Silva, Suelen S; Mizokami, Sandra S; Fanti, Jacqueline R; Miranda, Milena M; Kawakami, Natalia Y; Teixeira, Fernanda Humel; Araújo, Eduardo J A; Panis, Carolina; Watanabe, Maria A E; Sforcin, José M; Pavanelli, Wander R; Verri, Waldiceu A; Felipe, Ionice; Conchon-Costa, Ivete

    2016-04-01

    Experimental models of mouse paw infection with L. amazonensis show an induction of a strong inflammatory response in the skin, and parasitic migration may occur to secondary organs with consequent tissue injury. There are few studies focusing on the resolution of damage in secondary organs caused by Leishmania species-related cutaneous leishmaniasis. We investigated the propolis treatment effect on liver inflammation induced by Leishmania amazonensis infection in the mouse paw. BALB/c mice were infected in the hind paw with L. amazonensis (10(7)) promastigote forms. After 15 days, animals were treated daily with propolis (5 mg/kg), Glucantime (10 mg/kg), or with propolis plus Glucantime combined. After 60 days, mice were euthanized and livers were collected for inflammatory process analysis. Liver microscopic analysis showed that propolis reduced the inflammatory process compared to untreated infected control. There was a decrease of liver myeloperoxidase and N-acetyl-β-glucosaminidase activity levels, collagen fiber deposition, pro-inflammatory cytokine production, and plasma aspartate transaminase and alanine transaminase levels. Furthermore, propolis treatment enhanced anti-inflammatory cytokine levels and reversed hepatosplenomegaly. Our data demonstrated that daily low doses of Brazilian propolis reduced the secondary chronic inflammatory process in the liver caused by L. amazonensis subcutaneous infection in a susceptible mice strain.

  16. Oxidative Stress and Liver Morphology in Experimental Cyclosporine A-Induced Hepatotoxicity

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    Agnieszka Korolczuk

    2016-01-01

    Full Text Available Cyclosporine A is an immunosuppressive drug used after organ’s transplantation. The adverse effects on such organs as kidney or liver may limit its use. Oxidative stress is proposed as one of the mechanisms of organs injury. The study was designed to elucidate CsA-induced changes in liver function, morphology, oxidative stress parameters, and mitochondria in rat’s hepatocytes. Male Wistar rats were used: group A (control receiving physiological saline, group B cyclosporine A in a dose of 15 mg/kg/day subcutaneously, and group C the CsA-vehicle (olive oil. On the 28th day rats were anesthetized. The following biochemical changes were observed in CsA-treated animals: increased levels of ALT, AST, and bilirubin in the serum, statistically significant changes in oxidative stress parameters, and lipid peroxidation products in the liver supernatants: MDA+4HAE, GSH, GSSG, caspase 3 activity, and ADP/ATP, NAD+/NADH, and NADP+/NADPH ratios. Microscopy of the liver revealed congestion, sinusoidal dilatation, and focal hepatocytes necrosis with mononuclear cell infiltration. Electron microscope revealed marked mitochondrial damage. Biochemical studies indicated that CsA treatment impairs liver function and triggers oxidative stress and redox imbalance in rats hepatocytes. Changes of oxidative stress markers parallel with mitochondrial damage suggest that these mechanisms play a crucial role in the course of CsA hepatotoxicity.

  17. Oxidative Stress and Liver Morphology in Experimental Cyclosporine A-Induced Hepatotoxicity.

    Science.gov (United States)

    Korolczuk, Agnieszka; Caban, Kinga; Amarowicz, Magdalena; Czechowska, Grażyna; Irla-Miduch, Joanna

    2016-01-01

    Cyclosporine A is an immunosuppressive drug used after organ's transplantation. The adverse effects on such organs as kidney or liver may limit its use. Oxidative stress is proposed as one of the mechanisms of organs injury. The study was designed to elucidate CsA-induced changes in liver function, morphology, oxidative stress parameters, and mitochondria in rat's hepatocytes. Male Wistar rats were used: group A (control) receiving physiological saline, group B cyclosporine A in a dose of 15 mg/kg/day subcutaneously, and group C the CsA-vehicle (olive oil). On the 28th day rats were anesthetized. The following biochemical changes were observed in CsA-treated animals: increased levels of ALT, AST, and bilirubin in the serum, statistically significant changes in oxidative stress parameters, and lipid peroxidation products in the liver supernatants: MDA+4HAE, GSH, GSSG, caspase 3 activity, and ADP/ATP, NAD(+)/NADH, and NADP(+)/NADPH ratios. Microscopy of the liver revealed congestion, sinusoidal dilatation, and focal hepatocytes necrosis with mononuclear cell infiltration. Electron microscope revealed marked mitochondrial damage. Biochemical studies indicated that CsA treatment impairs liver function and triggers oxidative stress and redox imbalance in rats hepatocytes. Changes of oxidative stress markers parallel with mitochondrial damage suggest that these mechanisms play a crucial role in the course of CsA hepatotoxicity.

  18. Ganoderma tsugae Hepatoprotection against Exhaustive Exercise-Induced Liver Injury in Rats

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    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.

  19. 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.

  20. Protective Effects of Korean Red Ginseng against Alcohol-Induced Fatty Liver in Rats

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    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.

  1. Eosinophil-induced liver injury: an experimental model using IL-5 transgenic mice.

    Science.gov (United States)

    Tsuda, K; Maeda, T; Tominaga, A; Watanabe, Y; Miyazaki, E; Enzan, H; Akisawa, N; Iwasaki, S; Saibara, T; Onishi, S

    2001-02-01

    In certain liver diseases, activated eosinophils are considered to be important effector cells in addition to T-cell-mediated cytotoxicity. No experimental model, however, has been developed for in vivo analysis of the cytotoxic mechanisms. Interleukin-5 (IL-5) transgenic mice (C3H/HeN-TgN(IL-5)Imeg), which exhibit marked eosinophilia without liver injury, were injected once with 25 microg of lipopolysaccharide (LPS) intraperitoneally. The mice were sacrificed weekly and eosinophilic injuries were assessed microscopically. To clarify the role of Kupffer cells and tumor necrosis factor-alpha (TNF-alpha) in the liver injury, gadolinium chloride (GdCl3) and anti-TNF-alpha neutralizing antibody were administrated before the LPS injection. Two weeks after injection, transgenic mice exhibited marked infiltration of eosinophils and extensive lobular necrosis. Transmigration of eosinophils through vascular endothelium and degranulation of eosinophil cytotoxic granules in inflamed areas were observed. These eosinophilic injuries were transient, but liver-specific. Pre-administration of GdCl3 and anti-TNF-alpha markedly reduced the hepatic inflammation, suggesting that LPS-activated Kupffer cells play a key role in producing the cytotoxicity of eosinophils by releasing TNF-alpha. We have established an experimental model of eosinophil-induced liver injury using IL-5 transgenic mice. Since this model is simple and highly reproducible, it will be useful for analysis of in vivo cytotoxic mechanisms of eosinophils.

  2. Cell-swelling-induced taurine release from isolated perfused rat liver.

    Science.gov (United States)

    Brand, H S; Meijer, A J; Gustafson, L A; Jörning, G G; Leegwater, A C; Maas, M A; Chamuleau, R A

    1994-01-01

    Astrocytes and lymphocytes are able to release significant amounts of taurine during periods of hypotonicity to reduce the increase in cell volume. To investigate this mechanism in the liver, we studied the release of free amino acids from isolated perfused rat liver during hypotonicity. The osmolarity of the perfusion medium was reduced from 305 to 255 or 205 mosM by decreasing the NaCl concentration 25 or 50 mM, respectively. This induced an 6-8% increase in liver mass and was associated with a specific 1.7-fold (-50 mosM) and 14-fold (-100 mosM) increase of the taurine release. None of the other amino acids measured showed a significant increase in their concentration in the effluent. The increase in taurine release occurred within 30 s after exposure to hypotonicity (maximal after 1-1.5 min) and followed closely the changes in liver mass. The taurine release declined gradually during successive exposures of the isolated liver to -100 mosM. This release was 29 and 17% of the original during the second and third exposure, respectively.

  3. Carvacrol attenuates N-nitrosodiethylamine induced liver injury in experimental Wistar rats

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    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.

  4. Autotransplantation of Spleen Mitigates Drug-Induced Liver Damage in Splenectomized Mice.

    Science.gov (United States)

    Grunewald, Sabrine Teixeira Ferraz; Rezende, Alice Belleigoli; Figueiredo, Bárbara Bruna Muniz; Mendonça, Ana Carolina de Paula; Almeida, Caroline de Souza; de Oliveira, Erick Esteves; de Paoli, Flávia; Teixeira, Henrique Couto

    2017-12-01

    The spleen presents numerous functions, including the production of immunoglobulins and blood filtration, removing microorganisms and cellular debris. The spleen also has anatomical and functional relationship with the liver, but there are few studies on this topic. The aim of this study was to assess the effect of splenectomy and autologous spleen transplantation on both filtering functions of spleen and acetaminophen-induced hepatotoxicity. Fifty-two BALB/c mice were randomized into four groups: splenectomized; splenectomy and splenic autotransplantation in the greater omentum; sham operated control; and non-operated control. At day 7th, 14th, and 28th after surgery, splenic filtration was assessed by counting Howell-Jolly bodies (HJB) and pitted red cells (PIT). The animals received 400 mg/kg acetaminophen by gavage at day 28 th and after 12 or 24 hours were euthanized for evaluation of splenic and hepatic morphology. The splenectomized group demonstrated reduced filtration of HJB and PIT in all analyzes, while the autotransplanted group developed progressive recovery of function after the 14th day. At day 28 after surgery the implants showed similar histology in comparison to normal spleen. Liver histology showed more intense centrilobular necrosis in splenectomized group in comparison to the others, suggesting a protective role of spleen in acetaminophen-induced liver injury. Splenic implants showed structural and functional recovery, demonstrating the ability of autologous implant to rescue filtering function of intact spleen. Furthermore, the integrity of splenic function appears to influence liver morphology, since the presence of the splenic implants mitigated the effects of chemically-induced liver damage.

  5. Decreased apoptosis during CAR-mediated hepatoprotection against lithocholic acid-induced liver injury in mice.

    Science.gov (United States)

    Beilke, Lisa D; Aleksunes, Lauren M; Olson, Erik R; Besselsen, David G; Klaassen, Curtis D; Dvorak, Katerina; Cherrington, Nathan J

    2009-07-10

    Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of hepatoprotection. CAR(+/+) (WT) and CAR(-/-) (CAR-null) mice were pre-treated with compounds known to activate CAR prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Pre-treatment with the CAR activators phenobarbital (PB) and TCPOBOP (TC), as well as the non-CAR activator pregnenolone 16alpha-carbontrile (PCN), protected against LCA-induced liver injury in WT mice, whereas liver injury was more extensive without CAR (CAR-null). Unexpectedly, expression of anti-apoptotic Mcl-1 and Bcl-x(L) was not increased in hepatoprotected mice. Compared to unprotected groups, apoptosis was decreased in hepatoprotected mice as evidenced by the absence of cleaved caspase 3 (cCasp3). In contrast to the cytoplasmic localization in the injured livers (LCA and oltipraz), Mcl-1 protein was localized in the nucleus of hepatoprotected livers to potentially promote cell survival. This study demonstrates that although apoptosis is reduced in hepatoprotected mice pre-treated with CAR and non-CAR activators; hepatoprotection is not directly a result of CAR-induced Mcl-1 expression.

  6. Drug-induced Liver Injury is Frequently Associated with Severe Cutaneous Adverse Drug Reactions: Experience from Two Australian Tertiary Hospitals.

    Science.gov (United States)

    Fang, Wendy C; Adler, Nikki R; Graudins, Linda V; Goldblatt, Caitlin; Goh, Michelle Sy; Roberts, Stuart K; Trubiano, Jason A; Aung, Ar Kar

    2018-01-08

    Drug-induced liver injury can be associated with certain cutaneous adverse drug reactions. We aim to demonstrate the prevalence of drug-induced liver injury in patients with cutaneous adverse drug reactions. Severity and patterns of liver injury, risk factors, causal medications and outcomes are also examined. A retrospective cohort study of patients with cutaneous adverse drug reactions was conducted across two hospitals in Australia. Patients were identified through cross-linkage of multiple databases. 104 patients with cutaneous adverse drug reactions were identified. Of these, 33 (31.7%) had liver injury, representing 50% of patients with drug reaction with eosinophilia and systemic symptoms, and 30.2% of patients with Stevens-Johnson syndrome/toxic epidermal necrolysis. Most cases of liver injury (69.7%) were of a cholestatic/mixed pattern with severe disease in 18.2%. No significant risk factors for development of liver injury were noted, but peripheral lymphocytosis may represent a risk in patients with Stevens-Johnson syndrome (OR=6.0, 95% CI:1.8-19.7, p=0.003). Antimicrobials were the most common class to be implicated in drug-induced liver injury. The median length of inpatient stay was longer in patients with liver injury compared to those without (19 vs. 11 days, p=0.002). The mortality rate in those with liver injury was 15.2% and 9.9% in those without. No patients required liver transplantation. Drug-induced liver injury commonly occurs in patients with cutaneous adverse drug reactions and is associated with longer inpatient stay. Patients with Stevens-Johnson/toxic epidermal necrolysis and peripheral lymphocytosis appear to be at higher risk for developing associated liver injury. This article is protected by copyright. All rights reserved.

  7. Hepatoprotective activity of cinnamon ethanolic extract against CCI4-induced liver injury in rats

    Science.gov (United States)

    Eidi, Akram; Mortazavi, Pejman; Bazargan, Maryam; Zaringhalam, Jalal

    2012-01-01

    The inner bark of cinnamon (Cinnamomum zeylanicum L.) is commonly used as a spice and has also been widely employed in the treatment and prevention of disease. The aim of the present study is to evaluate the protective effect of cinnamon bark extract against carbon tetrachloride (CCl4)-induced liver damage in male Wistar rats. Administration with cinnamon extracts (0.01, 0.05 and 0.1 g/kg) for 28 days significantly reduced the impact of CCl4 toxicity on the serum markers of liver damage, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase. In addition, treatment of cinnamon extract resulted in markedly increased the levels of superoxide dismutase and catalase enzymes in rats. The histopathological studies in the liver of rats also supported that cinnamon extract markedly reduced the toxicity of CCl4 and preserved the histoarchitecture of the liver tissue to near normal. Thus, the results suggest that cinnamon extract acts as a potent hepatoprotective agent against CCl4 induced hepatotoxicity in rats. PMID:27547174

  8. 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

  9. 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

  10. Alleviation of Carbon-Tetrachloride-Induced Liver Injury and Fibrosis by Betaine Supplementation in Chickens.

    Science.gov (United States)

    Tsai, Meng-Tsz; Chen, Ching-Yi; Pan, Yu-Hui; Wang, Siou-Huei; Mersmann, Harry J; Ding, Shih-Torng

    2015-01-01

    Betaine is a food component with well-reported hepatoprotection effects. However, the effects and mechanisms of betaine on liver fibrosis development are still insufficient. Because metabolic functions of chicken and human liver is similar, we established a chicken model with carbon Tetrachloride- (CCl4-) induced fibrosis for studying antifibrotic effect of betaine in vivo and in vitro. Two-week-old male chicks were supplemented with betaine (1%, w/v) in drinking water for 2 weeks prior to the initiation of CCl4 treatment (i.p.) until sacrifice. Primary chicken hepatocytes were treated with CCl4 and betaine to mimic the in vivo supplementation. The supplementation of betaine significantly alleviated liver fibrosis development along with the inhibition of lipid peroxidation, hepatic inflammation cytokine, and transforming growth factor-β1 expression levels. These inhibitive effects were also accompanied with the attenuation of hepatic stellate cell activation. Furthermore, our in vitro studies confirmed that betaine provides antioxidant capacity for attenuating the hepatocyte necrosis by CCl4. Altogether, our results highlight the antioxidant ability of betaine, which alleviates CCl4-induced fibrogenesis process along with the suppression of hepatic stellate cells activation. Since betaine is a natural compound without toxicity, we suggest betaine can be used as a potent nutritional or therapeutic factor for reducing liver fibrosis.

  11. Alleviation of Carbon-Tetrachloride-Induced Liver Injury and Fibrosis by Betaine Supplementation in Chickens

    Directory of Open Access Journals (Sweden)

    Meng-Tsz Tsai

    2015-01-01

    Full Text Available Betaine is a food component with well-reported hepatoprotection effects. However, the effects and mechanisms of betaine on liver fibrosis development are still insufficient. Because metabolic functions of chicken and human liver is similar, we established a chicken model with carbon Tetrachloride- (CCl4- induced fibrosis for studying antifibrotic effect of betaine in vivo and in vitro. Two-week-old male chicks were supplemented with betaine (1%, w/v in drinking water for 2 weeks prior to the initiation of CCl4 treatment (i.p. until sacrifice. Primary chicken hepatocytes were treated with CCl4 and betaine to mimic the in vivo supplementation. The supplementation of betaine significantly alleviated liver fibrosis development along with the inhibition of lipid peroxidation, hepatic inflammation cytokine, and transforming growth factor-β1 expression levels. These inhibitive effects were also accompanied with the attenuation of hepatic stellate cell activation. Furthermore, our in vitro studies confirmed that betaine provides antioxidant capacity for attenuating the hepatocyte necrosis by CCl4. Altogether, our results highlight the antioxidant ability of betaine, which alleviates CCl4-induced fibrogenesis process along with the suppression of hepatic stellate cells activation. Since betaine is a natural compound without toxicity, we suggest betaine can be used as a potent nutritional or therapeutic factor for reducing liver fibrosis.

  12. 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.

  13. Experimental protoporphyria: effect of bile acids on liver damage induced by griseofulvin.

    Science.gov (United States)

    Martinez, María Del Carmen; Ruspini, Silvina Fernanda; Afonso, Susana Graciela; Meiss, Roberto; Buzaleh, Ana Maria; Batlle, Alcira

    2015-01-01

    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.

  14. Investigation of Hepatoprotective Activity of Induced Pluripotent Stem Cells in the Mouse Model of Liver Injury

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    Chih-Hung Chiang

    2011-01-01

    Full Text Available To date liver transplantation is the only effective treatment for end-stage liver diseases. Considering the potential of pluripotency and differentiation into tridermal lineages, induced pluripotent stem cells (iPSCs may serve as an alternative of cell-based therapy. Herein, we investigated the effect of iPSC transplantation on thioacetamide- (TAA- induced acute/fulminant hepatic failure (AHF in mice. Firstly, we demonstrated that iPSCs had the capacity to differentiate into hepatocyte-like cells (iPSC-Heps that expressed various hepatic markers, including albumin, α-fetoprotein, and hepatocyte nuclear factor-3β, and exhibited biological functions. Intravenous transplantation of iPSCs effectively reduced the hepatic necrotic area, improved liver functions and motor activity, and rescued TAA-treated mice from lethal AHF. 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate cell labeling revealed that iPSCs potentially mobilized to the damaged liver area. Taken together, iPSCs can effectively rescue experimental AHF and represent a potentially favorable cell source of cell-based therapy.

  15. An MLP classifier for prediction of HBV-induced liver cirrhosis using routinely available clinical parameters.

    Science.gov (United States)

    Cao, Yuan; Hu, Zhi-De; Liu, Xiao-Fei; Deng, An-Mei; Hu, Cheng-Jin

    2013-01-01

    Liver cirrhosis (LC) is the final stage of most of chronic liver diseases and is almost caused by chronic hepatitis B (CHB) in China. Liver biopsy is the reference method for the evaluation of liver cirrhosis. However, it is an invasive procedure with inherent risk. The aim of this study was to construct a new classifier based on the routine clinical markers for the prediction of HBV-induced LC. We collected routine clinical parameters from 124 LC patients with CHB and 115 with CHB. Training set (n = 120) and test set (n = 119) were built for model construction and evaluation, respectively. We describe a new classifier, MLP, for prediction of LC with CHB. MLP was built with seven routinely available clinical parameters, including age, ALT, AST, PT, PLT, HGB, and RDW. With optimal cutoff, we obtained a sensitivity of 95.2%, a specificity of 84.2%, and an overall accuracy of 89.9% on an independent test set, which were superior to those of FIB-4 and APRI. Our study suggests that the MLP classifier can be implemented for discriminating LC and non-LC cohorts by using machine learning method based on the routine available clinical parameters. It could be used for clinical practice in HBV-induced LC assessment.

  16. Dietary moderately oxidized oil induces expression of fibroblast growth factor 21 in the liver of pigs

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    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.

  17. 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

  18. PASS-Predicted Hepatoprotective Activity of Caesalpinia sappan in Thioacetamide-Induced Liver Fibrosis in Rats

    Directory of Open Access Journals (Sweden)

    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.

  19. Fresh garlic amelioration of high-fat-diet induced fatty liver in albino rats.

    Science.gov (United States)

    Qamar, Aisha; Siddiqui, Asma; Kumar, Hemant

    2015-10-01

    To observe the effect of fresh garlic on high-fat-diet-induced fatty liver changes. The experimental study was conducted at the Jinnah Postgraduate Medical Centre, Karachi, from October to November 2008, and comprised adult albino rats weighing 200-240g each. The rats were divided into 5 groups according to dietary regimen for eight weeks each. Group A received control diet; Group B received high saturated fat diet; Group C received high unsaturated fat diet; Group D received high saturated fat diet with fresh garlic; and Group E received high unsaturated fat diet with garlic for 8 weeks. Liver tissue slides were stained with Oil red-O and haematoxylin and Periodic acid-Schiff-haematoxylin. The 50 rats in the study were divided into five groups of 10(20%) each. There was marked deposition of fat in hepatocyte along with marked decrease in glycogen content in liver of rats in Groups B and C, with Group B showing more marked changes. The changes in fat and glycogen content were reversed and ameliorated close to Group A in rats belonging to Groups D and E. Fresh garlic minimised the high-fat-diet-induced fatty liver changes in rats.

  20. Sulforaphane Induces Nrf2 and Protects Against CYP2E1-dependent Binge Alcohol –induced Liver Steatosis

    Science.gov (United States)

    Zhou, Richard; Lin, Jianjun; Wu, Defeng

    2013-01-01

    Background The mechanism(s) by which alcohol causes cell injury are still not clear but a major mechanism appears to be the role of lipid peroxidation and oxidative stress in alcohol toxicity. CYP2E1-generated ROS contributes to the ethanol-induced oxidant stress and inhibition of CYP2E1 activity decreases ethanol-induced fatty liver. The transcription factor Nrf2 regulates the expression of many cytoprotective enzymes which results in cellular protection against a variety of toxins. Method The current study was designed to evaluate the ability of sulforaphane, an activator of Nrf2, to blunt CYP2E1-dependent, ethanol-induced steatosis in vivo and in vitro. Results The sulforaphane treatment activated Nrf2, increased levels of the Nrf2 target heme oxygenase -1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-Nitrotyrosine protein adducts and an increase in GSH levels after the acute ethanol treatment. It decreased ethanol-elevated liver levels of triglycerides and cholesterol and Oil Red O staining. Similar results were found in vitro as addition of sulforaphane to HepG2 E47 cells, which express CYP2E1, elevated Nrf2 levels and decreased the accumulation of lipid in cells cultured with ethanol. Sulforaphane treatment had no effect on levels of or activity of CYP2E1. Conclusions Sulforaphane proved to be an effective in vivo inhibitor of acute ethanol–induced fatty liver in mice. General significance The possible amelioration of liver injury which occurs under these conditions by chemical activators of Nrf2 is of clinical relevance and worthy of further study. PMID:24060752

  1. Sulforaphane induces Nrf2 and protects against CYP2E1-dependent binge alcohol-induced liver steatosis.

    Science.gov (United States)

    Zhou, Richard; Lin, Jianjun; Wu, Defeng

    2014-01-01

    The mechanism(s) by which alcohol causes cell injury are still not clear but a major mechanism appears to be the role of lipid peroxidation and oxidative stress in alcohol toxicity. CYP2E1-generated ROS contributes to the ethanol-induced oxidant stress and inhibition of CYP2E1 activity decreases ethanol-induced fatty liver. The transcription factor Nrf2 regulates the expression of many cytoprotective enzymes which results in cellular protection against a variety of toxins. The current study was designed to evaluate the ability of sulforaphane, an activator of Nrf2, to blunt CYP2E1-dependent, ethanol-induced steatosis in vivo and in vitro. The sulforaphane treatment activated Nrf2, increased levels of the Nrf2 target heme oxygenase-1 and subsequently lowered oxidant stress as shown by the decline in lipid peroxidation and 3-nitrotyrosine protein adducts and an increase in GSH levels after the acute ethanol treatment. It decreased ethanol-elevated liver levels of triglycerides and cholesterol and Oil Red O staining. Similar results were found in vitro as addition of sulforaphane to HepG2 E47 cells, which express CYP2E1, elevated Nrf2 levels and decreased the accumulation of lipid in cells cultured with ethanol. Sulforaphane treatment had no effect on levels of or activity of CYP2E1. Sulforaphane proved to be an effective in vivo inhibitor of acute ethanol-induced fatty liver in mice. The possible amelioration of liver injury which occurs under these conditions by chemical activators of Nrf2 is of clinical relevance and worthy of further study. © 2013.

  2. Participation of nuclear factor (erythroid 2-related), factor 2 in ameliorating lithocholic acid-induced cholestatic liver injury in mice.

    Science.gov (United States)

    Tan, K P; Wood, G A; Yang, M; Ito, S

    2010-11-01

    Lithocholic acid (LCA), the most toxic bile acid, induces cholestatic liver injury in rodents. We previously showed that LCA activates the oxidative stress-responsive nuclear factor (erythroid-2 like), factor 2 (Nrf2) in cultured liver cells, triggering adaptive responses that reduce cell injury. In this study, we determined whether Nrf2 protects the liver against LCA-induced toxicity in vivo. Nrf2 disrupted (Nrf2(-/-) ) and wild-type mice were treated with LCA (125 mg·kg(-1) body weight) to induce liver injury. Levels of mRNA, protein and function of important Nrf2 target genes coupled with liver histology and injury biomarkers of mice were examined. In 4 day LCA treatments, we observed a significantly higher hepatic induction of Nrf2 target, cytoprotective genes including thioredoxin reductase 1, glutamate cysteine ligase subunits, glutathione S-transferases, haeme oxygenase-1 and multidrug resistance-associated proteins 3 and 4 in the wild type as compared with the Nrf2(-/-) mice. Moreover, basal and LCA-induced hepatic glutathione and activities of glutathione S-transferases and thioredoxin reductases were higher in wild-type than in Nrf2(-/-) mice. This reduced production of cytoprotective genes against LCA toxicity rendered Nrf2(-/-) mice more susceptible to severe liver damage with the presence of multifocal liver necrosis, inflamed bile ducts and elevation of lipid peroxidation and liver injury biomarkers, such as alanine aminotransferase and alkaline phosphatase. Nrf2 plays a crucial cytoprotective role against LCA-induced liver injury by orchestrating adaptive responses. The pharmacological potential of targeting liver Nrf2 in the management of cholestatic liver diseases is proposed. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

  3. 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

  4. Role of gamma-irradiated Rosemary against Ethanol Induced Liver Injury in Rats

    International Nuclear Information System (INIS)

    Hamzaa, R.G.; El shahat, A.N.; Mekawey, H.M.S.

    2013-01-01

    Among natural antioxidants, rosemary contains several antioxidant oil and phenolic compounds that may be possessed hepato protective effect. This study aimed to investigate the effect of dietary supplementation with gamma irradiated rosemary on ethanol induced liver injury in rats. Rosemary essential oil was analyzed by gas chromatography/mass spectrometry (GC/MS). The results of biological study revealed that dietary supplementation of either raw or gamma-irradiated rosemary following ethanol administration exerts remarkable modulating effect by reducing the level of total bilirubin, the activity of transaminases, gamma glutamyl transferase and serum alkaline phosphatase, decreasing the concentration of some lipid fractions and malondialdehyde content and xanthine oxidase activity. Also, supplementation of dietary rosemary induced an increase of high density lipoprotein and reduced glutathione content and enhances the activity of xanthine dehydrogenase, superoxide dismutase and catalase activities. Thus, gamma-irradiated rosemary could be incorporated to the diet as a nutritional supplement, to augment the liver's defenses against oxidative stress

  5. 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...... performed in 239 patients with acetaminophen intoxication and a peak alanine aminotransferase (ALT) level above 1000 U/L. AFP was measured using an enzyme-linked immunoassay (EIA) with a detection limit below 0.4 microg/L. The optimum threshold of AFP to discriminate nonsurvivors was identified. An increase......%. In conclusion, an increase in AFP was strongly associated with a favorable outcome in patients with acetaminophen-induced liver injury. AFP may be useful as a supplement to existing prognostic criteria. We suggest that the introduction of highly sensitive EIAs for the detection of AFP will require...

  6. 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.

  7. Hepatectomy After Yttrium-90 (Y90) Radioembolization-Induced Liver Fibrosis.

    Science.gov (United States)

    Maker, Ajay V; August, Carey; Maker, Vijay K; Weisenberg, Elliot

    2016-04-01

    survival in patients with neuroendocrine liver metastases; however, hepatectomy after radioembolization is unique and carries increased morbidity/mortality, likely due to Y90-induced liver fibrosis. We demonstrate images of fibrotic yttrium-90 radiation-affected liver and histological sections of radioembolic microbeads in blood vessels and distributed around resected tumors.

  8. 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.

  9. Fetal Abuse.

    Science.gov (United States)

    Kent, Lindsey; And Others

    1997-01-01

    Five cases of fetal abuse by mothers suffering from depression are discussed. Four of the women had unplanned pregnancies and had considered termination of the pregnancy. Other factors associated with fetal abuse include pregnancy denial, pregnancy ambivalence, previous postpartum depression, and difficulties in relationships. Vigilance for…

  10. 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 ...

  11. Hepatoprotective effects of licochalcone B on carbon tetrachloride-induced liver toxicity in mice

    Directory of Open Access Journals (Sweden)

    Haifeng Teng

    2016-08-01

    Full Text Available Objective(s: The objective of this study was to investigate the hepatoprotective effect of licochalcone B (LCB in a mice model of carbon tetrachloride (CCl4-induced liver toxicity. Materials and Methods: Hepatotoxicity was induced in mice by a single subcutaneous injection (SC of CCl4. The LCB was administered orally once a day for seven days (PO as pretreatment at three doses of 1, 5, and 25 mg/kg/day. The levels of superoxide dismutase (SOD, malondialdehyde (MDA, glutathione (GSH, glutathione disulfide (GSSG, C-reactive protein (CRP, tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, alanine aminotransferase (ALT and aspartate aminotransferase (AST were analyzed by ELISA. The protein expression degrees of p38 mitogen activated protein kinases (p38 and nuclear factor-k-gene binding (NF-κB were assayed by western blotting. Results: CCl4-induced hepatotoxicity was manifested by an increase in the levels of ALT, AST, MDA, IL-6, CRP, and TNF-ɑ, and a decrease in the SOD level and GSH/GSSG ratio in the serum. The histopathological examination of the liver sections revealed necrosis and inflammatory reactions. Pretreatment with LCB decreased the levels of ALT, AST, MDA, GSSG, IL-6, CRP, TNF-ɑ, and the protein expression of p38 and NF-κB, increased the level of SOD and GSH, and normalized the hepatic histo-architecture. Conclusion: LCB protected the liver from CCl4-induced injury. Protection may be due to inhibition of p38 and NFκB signaling, which subsequently reduced inflammation in the liver.

  12. Histopathologic Evaluation of Nonalcoholic Fatty Liver Disease in Hypothyroidism-Induced Rats

    OpenAIRE

    Demir, Şule; Ünübol, Mustafa; Aypak, Serap Ünübol; İpek, Emrah; Aktaş, Serdar; Ekren, Gamze Sevri; Yılmaz, Murat; Tunca, Recai; Güney, Engin

    2016-01-01

    It is speculated that thyroid hormones may be involved in nonalcoholic fatty liver disease (NAFLD) pathogenesis. A literature scan, however, demonstrated conflicting results from studies investigating the relationship between hypothyroidism and NAFLD. Therefore, our study aims to evaluate NAFLD, from the histopathologic perspective, in hypothyroidism-induced rats. Wistar rats were divided into 2 groups: the experimental group consumed water containing methimazole 0.025% (MMI, Sigma, USA) for ...

  13. 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

  14. 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

  15. 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.

  16. Protective Effect of Bicyclol on Anti-Tuberculosis Drug Induced Liver Injury in Rats

    Directory of Open Access Journals (Sweden)

    Xin Liu

    2017-04-01

    Full Text Available The present study was performed to investigate the effect of bicyclol, a synthetic anti-hepatitis drug with anti-oxidative and anti-inflammatory properties, on anti-tuberculosis (anti-TB drug-induced liver injury and related mechanisms in rats. Bicyclol was given to rats by gavage 2 h before the oral administration of an anti-TB drug once a day for 30 days. Liver injury was evaluated by biochemical and histopathological examinations. Lipid peroxidation, mitochondrial function, and the activity of antioxidants were measured by spectrophotometric methods. Cytokines expression and CYP2E1 activity were determined by ELISA assay and liquid chromatography–tandem mass spectrometry (LC–MS/MS analysis. The expressions of hepatic CYP2E1 and hepatocyte growth factor (HGF were assessed by Western blotting. As a result, bicyclol significantly protected against anti-TB drug-induced liver injury by reducing the elevated serum aminotransferases levels and accumulation of hepatic lipids. Meanwhile, the histopathological changes were also attenuated in rats. The protective effect of bicyclol on anti-TB drug-induced hepatotoxicity was mainly due to its ability to attenuate oxidative stress, suppress the inflammatory cytokines and CYP2E1 expression, up-regulate the expression of HGF, and improve mitochondrial function. Furthermore, administration of bicyclol had no significant effect on the plasma pharmacokinetics of the anti-TB drug in rats.

  17. Hepatocyte Turnover in Chronic HCV-Induced Liver Injury and Cirrhosis

    Directory of Open Access Journals (Sweden)

    Nikolaos P. Karidis

    2015-01-01

    Full Text Available Chronic hepatitis C virus (HCV infection may eventually lead to progressive liver fibrosis and cirrhosis through a complex, multistep process involving hepatocyte death and regeneration. Despite common pathogenetic pathways present in all forms of liver cirrhosis irrespective of etiology, hepatocyte turnover and related molecular events in HCV-induced cirrhosis are increasingly being distinguished from even “similar” causes, such as hepatitis B virus- (HBV- related cirrhosis. New insights in HCV-induced hepatocellular injury, differential gene expression, and regenerative pathways have recently revealed a different pattern of progression to irreversible parenchymal liver damage. A shift to the significant role of the host immune response rather than the direct effect of HCV on hepatocytes and the imbalance between antiapoptotic and proapoptotic signals have been investigated in several studies but need to be further elucidated. The present review aims to comprehensively summarize the current evidence on HCV-induced hepatocellular turnover with a view to outline the significant trends of ongoing research.

  18. Protective effect of thymoquinone against lead-induced antioxidant defense system alteration in rat liver.

    Science.gov (United States)

    Mabrouk, Aymen

    2017-09-01

    Alteration of the antioxidant system may be related to lead (Pb) hepatotoxicity. This study was carried out to investigate the possible beneficial effect of thymoquinone (TQ), the major active ingredient of volatile oil of Nigella sativa seeds, against Pb-induced liver antioxidant defense system impairment. Adult male rats were randomized into four groups: control group received no treatment, Pb group was exposed to 2000 ppm of Pb acetate in drinking water, Pb-TQ group was cotreated with Pb plus TQ (5 mg/kg/day, per os) and TQ group receiving only TQ. All treatments were applied for five weeks. TQ alone did not induce any significant changes in the enzymatic and non-enzymatic antioxidant status. By contrast, Pb exposure significantly decreased not only reduced glutathione level, but also superoxide dismutase, glutathione peroxidase, catalase and glutathione reductase activities in the liver tissue. Interestingly, when coadministrated with Pb, TQ significantly improved the affected antioxidant parameters. In conclusion, our results indicate a protective effect of TQ against Pb-induced liver antioxidant capacity impairment and suggest that this component might be a clinically promising alternative in Pb hepatotoxicity.

  19. Protective effect of linalool against lipopolysaccharide/D-galactosamine-induced liver injury in mice.

    Science.gov (United States)

    Li, Jingyuan; Zhang, Xiaoyu; Huang, Haiying

    2014-12-01

    Linalool, a natural compound of the essential oils, has been shown to have antinociceptive, antimicrobial, and anti-inflammatory properties. The aim of this study was to investigate the effects of linalool against lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced liver injury in mice. Mice were administered with linalool 1h before receiving LPS (50 μg/kg) and GalN (800 mg/kg). The results demonstrated that linalool had a protective effect on LPS/GalN-induced acute liver injury, as evidenced by the attenuation of hepatic pathological damage, malondialdehyde (MDA) content, MPO activity and serum ALT and AST levels. Linalool alleviated serum and hepatic TNF-α and IL-6 production, as well as hepatic iNOS and COX-2 expression by inhibiting NF-κB activation. Treatment of linalool increased bcl-2 expression and inhibited caspase-3 and caspase-8 expression. In addition, linalool increased Nrf2 and heme oxygenase-1 expression up-regulation by LPS/GalN. In conclusion, our results suggested that linalool was protected against LPS/GalN-induced liver injury through induction of antioxidant defense via Nrf2 activating and reduction inflammatory response via NF-κB inhibition. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. 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.

  1. Putrescine treatment reverses α-tocopherol-induced desynchronization of polyamine and retinoid metabolism during rat liver regeneration

    Directory of Open Access Journals (Sweden)

    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

  2. Putrescine treatment reverses α-tocopherol-induced desynchronization of polyamine and retinoid metabolism during rat liver regeneration.

    Science.gov (United States)

    Sánchez-Sevilla, Lourdes; Mendieta-Condado, Edgar; Hernández-Muñoz, Rolando

    2016-10-26

    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. 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. 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. Putrescine counteracted most adverse actions exerted by α-tocopherol on rat liver regeneration, restoring liver proliferative potential and restituting the decreased retinoid levels induced by α-tocopherol. Therefore interactions

  3. Portulaca oleracea L. alleviates liver injury in streptozotocin-induced diabetic mice

    Directory of Open Access Journals (Sweden)

    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

  4. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

    International Nuclear Information System (INIS)

    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

  5. Exogenous normal lymph reduces liver injury induced by lipopolysaccharides in rats

    Energy Technology Data Exchange (ETDEWEB)

    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.

  6. 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

  7. 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

  8. Fetal rat metabonome alteration by prenatal caffeine ingestion probably due to the increased circulatory glucocorticoid level and altered peripheral glucose and lipid metabolic pathways

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    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

  9. Clinical Characteristics in Patients with Liver Cirrhosis Induced by HBV Infection and Combined with Mild Alcohol Intake

    Directory of Open Access Journals (Sweden)

    Xiaerfuhazi Ha-lida

    2014-09-01

    Full Text Available Objective To investigate the differences of clinical and biochemical characteristics between patients with liver cirrhosis induced by HBV infection combined with and without mild alcohol intake.

  10. Ginseng essence, a medicinal and edible herbal formulation, ameliorates carbon tetrachloride-induced oxidative stress and liver injury in rats

    Directory of Open Access Journals (Sweden)

    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.

  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. Neurotrophic peptides, ADNF-9 and NAP, prevent alcohol-induced apoptosis at midgestation in fetal brains of C57BL/6 mouse.

    Science.gov (United States)

    Sari, Youssef; Weedman, Jason M; Nkrumah-Abrokwah, Maxwell

    2013-01-01

    Prenatal alcohol exposure is known to induce fetal brain growth deficits at different embryonic stages. We focused this study on investigating the neuroprotective effects against alcohol-induced apoptosis at midgestation using activity-dependent neurotrophic factor (ADNF)-9, a peptide (SALLRSIPA) derived from activity-dependent neurotrophic factor, and NAP, a peptide (NAPVSIPQ) derived from activity-dependent neuroprotective protein. We used an established fetal alcohol exposure mouse model. On embryonic day 7 (E7), weight-matched pregnant females were assigned to the following groups: (1) ethanol liquid diet (ALC) group with 25 % (4.49 %, v/v) ethanol-derived calories, (2) pair-fed (PF) control group, (3) ALC combined with i.p. injections (1.5 mg/kg) of ADNF-9 (ALC/ADNF-9) group, (4) ALC combined with i.p. injections (1.5 mg/kg) of NAP (ALC/NAP) group, (5) PF liquid diet combined with i.p. injections of ADNF-9 (PF/ADNF-9) group, and (6) PF liquid diet combined with i.p. injections of NAP (PF/NAP) group. On day 15 (E15), fetal brains were collected, weighed, and assayed for TdT-mediated dUTP nick end labeling (TUNEL) staining. ADNF-9 or NAP was administered daily from E7 to E15 alongside PF or ALC liquid diet exposure. Our results show that NAP and ADNF-9 significantly prevented alcohol-induced weight reduction of fetal brains. Apoptosis was determined by TUNEL staining; NAP or ADNF-9 administration alongside alcohol exposure significantly prevented alcohol-induced increase in TUNEL-positive cells in primordium of the cingulate cortex and ganglionic eminence. These findings may pave the path toward potential therapeutics against alcohol intoxication during pregnancy stages.

  13. Do clinical and laboratory parameters effect maternal and fetal outcomes in pregnancies complicated with hemolysis, elevated liver enzymes, and low platelet count syndrome?

    Science.gov (United States)

    Bezircioğlu, Incim; Baloğlu, Ali; Cetinkaya, Burcu; Pirim, Betül

    2012-01-01

    The aim of the study was to investigate whether the clinical features and laboratory parameters affect maternal and fetal outcomes in pregnancies complicated with HELLP syndrome. The medical records of pregnant patients complicated with HELLP syndrome were analyzed retrospectively between June 01, 2003 and June 01, 2010. The demographic data, medical history, admission symptoms, clinical and laboratory findings and recovery time were evaluated. The adverse maternal outcomes including eclampsia, placental abruption, disseminated intravascular coagulation, postpartum hemorrhage, pulmonary complications, cerebral edema and visual loss were recorded. Fetal growth restriction, necessity for neonatal intensive care unit admission and perinatal mortality were recorded as an adverse fetal outcome. The incidence of HELLP syndrome was 0.52%. The mean age of the patients was 28.93±7.90 (range 17-45). HELLP syndrome was diagnosed on average in the 33.68±4.41(th) (ranged 24-40) week of gestation. Eighteen cases (40.9%) were nullipara and twenty-six cases (59.1%) multipara. The most common complications were eclampsia (40.9%) and abruption placenta (15.9%). Pregnancy was terminated within 48 hours in all patients. The rate of cesarean section was 90.9%. Perinatal mortality rate in HELLP syndrome was 31.8%. There was no maternal mortality. Neither clinical characteristics nor laboratory parameters was found effective for prediction of adverse maternal and fetal outcomes.

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

    Science.gov (United States)

    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.

  15. Serum acute phase reactants hallmark healthy individuals at risk for acetaminophen-induced liver injury.

    Science.gov (United States)

    Borlak, Jürgen; Chatterji, Bijon; Londhe, Kishor B; Watkins, Paul B

    2013-01-01

    Acetaminophen (APAP) is a commonly used analgesic. However, its use is associated with drug-induced liver injury (DILI). It is a prominent cause of acute liver failure, with APAP hepatotoxicity far exceeding other causes of acute liver failure in the United States. In order to improve its safe use this study aimed to identify individuals at risk for DILI prior to drug treatment by searching for non-genetic serum markers in healthy subjects susceptible to APAP-induced liver injury (AILI). Healthy volunteers (n = 36) received either placebo or acetaminophen at the maximum daily dose of 4 g for 7 days. Blood samples were taken prior to and after APAP treatment. Serum proteomic profiling was done by 2D SDS-PAGE and matrix-assisted laser desorption/ionization-time of flight-mass spectrometry. Additionally, the proteins C-reactive protein, haptoglobin and hemopexin were studied by quantitative immunoassays. One-third of study subjects presented more than four-fold increased alanine transaminase activity to evidence liver injury, while serum proteomics informed on 20 proteins as significantly regulated. These function primarily in acute phase and immune response. Pre-treatment associations included C-reactive protein, haptoglobin isoforms and retinol binding protein being up to six-fold higher in AILI susceptible individuals, whereas alpha1-antitrypsin, serum amyloid A, kininogen and transtyretin were regulated by nearly five-fold in AILI responders. When compared with published findings for steatohepatitis and cases of hepatocellular, cholestatic and mixed DILI, 10 proteins were identified as uniquely associated with risk for AILI, including plasminogen. Notably, this zymogen facilitates macrophage chemotactic migration and inflammatory response as reported for plasminogen-deficient mice shown to be resistant to APAP hepatotoxicity. Finally, analysis of a publicly available database of gene expression profiles of cultures of human hepatocytes treated with drugs

  16. 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

  17. 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

  18. Antioxidants as recipes for efavirenz-induced liver damage: A study in albino rats

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    Elias Adikwu

    2018-03-01

    Full Text Available Objective: Hepatotoxicity is a clinical challenge associated with the use of efavirenz (EFV. This study investigated the effects of n-acetylcysteine (NAC, vitamins C and E on EFV-induced hepatotoxicity in albino rats. Methods: Rats were divided into groups and administered with NAC (20mg/kg, Vit C (50mg/kg, Vit  E (50mg/kg, Vit C+ E and 60mg/kg of EFV respectively. Rats were also divided into groups and pretreated with NAC, Vit C, E, and combined doses of Vit C+E prior to treatment with EFV for 15 days respectively. After drug administration rats were sacrificed and serum was collected and evaluated for liver function parameters. Rats were dissected, liver was collected weighed and evaluated for alkaline phosphatase (ALP, alanine aminotransferase (AST, aspartate aminotransferase (ALT, gamma glutamyl transferase (GGT, lactate dehydrogenase (LDH, malondialdehyde (MDA, super oxide dismutase (SOD, catalase (CAT, glutathione (GSH, gluthatione peroxidase (GPX levels and pathological damage. Results: Effects were not significant (p>0.05 on body and liver weights, however, the levels of AST, ALT, AST, GGT, LDH, CB, TB and MDA were increased significantly (p<0.05 whereas SOD, CAT, SOD, GSH and GPX were decreased significantly (p<0.05 in EFV-treated rats in comparison to control. The liver of EFV-treated rats showed necrosis of hepatocytes. Nevertheless, EFV-induced alterations in the above parameters were significantly (p<0.05 ameliorated in antioxidants pretreated rats.  The combined doses of Vit C and E produced the best and significant (p<0.05 ameliorative effects in comparison to their individual doses. Conclusion: This study shows the prospects of antioxidants as candidates for the treatments of efavirenz-induced hepatotoxicity.

  19. New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure.

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    Nélson R Carvalho

    Full Text Available The acute liver failure (ALF induced by acetaminophen (APAP is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe2 to the N-acetylcysteine (NAC during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg, (PhSe2 (15.6 mg/kg, NAC (1200 mg/kg, APAP+(PhSe2 or APAP+NAC, where the (PhSe2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe2. The effectiveness of (PhSe2 was similar at a lower dose than NAC. In summary, (PhSe2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced.

  20. Parboiled Germinated Brown Rice Protects Against CCl4-Induced Oxidative Stress and Liver Injury in Rats.

    Science.gov (United States)

    Wunjuntuk, Kansuda; Kettawan, Aikkarach; Charoenkiatkul, Somsri; Rungruang, Thanaporn

    2016-01-01

    Parboiled germinated brown rice (PGBR) of Khao Dawk Mali 105 variety was produced by steaming germinated paddy rice, which is well-known for its nutrients and bioactive compounds. In this study we determined the in vivo antioxidant and hepatoprotective effects of PGBR in carbon tetrachloride (CCl(4))-induced oxidative stress in rats. Male Sprague-Dawley rats, (weight 200-250 g) were randomly divided into (1) control, (2) CCl(4), (3) white rice (WR)+CCl(4), (4) brown rice (BR)+CCl(4), and (5) PGBR+CCl(4) groups. PGBR, BR, and WR diets were produced by replacing corn starch in the AIN76A diet with cooked PGBR, BR, and WR powders, respectively. All rats except the control group were gavaged with 50% CCl4 in olive oil (v/v, 1 mL/kg) twice a week for 8 weeks. CCl(4)-treated rats exhibited significant liver injury, lipid peroxidation, protein oxidation, and DNA damage, as well as obvious changes to liver histopathology compared to control. In addition, CCl(4) treatment decreased the activities of CYP2E1 and antioxidant enzymes: glutathione S-transferase, glutathione peroxidase, superoxide dismutase and catalase, and glutathione (GSH) content. However, the PGBR+CCl(4) group exhibited less liver injury, lipid peroxidation, protein oxidation, and DNA damage, as well as better antioxidant enzyme activities and GSH content. Furthermore, PGBR inhibited degradation of CYP2E1 in CCl(4)-induced decrease of CYP2E1 activity. These data suggest that PGBR may prevent CCl(4)-induced liver oxidative stress and injury through enhancement of the antioxidant capacities, which may be due to complex actions of various bioactive compounds, including phenolic acids, γ-oryzanol, tocotrienol, and GABA.

  1. Oxidative stress modulation by Rosmarinus officinalis in CCl4-induced liver cirrhosis.

    Science.gov (United States)

    Gutiérrez, Rosalinda; Alvarado, José L; Presno, Manuel; Pérez-Veyna, Oscar; Serrano, Carmen J; Yahuaca, Patricia

    2010-04-01

    Rosmarinus officinalis (Lamiaceae) possesses antioxidant activity and hepatoprotective effects, and so may provide a possible therapeutic alternative for chronic liver disease. The effect produced by a methanolic extract of Rosmarinus officinalis on CCl(4)-induced liver cirrhosis in rats was investigated using both prevention and reversion models. Over the course of the development of cirrhosis, the increased enzymatic activities of gamma-glutamyl transpeptidase and alanine aminotransferase, and the rise in bilirubin levels caused by CCl(4) administration, were prevented by Rosmarinus officinalis co-administration. When the cirrhosis by oxidative stress was evaluated as an increase on liver lipoperoxidation, total lipid peroxides, nitric oxide in serum, and loss of erythrocyte plasma membrane stability, R. officinalis was shown to prevent such alterations. On cirrhotic animals treated with CCl(4), histological studies showed massive necrosis, periportal inflammation and fibrosis which were modified by R. officinalis. These benefits on experimental cirrhosis suggest a potential therapeutic use for R. officinalis as an alternative for liver cirrhosis. Copyright (c) 2009 John Wiley & Sons, Ltd.

  2. Protective function of complement against alcohol-induced rat liver damage.

    Science.gov (United States)

    Bykov, Igor L; Väkevä, Antti; Järveläinen, Harri A; Meri, Seppo; Lindros, Kai O

    2004-11-01

    The complement system can promote tissue damage or play a homeostatic role in the clearance and disposal of damaged tissue. We assessed the role of the terminal complement pathway in alcohol-induced liver damage in complement C6 (C6-/-) genetically deficient rats. C6-/- and corresponding C6+/+ rats were continuously exposed to ethanol by feeding ethanol-supplemented liquid diet for six weeks. Liver samples were analyzed for histopathology and complement component deposition by immunofluorescence microscopy. Prostaglandin E receptors and cytokine mRNA levels were analyzed by RT-PCR and plasma cytokines by ELISA. Deposition of complement components C1, C3, C8 and C9 was observed in C6+/+ rats, but not in C6-/- animals. The histopathological changes, the liver weight increase and the elevation of the plasma pro-/anti-inflammatory TNF-alpha/IL-10 ratio were, on the other hand, more marked in C6-/- rats. Furthermore, ethanol enhanced the hepatic mRNA expression of the prostaglandin E receptors EP2R and EP4R exclusively in the C6-/- rats. Our results indicate that a deficient terminal complement pathway predisposes to tissue injury and promotes a pro-inflammatory cytokine response. This suggests that an intact complement system has a protective function in the development of alcoholic liver damage.

  3. Efficacy of Boesenbergia rotunda Treatment against Thioacetamide-Induced Liver Cirrhosis in a Rat Model

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    Suzy M. Salama

    2012-01-01

    Full Text Available Background. Experimental research in hepatology has focused on developing traditional medicines into potential pharmacological solutions aimed at protecting liver from cirrhosis. Along the same line, this study investigated the effects of ethanol-based extract from a traditional medicine plant Boesenbergia rotunda (BR on liver cirrhosis. Methodology/Results. The BR extract was tested for toxicity on 3 groups of rats subjected to vehicle (10% Tween 20, 5 mL/kg and 2g/kg and 5g/kg doses of the extract, respectively. Next, experiments were conducted on a rat model of cirrhosis induced by thioacetamide injection. The rats were divided into five groups and, respectively, administered orally with 10% Tween-20 (5 mL/kg (normal control group, 10% Tween-20 (5 mL/kg (cirrhosis control group, 50 mg/kg of silymarin (reference control group, and 250 mg/kg and 500 mg/kg of BR extract (experimental groups daily for 8 weeks. The rats in normal group were intraperitoneally injected with sterile distilled water (1 mL/kg 3 times/week, and those in the remaining groups were injected intraperitoneally with thioacetamide (200 mg/kg thrice weekly. At the end of the 8 weeks, the animals were sacrificed and samples were collected for comprehensive histopathological, coagulation profile and biochemical evaluations. Also, the antioxidant activity of the BR extract was determined and compared with that of silymarin. Data from the acute toxicity tests showed that the extract was safe to use. Histological analysis of the livers of the rats in cirrhosis control group revealed uniform coarse granules on their surfaces, hepatocytic necrosis, and lymphocytes infiltration. But, the surfaces morphologically looked much smoother and the cell damage was much lesser in those livers from the normal control, silymarin and BR-treated groups. In the high-dose BR treatment group, the livers of the rats exhibited nearly normal looking lobular architecture, minimal inflammation

  4. Chronic administration of Satsuma mandarin fruit (Citrus unshiu Marc.) improves oxidative stress in streptozotocin-induced diabetic rat liver.

    Science.gov (United States)

    Sugiura, Minoru; Ohshima, Makoto; Ogawa, Kazunori; Yano, Masamichi

    2006-03-01

    Fruits and vegetables contain numerous antioxidants such as carotenoids, vitamins, and phenolic phytochemicals. Recent studies have demonstrated that antioxidants may reduce the risk for diabetes or its complications. In this study, we investigated the effects of the chronic administration of Satsuma mandarin fruit on an antioxidant defense system in streptozotocin (STZ)-induced diabetic rat liver. After a ten-week administration of Satsuma mandarin, antioxidant enzymes and glutathione levels in the liver were evaluated. The superoxide dismutase (SOD), catalase, and glutathione-peroxidase (GPx) activities, and glutathione level in the STZ-induced diabetic rats liver decreased significantly compared with those in the age-matched normal rats. The glutathione-reductase (GR) activities did not differ significantly between these two groups. In contrast, the SOD, GR, and glutathione levels in the Satsuma mandarin (1% or 3%) diet-fed STZ-diabetic rat livers were significantly higher than those in the normal diet-fed STZ-diabetic rat livers. In addition, although the serum alanine aminotransferase and gamma-glutamyl-aminotransferase concentrations of normal diet-fed STZ-diabetic rats were significantly higher than those of the age-matched normal rats, these increments of serum liver enzymes were diminished by the chronic administration of Satsuma mandarin. These results suggest that Satsuma mandarin may act as a suppressor against liver cell damage and inhibit the progression of liver dysfunction induced by chronic hyperglycemia.

  5. 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

  6. Hepatic Differentiation of Human Induced Pluripotent Stem Cells in a Perfused 3D Porous Polymer Scaffold for Liver Tissue Engineering

    DEFF Research Database (Denmark)

    Hemmingsen, Mette; Muhammad, Haseena Bashir; Mohanty, Soumyaranjan

    A huge shortage of liver organs for transplantation has motivated the research field of tissue engineering to develop bioartificial liver tissue and even a whole liver. The goal of NanoBio4Trans is to create a vascularized bioartificial liver tissue, initially as a liver-support system. Due...... to limitations of primary hepatocytes regarding availability and maintenance of functionality, stem cells and especially human induced pluripotent stem cells (hIPS cells) are an attractive cell source for liver tissue engineering. The aim of this part of NanoBio4Trans is to optimize culture and hepatic...... differentiation of hIPS-derived definitive endoderm (DE) cells in a 3D porous polymer scaffold built-in a perfusable bioreactor. The use of a microfluidic bioreactor array enables the culture of 16 independent tissues in one experimental run and thereby an optimization study to be performed....

  7. Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-α and prevents early alcohol-induced liver injury in mice

    DEFF Research Database (Denmark)

    Ge, Xiadong; Leung, Tung-Ming; Arriazu, Elena

    2014-01-01

    , tumor necrosis factor-α (TNFα) production, and liver injury. Since OPN is protective for the intestinal mucosa, we postulated that enhancing OPN expression in the liver and consequently in the blood and/or in the gut could protect from early alcohol-induced liver injury. Wild-type (WT), OPN knockout...... score, and the number of macrophages and TNFα+ cells. To establish if OPN could limit LPS availability and its noxious effects in the liver, binding studies were performed. OPN showed binding affinity for LPS which prevented macrophage activation, reactive oxygen, and nitrogen species generation...... by decreased liver-to-body weight ratio, hepatic triglycerides, the steatosis score, oil red-O staining, and lipid peroxidation. There was also less inflammation and liver injury as demonstrated by lower alanine aminotransferase (ALT) activity, hepatocyte ballooning degeneration, LPS levels, the inflammation...

  8. Precision-cut mouse liver slices as an ex vivo model to study the mechanism of inflammatory stress-related idiosyncratic drug-induced liver injury

    NARCIS (Netherlands)

    Hadi, Mackenzie; Chen, Y.; Starokozhko, Viktoriia; Merema, Maja; Groothuis, Genoveva

    2012-01-01

    Idiosyncratic drug reactions (IDRs) can be defined as adverse drug reactions that occur in a small minority of the patients taking clinically-relevant doses and do not involve the known pharmacological effects of the drug. IDR related to hepatotoxicity or idiosyncratic drug-induced liver injury

  9. Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

    Science.gov (United States)

    Kristiansen, Maria Nicoline Baandrup; Veidal, Sanne Skovgård; Rigbolt, Kristoffer Tobias Gustav; Tølbøl, Kirstine Sloth; Roth, Jonathan David; Jelsing, Jacob; Vrang, Niels; Feigh, Michael

    2016-01-01

    AIM: To characterize development of diet-induced nonalcoholic steatohepatitis (NASH) by performing liver biopsy in wild-type and genetically obese mice. METHODS: Male wild-type C57BL/6J (C57) mice (DIO-NASH) and male Lepob/Lepob (ob/ob) mice (ob/ob-NASH) were maintained on a diet high in trans-fat (40%), fructose (22%) and cholesterol (2%) for 26 and 12 wk, respectively. A normal chow diet served as control in C57 mice (lean chow) and ob/ob mice (ob/ob chow). After the diet-induction period, mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted. Mice were then stratified into groups counterbalanced for steatosis score and fibrosis stage and continued on diet and to receive daily PO dosing of vehicle for 8 wk. Global gene expression in liver tissue was assessed by RNA sequencing and bioinformatics. Metabolic parameters, plasma liver enzymes and lipids (total cholesterol, triglycerides) as well as hepatic lipids and collagen content were measured by biochemical analysis. Non-alcoholic fatty liver disease activity score (NAS) (steatosis/inflammation/ballooning degeneration) and fibrosis were scored. Steatosis and fibrosis were also quantified using percent fractional area. RESULTS: Diet-induction for 26 and 12 wk in DIO-NASH and ob/ob-NASH mice, respectively, elicited progressive metabolic perturbations characterized by increased adiposity, total cholesterol and elevated plasma liver enzymes. The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis. Overall, the metabolic NASH phenotype was more pronounced in ob/ob-NASH vs DIO-NASH mice. During the eight week repeated vehicle dosing period, the metabolic phenotype was sustained in DIO-NASH and ob/ob-NASH mice in conjunction with hepatomegaly and increased hepatic lipids and collagen accumulation. Histopathological scoring demonstrated significantly increased NAS of DIO-NASH mice (0 vs 4.7 ± 0.4, P NASH mice (2.4 ± 0.3 vs 6.3

  10. Investigation of the hepatoprotective effects of Sesame (Sesamum indicum L.) in carbon tetrachloride-induced liver toxicity.

    Science.gov (United States)

    Cengiz, Nureddin; Kavak, Servet; Güzel, Ali; Ozbek, Hanefi; Bektaş, Hava; Him, Aydın; Erdoğan, Ender; Balahoroğlu, Ragıb

    2013-01-01

    More than 600 chemicals can cause damage in liver, one of which is carbon tetrachloride (CCl₄). Hepatoprotective agents could prevent tissue damage and reduce morbidity and mortality rates; such agents may include alternative or folkloric treatments. We investigated sesame (Sesamum indicum L.) for its hepatoprotective effect in CCl₄-induced experimental liver damage. To this end, 0.8 mg/kg of sesame fixed oil was provided intraperitoneally to rats whose livers were damaged by CCl₄. Tissue and blood samples were taken at the end of the experiments and evaluated histologically and biochemically. Ballooning degenerations and an increase in lipid droplets in liver parenchyma and increases in serum alanine transaminase, aspartate transaminase, and bilirubin were found in the CCl₄ group. Biochemical and histopathological findings in the sesame fixed oil treated group were not significantly different from the CCl₄ group. Sesame did not show a hepatoprotective effect in CCl₄-induced liver toxicity.

  11. Human immunodeficiency virus type 1 efficiently binds to human fetal astrocytes and induces neuroinflammatory responses independent of infection

    Directory of Open Access Journals (Sweden)

    Potash Mary

    2007-05-01

    Full Text Available Abstract Background HIV-1 infects human astrocytes in vitro and in vivo but the frequency of infected cells is low and its biological significance is unknown. In studies in vitro, recombinant gp120 alone can induce profound effects on astrocyte biology, suggesting that HIV-1 interaction with astrocytes and its functional consequences extend beyond the limited levels of infection in these cells. Here we determined the relative efficiencies of HIV-1 binding and infection in human fetal astrocytes (HFA, mainly at the single cell level, using HIV-1 tagged with green fluorescence protein (GFP-Vpr fusion proteins, termed HIV-GFP, to detect virus binding and HIV-1 expressing Rev and NefGFP fusion proteins to detect productive infection. Results Essentially all HFA in a population bound HIV-GFP specifically and independently of CCR5 and CXCR4. The dynamics of this binding at 37°C resembled binding of an HIV fusion mutant to CD4-positive cells, indicating that most of HIV-GFP arrested infection of HFA at the stage of virus-cell fusion. Despite extensive binding, only about 1% of HFA were detectably infected by HIV-RevGFP or HIV-NefGFP, but this proportion increased to the majority of HFA when the viruses were pseudotyped with vesicular stomatitis virus envelope glycoprotein G, confirming that HFA impose a restriction upon HIV-1 entry. Exposure of HFA to HIV-1 through its native proteins rapidly induced synthesis of interleukin-6 and interleukin-8 with increased mRNA detected within 3 h and increased protein detected within 18 h of exposure. Conclusion Our results indicate that HIV-1 binding to human astrocytes, although extensive, is not generally followed by virus entry and replication. Astrocytes respond to HIV-1 binding by rapidly increased cytokine production suggesting a role of this virus-brain cell interaction in HIV-1 neuropathogenesis.

  12. Hepatitis E Virus Induced Acute Liver Failure with Scrub Typhus Coinfection in a Pregnant Woman.

    Science.gov (United States)

    Verma, Nipun; Sharma, Megha; Biswal, Manisha; Taneja, Sunil; Batra, Nitya; Kumar, Abhay; Dhiman, Radha K

    2017-06-01

    Coinfections contribute significantly to diagnostic challenges of acute febrile illnesses, especially in endemic areas. The confusion caused by overlapping clinical features impedes timely management. Herein, we report an unusual, previously unreported case of a pregnant woman suffering from a coinfection of scrub typhus and hepatitis E virus. A 25-year-old, 31-week pregnant woman presented with jaundice for 5 days and altered sensorium for 2 days. She had features of both viral acute liver failure (ALF) and tropical infections mimicking ALF, including hyperbilirubinemia, coagulopathy, anemia, thrombocytopenia, intravascular hemolysis, and hepatosplenomegaly. Etiological workup revealed rare coinfection of hepatitis E and scrub typhus. Despite all supportive measures, the patient succumbed to her illness (i.e., absent brainstem reflexes and intracranial bleed secondary to coagulopathy) and had poor fetal outcome, which resulted in stillbirth. ALF in a pregnant woman is a medical and obstetric emergency. It can result from varied etiologies that though differ in their incidence, mode of occurrence, and pregnancy outcome, can clinically masquerade as each other, causing diagnostic dilemma. This unusual case report highlights the significance of keeping all such possibilities in mind while managing a pregnant woman with ALF, especially in a country like India where maternal and perinatal mortality rates, the core indicators of national health, are still among the highest in the world.

  13. Mesenchymal stem cell-conditioned medium prevents radiation-induced liver injury by inhibiting inflammation and protecting sinusoidal endothelial cells

    International Nuclear Information System (INIS)

    Chen Yixing; Zeng Zhaochong; Sun Jing; Huang Yan; Zhang Zhenyu; Zeng Haiying

    2015-01-01

    Current management of radiation-induced liver injury is limited. Sinusoidal endothelial cell (SEC) apoptosis and inflammation are considered to be initiating events in hepatic damage. We hypothesized that mesenchymal stem cells (MSCs) possess anti-apoptotic and anti-inflammatory actions during hepatic irradiation, acting via paracrine mechanisms. This study aims to examine whether MSC-derived bioactive components are protective against radiation-induced liver injury in rats. MSC-conditioned medium (MSC-CM) was generated from rat bone marrow–derived MSCs. The effect of MSC-CM on the viability of irradiated SECs was examined by flow cytometric analysis. Activation of the Akt and ERK pathways was analyzed by western blot. MSC-CM was also delivered to Sprague–Dawley rats immediately before receiving liver irradiation, followed by testing for pathological features, changes in serum hyaluronic acid, ALT, and inflammatory cytokine levels, and liver cell apoptosis. MSC-CM enhanced the viability of irradiated SECs in vitro and induced Akt and ERK phosphorylation in these cells. Infusion of MSC-CM immediately before liver irradiation provided a significant anti-apoptotic effect on SECs and improved the histopathological features of injury in the irradiated liver. MSC-CM also reduced the secretion and expression of inflammatory cytokines and increased the expression of anti-inflammatory cytokines. MSC-derived bioactive components could be a novel therapeutic approach for treating radiation-induced liver injury. (author)

  14. [Preventive effects of lutein on liver toxicity in mice induced by arsenic].

    Science.gov (United States)

    Niu, Mingke; Li, Shugang; Niu, Qiang; Xu, Shangzhi; Xiao, Jiaonan; Ding, Li; Liu, Jiaqing; Wen, Hui; Feng, Gangling

    2015-07-01

    To explore the intervention effects of lutein on liver toxicity in mice induced by arsenic trioxide (As2O3) and to evaluate the preventive effect and the antioxidant mechanism of lutein. A total of 84 healthy KM mice were randomly divided into eight groups. There were 35 d control group, 70 d control group, 35 d lutein group, 70 d lutein group, arsenic exposure group, lutein treatment group and lutein prevention group. The activity and level of AST, ALT, T-AOC, MDA, GSH, SOD, NO in liver tissue were measured by kits. Compares the difference between each group of the single factor analysis of variance. The activity of ALT, AST and the contents of MDA of 70 d control group were significantly lower than that arsenic exposure group. The contents of GSH, T-AOC, NO and the activity of SOD of 70 d control group were increased significantly than arsenic exposure group. The activity of ALT, AST and the contents of MDA of lutein prevention group were significantly lower than that lutein treatment group. The contents of GSH, T-AOC, NO and the activity of SOD of lutein prevention group were increased significantly than lutein treatment group. The differences were statistically significant (P Lutein can improve antioxidation function and has protective effect on liver injury of mice induced by arsenic.

  15. Liver Afferents Contribute to Water Drinking-Induced Sympathetic Activation in Human Subjects: A Clinical Trial

    Science.gov (United States)

    May, Marcus; Gueler, Faikah; Barg-Hock, Hannelore; Heiringhoff, Karl-Heinz; Engeli, Stefan; Heusser, Karsten; Diedrich, André; Brandt, André; Strassburg, Christian P.; Tank, Jens; Sweep, Fred C. G. J.; Jordan, Jens

    2011-01-01

    Water drinking acutely increases sympathetic activity in human subjects. In animals, the response appears to be mediated through transient receptor potential channel TRPV4 activation on osmosensitive hepatic spinal afferents, described as osmopressor response. We hypothesized that hepatic denervation attenuates water drinking-induced sympathetic activation. We studied 20 liver transplant recipients (44±2.6 years, 1.2±0.1 years post transplant) as model of hepatic denervation and 20 kidney transplant recipients (43±2.6 years, 0.8±0.1 years post transplant) as immunosuppressive drug matched control group. Before and after 500 ml water ingestion, we obtained venous blood samples for catecholamine analysis. We also monitored brachial and finger blood pressure, ECG, and thoracic bioimpedance. Plasma norepinephrine concentration had changed by 0.01±0.07 nmol/l in liver and by 0.21±0.07 nmol/l in kidney transplant recipients (pwater drinking. While blood pressure and systemic vascular resistance increased in both groups, the responses tended to be attenuated in liver transplant recipients. Our findings support the idea that osmosensitive hepatic afferents are involved in water drinking-induced sympathetic activation in human subjects. Trial Registration ClinicalTrials.gov NCT01237431 PMID:22016786

  16. Liver afferents contribute to water drinking-induced sympathetic activation in human subjects: a clinical trial.

    Directory of Open Access Journals (Sweden)

    Marcus May

    Full Text Available Water drinking acutely increases sympathetic activity in human subjects. In animals, the response appears to be mediated through transient receptor potential channel TRPV4 activation on osmosensitive hepatic spinal afferents, described as osmopressor response. We hypothesized that hepatic denervation attenuates water drinking-induced sympathetic activation. We studied 20 liver transplant recipients (44±2.6 years, 1.2±0.1 years post transplant as model of hepatic denervation and 20 kidney transplant recipients (43±2.6 years, 0.8±0.1 years post transplant as immunosuppressive drug matched control group. Before and after 500 ml water ingestion, we obtained venous blood samples for catecholamine analysis. We also monitored brachial and finger blood pressure, ECG, and thoracic bioimpedance. Plasma norepinephrine concentration had changed by 0.01±0.07 nmol/l in liver and by 0.21±0.07 nmol/l in kidney transplant recipients (p<0.05 between groups after 30-40 minutes of water drinking. While blood pressure and systemic vascular resistance increased in both groups, the responses tended to be attenuated in liver transplant recipients. Our findings support the idea that osmosensitive hepatic afferents are involved in water drinking-induced sympathetic activation in human subjects.ClinicalTrials.gov NCT01237431.

  17. Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

    International Nuclear Information System (INIS)

    Zhou, Yan; Ruan, Zheng; Zhou, Lili; Shu, Xugang; Sun, Xiaohong; Mi, Shumei; Yang, Yuhui; Yin, Yulong

    2016-01-01

    Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. - Highlights: • Dietary supplementation with chlorogenic acid (CGA) improved endotoxin-induced liver injury. • Chlorogenic acid enhances ATP increase and shifts energy metabolism, which is correlated with up-regulation AMPK and PGC-1α. • The possible mechanism of CGA on mitochondrial biogenesis was correlated with up-regulation AMPK and PGC-1α.

  18. Saccharin induced liver inflammation in mice by altering the gut microbiota and its metabolic functions.

    Science.gov (United States)

    Bian, Xiaoming; Tu, Pengcheng; Chi, Liang; Gao, Bei; Ru, Hongyu; Lu, Kun

    2017-09-01

    Maintaining the balance of the gut microbiota and its metabolic functions is vital for human health, however, this balance can be disrupted by various external factors including food additives. A range of food and beverages are sweetened by saccharin, which is generally considered to be safe despite controversial debates. However, recent studies indicated that saccharin perturbed the gut microbiota. Inflammation is frequently associated with disruptions of the gut microbiota. The aim of this study is to investigate the relationship between host inflammation and perturbed gut microbiome by saccharin. C57BL/6J male mice were treated with saccharin in drinking water for six months. Q-PCR was used to detect inflammatory markers in mouse liver, while 16S rRNA gene sequencing and metabolomics were used to reveal changes of the gut microbiota and its metabolomic profiles. Elevated expression of pro-inflammatory iNOS and TNF-α in liver indicated that saccharin induced inflammation in mice. The altered gut bacterial genera, enriched orthologs of pathogen-associated molecular patterns, such as LPS and bacterial toxins, in concert with increased pro-inflammatory metabolites suggested that the saccharin-induced liver inflammation could be associated with the perturbation of the gut microbiota and its metabolic functions. Copyright © 2017. Published by Elsevier Ltd.

  19. Inhibitory effect of TCCE on CCl4-induced overexpression of IL-6 in acute liver injury.

    Science.gov (United States)

    Gao, Jing; Dou, Huan; Tang, Xin-Hui; Xu, Li-Zhi; Fan, Yi-Mei; Zhao, Xiao-Ning

    2004-11-01

    Terminalia catappa L. leaves have been shown to protect against acute liver injury produced by some hepatotoxicants, but the active components and mechanisms are not clear. This study was designed to characterize the protective effects of the chloroform fraction of the ethanol extract of T. catappa leaves (TCCE) against carbon tetrachloride (CCl4)-induced hepatotoxicity in mice, and analyze the changes in expression level of interleukin-6 (IL-6) in the process. It was found that TCCE pretreatment (10 or 30 mg/kg, ig) protected mice from CCl4 toxicity, as evidenced by the reversed alterations in serum alanine aminotransferase (sALT) and serum aspartate aminotransferase (sAST) activities. Additionally liver tissues were subjected to RT-PCR, Western blot and immunohistochemistry to analyze changes in IL-6 expression. It was found that TCCE markedly suppressed the CCl4-induced over-transcription of IL-6 gene. Consistent with the result, the expression of IL-6 protein was also blocked by TCCE in CCl4-stimulated mice, especially in the area around central vein on liver tissue section. In conclusion, TCCE is effective in protecting mice from the hepatotoxicity produced by CCl4, and the mechanisms underlying its protective effects may be related to the inhibition on the overexpression of IL-6 mainly around terminal hepatic vein.

  20. Idiosyncratic Drug-Induced Liver Injury: Is Drug-Cytokine Interaction the Linchpin?

    Science.gov (United States)

    Roth, Robert A; Maiuri, Ashley R; Ganey, Patricia E

    2017-02-01

    Idiosyncratic drug-induced liver injury continues to be a human health problem in part because drugs that cause these reactions are not identified in current preclinical testing and because progress in prevention is hampered by incomplete knowledge of mechanisms that underlie these adverse responses. Several hypotheses involving adaptive immune responses, inflammatory stress, inability to adapt to stress, and multiple, concurrent factors have been proposed. Yet much remains unknown about how drugs interact with the liver to effect death of hepatocytes. Evidence supporting hypotheses implicating adaptive or innate immune responses in afflicted patients has begun to emerge and is bolstered by results obtained in experimental animal models and in vitro systems. A commonality in adaptive and innate immunity is the production of cytokines, including interferon-γ (IFNγ). IFNγ initiates cell signaling pathways that culminate in cell death or inhibition of proliferative repair. Tumor necrosis factor-α, another cytokine prominent in immune responses, can also promote cell death. Furthermore, tumor necrosis factor-α interacts with IFNγ, leading to enhanced cellular responses to each cytokine. In this short review, we propose that the interaction of drugs with these cytokines contributes to idiosyncratic drug-induced liver injury, and mechanisms by which this could occur are discussed. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

  1. Effects of exogenous metallothionein against thallium-induced oxidative stress in rat liver.

    Science.gov (United States)

    Kiliç, Gözde Aydoğan; Kutlu, Mehtap

    2010-03-01

    Metallothionein (MT) is a low-molecular weight sulfur-rich protein that plays role in metal homeostasis/detoxification and radical scavenging. The following study investigated the ability of exogenous MT to protect against oxidative damage induced by thallium (TI) in rat liver. Male Wistar rats were divided into four groups; a control and three experimental groups. The control group received physiological saline. Group 1 animals were injected with thallium acetate intraperitoneally (i.p.) at a single dose of LD(50) (32 mg/kg). In group 2 and group 3, metallothionein I was administrated once at two different doses (1 or 2.5mg/kg i.p., respectively) 1h before TI intoxication. Levels of endogenous antioxidants, oxidative stress markers were measured and histopathological examinations were performed 4 days after TI administration. TI accumulation in liver decreased related to the dose of MT. Mostly all of the alterations in the levels antioxidants restored to normal levels in MT administrated animals. H(2)O(2) levels and lipid peroxidation decreased, integrity of hepatocytes and membranous structures inside the cells were preserved. The toxic effects of TI were modulated in MT administrated animals particularly at the dose of 2.5mg/kg. These findings suggest an active role of exogenous MT against TI-induced oxidative stress in rat liver. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  2. N-Nitrosodiethylamine-Induced Pig Liver Hepatocellular Carcinoma Model: Radiological and Histopathological Studies

    International Nuclear Information System (INIS)

    Li Xiao; Zhou Xiangping; Guan Yongsong; Wang, Yi-Xiang J.; Scutt, Diane; Gong Qiyong

    2006-01-01

    Experimental research involving animal models plays a critical role in the development and improvement of minimally invasive therapies for hepatocellular carcinoma (HCC). As a large animal, the pig is commonly used for surgery and interventional radiology research. In this study, liver multicentric HCC with cirrhosis was induced in six China Taihu pigs by intraperitoneal injection of 10 mg/kg of N-nitrosodiethylamine once a week for 3 months, followed by a period of 10-12 months without N-nitrosodiethylamine treatment. All pigs were in generally good health until the end of the study. The tumor nodules appeared hyperattenuating in the arterial phase of a dynamic computed tomography (CT) scan. Digital subtraction angiography (DSA) and CT angiography demonstrated that the tumors derived their blood supply mainly from the hepatic artery system. Lipiodol-CT showed Lipiodol retention in tumor areas. The histology and electron microscopic ultrastructure of the chemically induced liver HCC in this study resembled human HCC with a cirrhosis background. An immunohistochemistry study confirmed that the tumors were of hepatocyte origin. All highly, moderately, and poorly differentiated HCC tumors were identified in this study. Cholangiocarcinoma was not seen in any of the animals. Due to its comparable size to human anatomy, the pig liver HCC model would give a better scope for interventional and surgical manipulations than small animal models

  3. Chlorogenic acid ameliorates endotoxin-induced liver injury by promoting mitochondrial oxidative phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Yan [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); College of Food Safety, Guizhou Medical University, Guiyang 550025 (China); Ruan, Zheng, E-mail: ruanzheng@ncu.edu.cn [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Zhou, Lili; Shu, Xugang [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Sun, Xiaohong [College of Food Safety, Guizhou Medical University, Guiyang 550025 (China); Mi, Shumei; Yang, Yuhui [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Yin, Yulong, E-mail: yinyulong@isa.ac.cn [State Key Laboratory of Food Science and Technology and School of Food Science, Nanchang University, Nanchang 330047 (China); Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha 410125 (China)

    2016-01-22

    Acute or chronic hepatic injury is a common pathology worldwide. Mitochondrial dysfunction and the depletion of adenosine triphosphate (ATP) play important roles in liver injury. Chlorogenic acids (CGA) are some of the most abundant phenolic acids in human diet. This study was designed to test the hypothesis that CGA may protect against chronic lipopolysaccharide (LPS)-induced liver injury by modulating mitochondrial energy generation. CGA decreased the activities of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. The contents of ATP and adenosine monophosphate (AMP), as well as the ratio of AMP/ATP, were increased after CGA supplementation. The activities of enzymes that are involved in glycolysis were reduced, while those of enzymes involved in oxidative phosphorylation were increased. Moreover, phosphorylated AMP-activated protein kinase (AMPK), and mRNA levels of AMPK-α, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial DNA transcription factor A were increased after CGA supplementation. Collectively, these findings suggest that the hepatoprotective effect of CGA might be associated with enhanced ATP production, the stimulation of mitochondrial oxidative phosphorylation and the inhibition of glycolysis. - Highlights: • Dietary supplementation with chlorogenic acid (CGA) improved endotoxin-induced liver injury. • Chlorogenic acid enhances ATP increase and shifts energy metabolism, which is correlated with up-regulation AMPK and PGC-1α. • The possible mechanism of CGA on mitochondrial biogenesis was correlated with up-regulation AMPK and PGC-1α.

  4. Hepatoprotection of emodin and Polygonum multiflorum against CCl(4)-induced liver injury.

    Science.gov (United States)

    Lee, Bao-Hong; Huang, Ya-Yin; Duh, Pin-Der; Wu, She-Ching

    2012-03-01

    Polygonum multiflorum is known as a medicinal plant. It has been used a