Sample records for hepatic foci induced

  1. Telomere Dysfunction Induced Foci (TIF) Analysis.

    PubMed

    Mender, Ilgen; Shay, Jerry W

    2015-11-20

    Telomerase maintains telomeric DNA in eukaryotes during early developments, ~90% of cancer cells and some proliferative stem like cells. Telomeric repeats at the end of chromosomes are associated with the shelterin complex. This complex consists of TRF1, TRF2, Rap1, TIN2, TPP1, POT1 which protect DNA from being recognized as DNA double-stranded breaks. Critically short telomeres or impaired shelterin proteins can cause telomere dysfunction, which eventually induces DNA damage responses at the telomeres. DNA damage responses can be identified by antibodies to 53BP1, gammaH2AX, Rad17, ATM, and Mre11. DNA damage foci at uncapped telomeres are referred to as Telomere dysfunction-Induced Foci (TIFs) (de Lange, 2005; Takai et al. , 2003). The TIF assay is based on the co-localization detection of DNA damage by an antibody against DNA damage markers, such as gamma-H2AX, and telomeres using an antibody against one of the shelterin proteins such as TRF2 (Takai et al. , 2003; de Lange, 2002; Karlseder et al. , 1999). The method we describe here can be used in normal human and cancer cells. Other commonly used methods-Telomere Restriction Fragment (TRF) Analysis (Mender and Shay, 2015b) and Telomere Repeat Amplification Protocol (TRAP) (Mender and Shay, 2015a)- in telomere biology can be found by clicking on the indicated links.

  2. Protective effect of thymoquinone against lead-induced hepatic toxicity in rats.

    PubMed

    Mabrouk, Aymen; Bel Hadj Salah, Imen; Chaieb, Wafa; Ben Cheikh, Hassen

    2016-06-01

    Lead (Pb) intoxication is a worldwide health problem which frequently affects the liver. This study was carried out to investigate the potential protective effect of thymoquinone (TQ), the major active ingredient of volatile oil of Nigella sativa seeds, against Pb-induced liver damage. Adult male rats were randomized into four groups: Control group received no treatment, Pb group was exposed to 2000 ppm Pb acetate in drinking water, Pb-TQ group was cotreated with Pb plus TQ (5 mg/kg/day, per orally), and TQ group receiving only TQ. All treatments were applied for 5 weeks. Results indicated that Pb exposure increased hepatic Pb content, damaged hepatic histological structure (necrotic foci, hepatic strands disorganization, hypertrophied hepatocytes, cytoplasmic vacuolization, cytoplasmic loss, chromatin condensation, mononuclear cell infiltration, congestion, centrilobular swelling), and changed liver function investigated by plasma biochemical parameters (AST, ALT, ALP, γ-GT, LDH). Pb treatment also decreased total antioxidant status level and increased lipid peroxidation in the liver. Supplementation with TQ remarkably improved the Pb-induced adverse effects without significantly reducing the metal accumulation in the liver. In conclusion, our results indicate, for the first time, a protective effect of TQ against Pb-induced hepatotoxicity and suggest that this component might be clinically useful in Pb intoxication.

  3. Image-based modeling of radiation-induced foci

    NASA Astrophysics Data System (ADS)

    Costes, Sylvain; Cucinotta, Francis A.; Ponomarev, Artem; Barcellos-Hoff, Mary Helen; Chen, James; Chou, William; Gascard, Philippe

    Several proteins involved in the response to DNA double strand breaks (DSB) form microscopically visible nuclear domains, or foci, after exposure to ionizing radiation. Radiation-induced foci (RIF) are believed to be located where DNA damage occurs. To test this assumption, we used Monte Carlo simulations to predict the spatial distribution of DSB in human nuclei exposed to high or low-LET radiation. We then compared these predictions to the distribution patterns of three DNA damage sensing proteins, i.e. 53BP1, phosphorylated ATM and γH2AX in human mammary epithelial. The probability to induce DSB can be derived from DNA fragment data measured experimentally by pulsed-field gel electrophoresis. We first used this probability in Monte Carlo simulations to predict DSB locations in synthetic nuclei geometrically described by a complete set of human chromosomes, taking into account microscope optics from real experiments. Simulations showed a very good agreement for high-LET, predicting 0.7 foci/µm along the path of a 1 GeV/amu Fe particle against measurement of 0.69 to 0.82 foci/µm for various RIF 5 min following exposure (LET 150 keV/µm). On the other hand, discrepancies were shown in foci frequency for low-LET, with measurements 20One drawback using a theoretical model for the nucleus is that it assumes a simplistic and static pattern for DNA densities. However DNA damage pattern is highly correlated to DNA density pattern (i.e. the more DNA, the more likely to have a break). Therefore, we generalized our Monte Carlo approach to real microscope images, assuming pixel intensity of DAPI in the nucleus was directly proportional to the amount of DNA in that pixel. With such approach we could predict DNA damage pattern in real images on a per nucleus basis. Since energy is randomly deposited along high-LET particle paths, RIF along these paths should also be randomly distributed. As expected, simulations produced DNA-weighted random (Poisson) distributions. In

  4. X-ray induced formation of γ-H2AX foci after full-field digital mammography and digital breast-tomosynthesis.

    PubMed

    Schwab, Siegfried A; Brand, Michael; Schlude, Ina-Kristin; Wuest, Wolfgang; Meier-Meitinger, Martina; Distel, Luitpold; Schulz-Wendtland, Ruediger; Uder, Michael; Kuefner, Michael A

    2013-01-01

    To determine in-vivo formation of x-ray induced γ-H2AX foci in systemic blood lymphocytes of patients undergoing full-field digital mammography (FFDM) and to estimate foci after FFDM and digital breast-tomosynthesis (DBT) using a biological phantom model. The study complies with the Declaration of Helsinki and was performed following approval by the ethic committee of the University of Erlangen-Nuremberg. Written informed consent was obtained from every patient. For in-vivo tests, systemic blood lymphocytes were obtained from 20 patients before and after FFDM. In order to compare in-vivo post-exposure with pre-exposure foci levels, the Wilcoxon matched pairs test was used. For in-vitro experiments, isolated blood lymphocytes from healthy volunteers were irradiated at skin and glandular level of a porcine breast using FFDM and DBT. Cells were stained against the phosphorylated histone variant γ-H2AX, and foci representing distinct DNA damages were quantified. Median in-vivo foci level/cell was 0.086 (range 0.067-0.116) before and 0.094 (0.076-0.126) after FFDM (p = 0.0004). In the in-vitro model, the median x-ray induced foci level/cell after FFDM was 0.120 (range 0.086-0.140) at skin level and 0.035 (range 0.030-0.050) at glandular level. After DBT, the median x-ray induced foci level/cell was 0.061 (range 0.040-0.081) at skin level and 0.015 (range 0.006-0.020) at glandular level. In patients, mammography induces a slight but significant increase of γ-H2AX foci in systemic blood lymphocytes. The introduced biological phantom model is suitable for the estimation of x-ray induced DNA damages in breast tissue in different breast imaging techniques.

  5. THE LIVER OF WOODCHUCKS CHRONICALLY INFECTED WITH THE WOODCHUCK HEPATITIS VIRUS CONTAINS FOCI OF VIRUS CORE ANTIGEN NEGATIVE HEPATOCYTES WITH BOTH ALTERED AND NORMAL MORPHOLOGY

    PubMed Central

    Xu, Chunxiao; Yamamoto, Toshiki; Zhou, Tianlun; Aldrich, Carol E.; Frank, Katy; Cullen, John M.; Jilbert, Allison R.; Mason, William S.

    2007-01-01

    The livers of woodchucks chronically infected with woodchuck hepatitis virus (WHV) contain foci of morphologically altered hepatocytes (FAH) with “basophilic”, “amphophilic” and “clear cell” phenotypes, which are possibly pre-neoplastic in nature. Interestingly, most fail to express detectable levels of WHV proteins and nucleic acids. We studied sections of WHV-infected liver tissue to determine if all foci of hepatocytes that failed to express detectable levels of WHV, as assessed by immunoperoxidase staining for WHV core antigen, could be classified morphologically as FAH. We found that at least half of the foci of WHV core antigen negative hepatocytes did not show clear morphological differences in either H&E or PAS (periodic acid Schiff) stained sections from surrounding hepatocytes, and were therefore not designated as FAH. In the second approach, we assayed core antigen negative foci for the presence of fetuin B, a serum protein produced by normal hepatocytes, but not by neoplastic hepatocytes in hepatocellular carcinomas. Basophilic and amphophilic FAH had reduced levels of fetuin B compared to hepatocytes present in the surrounding liver; fetuin B staining was detected in clear cell FAH but the level could not be accurately assessed because of the displacement of fetuin B to the cell periphery by accumulated glycogen. The foci of morphologically normal WHV core antigen negative hepatocytes had similar levels of fetuin B to that of the surrounding hepatocytes. The co-existence of at least four types of WHV core antigen negative foci, including those with no obvious morphologic changes, raises the possibility that the different foci arise from distinct primary events. We hypothesize that a common event is loss of the ability to express WHV, allowing these hepatocytes to escape immune mediated cell death and to undergo clonal expansion to form distinct foci. PMID:17078989

  6. RAD18 and associated proteins are immobilized in nuclear foci in human cells entering S-phase with ultraviolet light-induced damage

    PubMed Central

    Watson, Nicholas B.; Nelson, Eric; Digman, Michelle; Thornburg, Joshua A.; Alphenaar, Bruce W.; McGregor, W. Glenn

    2008-01-01

    Proteins required for translesion DNA synthesis localize in nuclear foci of cells with replication-blocking lesions. The dynamics of this process were examined in human cells with fluorescence-based biophysical techniques. Photobleaching recovery and raster image correlation spectroscopy experiments indicated that involvement in the nuclear foci reduced the movement of RAD18 from diffusion-controlled to virtual immobility. Examination of the mobility of REV1 indicated that it is similarly immobilized when it is observed in nuclear foci. Reducing the level of RAD18 greatly reduced the focal accumulation of REV1 and reduced UV mutagenesis to background frequencies. Fluorescence lifetime measurements indicated that RAD18 and RAD6A or polη only transferred resonance energy when these proteins colocalized in damage-induced nuclear foci, indicating a close physical association only within such foci. Our data support a model in which RAD18 within damage-induced nuclear foci is immobilized and is required for recruitment of Y-family DNA polymerases and subsequent mutagenesis. In the absence of damage these proteins are not physically associated within the nucleoplasm. PMID:18926833

  7. Radiation-induced liver disease as a mimic of liver metastases at serial PET/CT during neoadjuvant chemoradiation of distal esophageal cancer.

    PubMed

    Grant, Michael J; Didier, Ryne A; Stevens, Jeffrey S; Beyder, Dmitry D; Hunter, John G; Thomas, Charles R; Coakley, Fergus V

    2014-10-01

    To determine the frequency and appearance of radiation-induced liver disease on PET/CT in patients undergoing serial imaging during neoadjuvant chemoradiation of distal esophageal cancer. In this IRB-approved, HIPAA-compliant retrospective analysis, we identified 112 patients with distal esophageal cancer treated by neoadjuvant chemoradiation who had serial PET/CT imaging available for review. Two readers reviewed all studies in consensus and recorded those cases where new foci of visually detectable increased FDG avidity appeared in the liver during therapy. The etiology of such foci was determined from corresponding findings at CT or MRI, by hepatic biopsy during surgery, by characteristic evolution on post-operative imaging, or by a combination of these methods. New foci of FDG avidity developed in the liver during neoadjuvant therapy in 10 of 112 (9%) patients, of whom nine (8%) were determined to have radiation-induced liver disease based on further imaging and/or biopsy and one of whom had developed interval metastatic disease based on biopsy. In the cases of radiation-induced liver disease, the abnormal foci were found only in the caudate and left hepatic lobes, near the primary tumor, while the patient who developed interval metastatic disease had involvement of the inferior right hepatic lobe, remote from the radiation therapy field. New foci of increased FDG avidity are commonly seen in the caudate and left hepatic lobes of the liver during neoadjuvant chemoradiation of distal esophageal cancer, and these findings generally reflect radiation-induced liver disease rather than metastatic disease.

  8. Aloe-induced Toxic Hepatitis

    PubMed Central

    Yang, Ha Na; Kim, Young Mook; Kim, Byoung Ho; Sohn, Kyoung Min; Choi, Myung Jin; Choi, Young Hee

    2010-01-01

    Aloe has been widely used in phytomedicine. Phytomedicine describes aloe as a herb which has anti-inflammatory, anti-proliferative, anti-aging effects. In recent years several cases of aloe-induced hepatotoxicity were reported. But its pharmacokinetics and toxicity are poorly described in the literature. Here we report three cases with aloe-induced toxic hepatitis. A 57-yr-old woman, a 62-yr-old woman and a 55-yr-old woman were admitted to the hospital for acute hepatitis. They had taken aloe preparation for months. Their clinical manifestation, laboratory findings and histologic findings met diagnostic criteria (RUCAM scale) of toxic hepatitis. Upon discontinuation of the oral aloe preparations, liver enzymes returned to normal level. Aloe should be considered as a causative agent in hepatotoxicity. PMID:20191055

  9. NEK8 regulates DNA damage-induced RAD51 foci formation and replication fork protection

    PubMed Central

    Abeyta, Antonio; Castella, Maria; Jacquemont, Celine; Taniguchi, Toshiyasu

    2017-01-01

    ABSTRACT Proteins essential for homologous recombination play a pivotal role in the repair of DNA double strand breaks, DNA inter-strand crosslinks and replication fork stability. Defects in homologous recombination also play a critical role in the development of cancer and the sensitivity of these cancers to chemotherapy. RAD51, an essential factor for homologous recombination and replication fork protection, accumulates and forms immunocytochemically detectable nuclear foci at sites of DNA damage. To identify kinases that may regulate RAD51 localization to sites of DNA damage, we performed a human kinome siRNA library screen, using DNA damage-induced RAD51 foci formation as readout. We found that NEK8, a NIMA family kinase member, is required for efficient DNA damage-induced RAD51 foci formation. Interestingly, knockout of Nek8 in murine embryonic fibroblasts led to cellular sensitivity to the replication inhibitor, hydroxyurea, and inhibition of the ATR kinase. Furthermore, NEK8 was required for proper replication fork protection following replication stall with hydroxyurea. Loading of RAD51 to chromatin was decreased in NEK8-depleted cells and Nek8-knockout cells. Single-molecule DNA fiber analyses revealed that nascent DNA tracts were degraded in the absence of NEK8 following treatment with hydroxyurea. Consistent with this, Nek8-knockout cells showed increased chromosome breaks following treatment with hydroxyurea. Thus, NEK8 plays a critical role in replication fork stability through its regulation of the DNA repair and replication fork protection protein RAD51. PMID:27892797

  10. NEK8 regulates DNA damage-induced RAD51 foci formation and replication fork protection.

    PubMed

    Abeyta, Antonio; Castella, Maria; Jacquemont, Celine; Taniguchi, Toshiyasu

    2017-02-16

    Proteins essential for homologous recombination play a pivotal role in the repair of DNA double strand breaks, DNA inter-strand crosslinks and replication fork stability. Defects in homologous recombination also play a critical role in the development of cancer and the sensitivity of these cancers to chemotherapy. RAD51, an essential factor for homologous recombination and replication fork protection, accumulates and forms immunocytochemically detectable nuclear foci at sites of DNA damage. To identify kinases that may regulate RAD51 localization to sites of DNA damage, we performed a human kinome siRNA library screen, using DNA damage-induced RAD51 foci formation as readout. We found that NEK8, a NIMA family kinase member, is required for efficient DNA damage-induced RAD51 foci formation. Interestingly, knockout of Nek8 in murine embryonic fibroblasts led to cellular sensitivity to the replication inhibitor, hydroxyurea, and inhibition of the ATR kinase. Furthermore, NEK8 was required for proper replication fork protection following replication stall with hydroxyurea. Loading of RAD51 to chromatin was decreased in NEK8-depleted cells and Nek8-knockout cells. Single-molecule DNA fiber analyses revealed that nascent DNA tracts were degraded in the absence of NEK8 following treatment with hydroxyurea. Consistent with this, Nek8-knockout cells showed increased chromosome breaks following treatment with hydroxyurea. Thus, NEK8 plays a critical role in replication fork stability through its regulation of the DNA repair and replication fork protection protein RAD51.

  11. Insulin-Inducible SMILE Inhibits Hepatic Gluconeogenesis.

    PubMed

    Lee, Ji-Min; Seo, Woo-Young; Han, Hye-Sook; Oh, Kyoung-Jin; Lee, Yong-Soo; Kim, Don-Kyu; Choi, Seri; Choi, Byeong Hun; Harris, Robert A; Lee, Chul-Ho; Koo, Seung-Hoi; Choi, Hueng-Sik

    2016-01-01

    The role of a glucagon/cAMP-dependent protein kinase-inducible coactivator PGC-1α signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner-interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB β-deficient (PKBβ(-/-)) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4-mediated transcriptional activity via direct competition with PGC-1α. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  12. Rifampicin-Induced Concomitant Renal Injury and Hepatitis

    PubMed Central

    Chogtu, Bharti; Surendra, Vyshak Uddur; Acharya, Preetam Rajgopal; Yerrapragada, Devesh Bhaskar

    2016-01-01

    Adverse drug reactions are not unusual during Anti-Tubercular Therapy (ATT). One of the common complications of anti-tubercular treatment is drug induced hepatitis and renal insufficiency has also been reported. Renal failure and/or hepatitis encountered during treatment of tuberculosis can have varied aetiologies: drug induced, concomitant viral infection, pre-existing co-morbidities or a combination of these. Since, hepatitis and/or renal insufficiency can be life threatening a prompt diagnosis is warranted, where drugs should be kept as one of the important cause. Identifying the drug helps in treating hepatitis and/or renal insufficiency along with helping the physician to change the combination of ATT regimen. Rifampicin is one of the most important first line drugs in the treatment of tuberculosis. Hepatitis, epigastric distress, anaemia, thrombocytopenia, and interstitial nephritis are reported adverse drug reactions to rifampicin. As per literature rifampicin induced renal toxicity is usually seen on rifampicin re-exposure, or rifampicin administration on alternate days, both being present in this case. Here we are reporting a case of ATT induced renal failure with concomitant hepatitis where rifampicin was suspected to be the cause. PMID:27790502

  13. Drug-induced hepatitis

    MedlinePlus

    ... induced hepatitis. Painkillers and fever reducers that contain acetaminophen are a common cause of liver injury, particularly ... problem. However, if you took high doses of acetaminophen , treatment should be started as soon as possible ...

  14. Hepatitis C virus core protein induces hepatic steatosis via Sirt1-dependent pathway.

    PubMed

    Zhang, Chuanhai; Wang, Jingjing; Zhang, Hanlin; Liu, Shunai; Lee, Hyuek Jong; Jin, Wanzhu; Cheng, Jun

    2018-05-01

    Hepatic steatosis is a common feature of patients with chronic hepatitis C. Previous reports have shown that the overexpression of hepatitis C virus core-encoding sequences (hepatitis C virus genotypes 3a and 1b) significantly induces intracellular triglyceride accumulation. However, the underlying mechanism has not yet been revealed. To investigate whether Sirt1 is involved in hepatitis C virus-mediated hepatic steatosis, the overexpression of hepatitis C virus core 1b protein and Sirt1 and the knockdown of Sirt1 in HepG2 cells were performed. To confirm the results of the cellular experiment liver-specific Sirt1 KO mice with lentivirus-mediated hepatitis C virus core 1b overexpression were studied. Our results show that hepatitis C virus core 1b protein overexpression led to the accumulation of triglycerides in HepG2 cells. Notably the expression of PPARγ2 was dramatically increased at both the mRNA and protein levels by hepatitis C virus core 1b overexpression. The protein expression of Sirt1 is an upstream regulator of PPARγ2 and was also significantly increased after core 1b overexpression. In addition, the overexpression or knockdown of Sirt1 expression alone was sufficient to modulate p300-mediated PPARγ2 deacetylation. In vivo studies showed that hepatitis C virus core protein 1b-induced hepatic steatosis was attenuated in liver-specific Sirt1 KO mice by downregulation of PPARγ2 expression. Sirt1 mediates hepatitis C virus core protein 1b-induced hepatic steatosis by regulation of PPARγ2 expression. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Nuclear dynamics of radiation-induced foci in euchromatin and heterochromatin

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chiolo, Irene; Tang, Jonathan; Georgescu, Walter

    2013-10-01

    Repair of double strand breaks (DSBs) is essential for cell survival and genome integrity. While much is known about the molecular mechanisms involved in DSB repair and checkpoint activation, the roles of nuclear dynamics of radiation-induced foci (RIF) in DNA repair are just beginning to emerge. Here, we summarize results from recent studies that point to distinct features of these dynamics in two different chromatin environments: heterochromatin and euchromatin. We also discuss how nuclear architecture and chromatin components might control these dynamics, and the need of novel quantification methods for a better description and interpretation of these phenomena. These studiesmore » are expected to provide new biomarkers for radiation risk and new strategies for cancer detection and treatment.« less

  16. Phenylbutyric acid protects against carbon tetrachloride-induced hepatic fibrogenesis in mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wang, Jian-Qing; Second Affiliated Hospital, Anhui Medical University, Hefei 230601; Chen, Xi

    2013-01-15

    A recent report showed that the unfolded protein response (UPR) signaling was activated in the pathogenesis of carbon tetrachloride (CCl{sub 4})-induced hepatic fibrosis. Phenylbutyric acid (PBA) is a well-known chemical chaperone that inhibits endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling. In the present study, we investigated the effects of PBA on CCl{sub 4}-induced hepatic fibrosis in mice. All mice were intraperitoneally (i.p.) injected with CCl{sub 4} (0.15 ml/kg BW, twice per week) for 8 weeks. In CCl{sub 4} + PBA group, mice were i.p. injected with PBA (150 mg/kg, twice per day) from the beginning of CCl{submore » 4} injection to the end. As expected, PBA significantly attenuated CCl{sub 4}-induced hepatic ER stress and UPR activation. Although PBA alleviated, only to a less extent, hepatic necrosis, it obviously inhibited CCl{sub 4}-induced tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β). Moreover, PBA inhibited CCl{sub 4}-induced hepatic nuclear factor kappa B (NF-κB) p65 translocation and extracellular signal-regulated kinase (ERK) and c-Jun N-terminal Kinase (JNK) phosphorylation. Interestingly, CCl{sub 4}-induced α-smooth muscle actin (α-SMA), a marker for the initiation phase of HSC activation, was significantly attenuated in mice pretreated with PBA. Correspondingly, CCl{sub 4}-induced hepatic collagen (Col)1α1 and Col1α2, markers for the perpetuation phase of HSC activation, were inhibited in PBA-treated mice. Importantly, CCl{sub 4}-induced hepatic fibrosis, as determined using Sirius red staining, was obviously attenuated by PBA. In conclusion, PBA prevents CCl{sub 4}-induced hepatic fibrosis through inhibiting hepatic inflammatory response and HSC activation. Highlights: ► CCl{sub 4} induces hepatic ER stress, inflammation, HSC activation and hepatic fibrosis. ► PBA alleviates CCl{sub 4}-induced hepatic ER stress and UPR signaling activation. ► PBA inhibits CCl{sub 4

  17. Live Dynamics of 53BP1 Foci Following Simultaneous Induction of Clustered and Dispersed DNA Damage in U2OS Cells

    PubMed Central

    Sollazzo, Alice; Brzozowska, Beata; Cheng, Lei; Lundholm, Lovisa; Scherthan, Harry

    2018-01-01

    Cells react differently to clustered and dispersed DNA double strand breaks (DSB). Little is known about the initial reaction to simultaneous induction of DSBs with different complexities. Here, we used live cell microscopy to analyse the behaviour of 53BP1-GFP (green fluorescence protein) foci formation at DSBs induced in U2OS cells by alpha particles, X-rays or mixed beams over a 75 min period post irradiation. X-ray-induced foci rapidly increased and declined over the observation interval. After an initial increase, mixed beam-induced foci remained at a constant level over the observation interval, similarly as alpha-induced foci. The average areas of radiation-induced foci were similar for mixed beams and X-rays, being significantly smaller than those induced by alpha particles. Pixel intensities were highest for mixed beam-induced foci and showed the lowest level of variability over time as compared to foci induced by alphas and X-rays alone. Finally, mixed beam-exposed foci showed the lowest level of mobility as compared to alpha and X-ray exposure. The results suggest paralysation of chromatin around foci containing clustered DNA damage. PMID:29419809

  18. ALLYLISOPROPYLACETAMIDE INDUCES RAT HEPATIC ORNITHINE DECARBOXYLASE

    EPA Science Inventory

    In rat liver, allylisopropylacetamide (AIA) treatment strongly induced (25-fold) the activity of rat hepatic ornithine decarboxylase (ODC). y either the oral or the subcutaneous routes, AIA produced a long-lasting induction (30 to 4O hours) of hepatic ODC activity. hree analogs o...

  19. Forced Hepatic Overexpression of CEACAM1 Curtails Diet-Induced Insulin Resistance

    PubMed Central

    Al-Share, Qusai Y.; DeAngelis, Anthony M.; Lester, Sumona Ghosh; Bowman, Thomas A.; Ramakrishnan, Sadeesh K.; Abdallah, Simon L.; Russo, Lucia; Patel, Payal R.; Kaw, Meenakshi K.; Raphael, Christian K.; Kim, Andrea Jung; Heinrich, Garrett; Lee, Abraham D.; Kim, Jason K.; Kulkarni, Rohit N.; Philbrick, William M.

    2015-01-01

    Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) regulates insulin sensitivity by promoting hepatic insulin clearance. Liver-specific inactivation or global null-mutation of Ceacam1 impairs hepatic insulin extraction to cause chronic hyperinsulinemia, resulting in insulin resistance and visceral obesity. In this study we investigated whether diet-induced insulin resistance implicates changes in hepatic CEACAM1. We report that feeding C57/BL6J mice a high-fat diet reduced hepatic CEACAM1 levels by >50% beginning at 21 days, causing hyperinsulinemia, insulin resistance, and elevation in hepatic triacylglycerol content. Conversely, liver-specific inducible CEACAM1 expression prevented hyperinsulinemia and markedly limited insulin resistance and hepatic lipid accumulation that were induced by prolonged high-fat intake. This was partly mediated by increased hepatic β-fatty acid oxidation and energy expenditure. The data demonstrate that the high-fat diet reduced hepatic CEACAM1 expression and that overexpressing CEACAM1 in liver curtailed diet-induced metabolic abnormalities by protecting hepatic insulin clearance. PMID:25972571

  20. Squamous cell hyperplastic foci: precursors of cutaneous papillomas induced in SENCAR mice by a two-stage carcinogenesis regimen.

    PubMed

    Binder, R L; Johnson, G R; Gallagher, P M; Stockman, S L; Sundberg, J P; Conti, C J

    1998-10-01

    We have conducted a series of experiments to characterize the lesions that are precursors of cutaneous papillomas in SENCAR mice initiated with 7,12-dimethylbenz(a)anthracene (DMBA) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). The first grossly detectable lesions at sites where papillomas subsequently developed were papules, slightly raised areas of skin ranging in diameter from 0.25 to approximately 1.5 mm. Papules were first detected in DMBA-initiated mice 21 days after the start of dosing with TPA. Of 78 DMBA/TPA-induced papules tracked during 15 weeks of TPA treatments, 68% progressed to papillomas, 9% persisted as papules, and 22% completely regressed. Histological evaluation of serial sections of 69 DMBA/TPA-induced papules revealed that they were focal hyperplastic lesions that we refer to as squamous cell hyperplastic foci (SCHF). These hyperproliferative lesions appeared to progress through two distinct stages. Stage I SCHF were characterized as regular hyperplastic foci involving the interfollicular epidermis and the outer root sheaths of 1 or more hair follicles down to the level of the sebaceous glands. Stage II SCHF were foci of irregular epithelial hyperplasia with increased fibrovascular stroma and involved from 3 to >10 hair follicles. Prominent dilated capillaries and inflammatory cell infiltrates were frequently associated with both stage I and II SCHF. Ha-ras gene codon 61 mutations were detected in 7 of 10 stage I SCHF and 13 of 14 stage II SCHF microdissected from histological sections and 7 of 7 of whole papules by mutation-specific PCR analysis. These data provide molecular evidence that SCHF are foci of initiated cells. Further study of these lesions may contribute to more fully defining the sequence of molecular and cellular changes necessary for tumorigenesis in mouse skin. SCHF may also have utility as early indicators of potential skin tumorigenicity in cancer bioassays.

  1. Mineral metabolism in dimethylnitrosamine-induced hepatic fibrosis.

    PubMed

    George, Joseph

    2006-10-01

    Complications such as ascites during the pathogenesis of hepatic fibrosis and cirrhosis may lead to several abnormalities in mineral metabolism. In the present investigation, we have monitored serum and liver concentrations of calcium, magnesium, sodium and potassium during experimentally induced hepatic fibrosis in rats. The liver injury was induced by intraperitoneal injections of dimethylnitrosamine (DMN; N-nitrosodimethylamine, NDMA) in doses 1 mg/100 g body weight on 3 consecutive days of each week over a period of 21 days. Calcium, magnesium, sodium and potassium were measured by atomic absorption spectrophotometry in the serum and liver on days 7, 14 and 21 after the start of DMN administration. Negative correlations were observed between liver function tests and serum mineral levels, except with albumin. Calcium, magnesium, potassium and sodium concentrations in the serum were decreased after the induction of liver injury. The liver calcium content was increased after DMN treatment. No change occurred in liver sodium content. However, magnesium and potassium content was significantly reduced in the hepatic tissue. The results suggest that DMN-induced hepatic fibrosis plays certain role in the alteration of essential elements. The low levels of albumin and the related ascites may be one of the major causes of the imbalance of mineral metabolism in hepatic fibrosis and further aggravation of the disease.

  2. Induction and quantification of gammma-H2AX foci following cx- and gamma-irradiaton

    NASA Technical Reports Server (NTRS)

    Leatherbarrow, E. L.; Cucinotta, F. A.; O'Neill, Peter

    2004-01-01

    Following DNA damage the histone H2AX becomes phosphorylated and can be visualised by immunofluorescence as an indicator of DSBs in individual cells. Using a wild type hamster cell line (V79-4) exposed to either a-particles or to Co-60 gamma-rays to induce DNA DSBs at different doses (20-200OmGy), the dose dependent induction of gamma-H2AX foci were scored both manually (by eye) and using image analysis. A linearly dependence on dose was found for both radiations. The number of DSBs determined by image analysis after a post-irradiation period of 30 minutes at 37 C, is 16.6 foci/cell/Gy for alpha-irradiation and 12.2 foci/cell/Gy for gamma-irradiation; the latter being 3-4 times the levels observed by eye and comparable to gamma-radiation-induced levels of prompt DSBs more recently reported using pulse field gel electrophoresis (approx. 16 DSBs/Gy). The average size of the gamma-H2AX foci induced by alpha-irradiation (0.30 square micrometers) is approximately 1.5 times larger than those induced by gamma-irradiation (0.19 square micrometers). The timescale of induction and removal of DSBs up to 24 hours post-irradiation, was investigated with gamma-H2AX foci levels found to remain significantly higher than controls for 4 or 6 hours in gamma-irradiated samples or alpha irradiated samples, respectively. These results demonstrate that not only gamma radiation but also alpha-radiation induce phosphorylation of the H2AX histone in response to DSBs even at low doses (20mGy for gamma-rays, 1 track/cell on average for alpha-particles) and the variation in size and dephosphorylation of the induced foci is dependent on radiation quality (LET).

  3. Stereotype threat and performance: how self-stereotypes influence processing by inducing regulatory foci.

    PubMed

    Seibt, Beate; Förster, Jens

    2004-07-01

    The authors hypothesized that activated self-stereotypes can influence the strategies of task solution by inducing regulatory foci. More specifically, positive self-stereotypes should induce a promotion focus state of eagerness, whereas negative stereotypes should induce a prevention focus state of vigilance. Study 1 showed that a negative ascribed stereotype with regard to task performance leads to better recall for avoidance-related statements whereas a positive stereotype leads to better recall for approach-related statements. In Studies 2 and 3, both an experimental manipulation of group performance expectation and the preexisting stereotype of better verbal skills in women than in men led to faster and less accurate performance in the positive as compared with the negative stereotype group. Studies 4 and 5 showed that positive in-group stereotypes led to more creative performance whereas negative stereotypes led to better analytical performance. These results point to a possible mechanism for stereotype-threat effects. Copyright 2004 American Psychological Association

  4. High dose lycopene supplementation increases hepatic cytochrome P4502E1 protein and inflammation in alcohol-fed rats.

    PubMed

    Veeramachaneni, Sudipta; Ausman, Lynne M; Choi, Sang Woon; Russell, Robert M; Wang, Xiang-Dong

    2008-07-01

    Recent in vitro evidence suggests that the antioxidant lycopene can prevent alcohol-induced oxidative stress and inflammation. However, knowledge of possible interactions in vivo between escalating doses of lycopene and chronic alcohol ingestion are lacking. In this study, we investigated potential interactions between alcohol ingestion and lycopene supplementation and their effect on hepatic lycopene concentration, cytochrome P4502E1 (CYP2E1) induction, and inflammation. Fischer 344 rats (6 groups, n = 10 per group) were fed either a liquid ethanol Lieber-DeCarli diet or a control diet (isocaloric maltodextrin substituted for ethanol) with or without lycopene supplementation at 2 doses (1.1 or 3.3 mg x kg body weight(-1) x d(-1)) for 11 wk. Plasma and hepatic concentrations of lycopene isomers were assessed by HPLC analysis. We examined expressions of hepatic CYP2E1 and tumor necrosis factor-alpha (TNFalpha) and the incidence of hepatic inflammatory foci. Both plasma and hepatic lycopene concentrations were greater in alcohol-fed rats than in control rats supplemented with identical doses of lycopene. In contrast, alcohol-fed rats had a lower percentage of lycopene cis isomers in the plasma and the liver compared with control rats fed the same dose of lycopene. Notably, lycopene supplementation at the higher dose significantly induced hepatic CYP2E1 protein, TNFalpha mRNA, and the incidence of inflammatory foci in the alcohol-fed rats but not in the control rats. These data indicate an interaction between chronic alcohol ingestion and lycopene supplementation and suggest a need for caution among individuals consuming high amounts of both alcohol and lycopene.

  5. In vitro differentiated hepatic oval-like cells enhance hepatic regeneration in CCl4 -induced hepatic injury.

    PubMed

    Awan, Sana Javaid; Baig, Maria Tayyab; Yaqub, Faiza; Tayyeb, Asima; Ali, Gibran

    2017-01-01

    Hepatic oval cells are likely to be activated during advanced stage of liver fibrosis to reconstruct damaged hepatic tissue. However, their scarcity, difficulties in isolation, and in vitro expansion hampered their transplantation in fibrotic liver. This study was aimed to investigate the repair potential of in vitro differentiated hepatic oval-like cells in CCl 4 -induced liver fibrosis. BMSCs and oval cells were isolated and characterized from C57BL/6 GFP + mice. BMSCs were differentiated into oval cells by preconditioning with HGF, EGF, SCF, and LIF and analyzed for the oval cells-specific genes. Efficiency of oval cells to reduce hepatocyte injury was studied by determining cell viability, release of LDH, and biochemical tests in a co-culture system. Further, in vivo repair potential of differentiated oval cells was determined in CCl 4 -induced fibrotic model by gene expression analysis, biochemical tests, mason trichrome, and Sirius red staining. Differentiated oval cells expressed hepatic oval cells-specific markers AFP, ALB, CK8, CK18, CK19. These differentiated cells when co-cultured with injured hepatocytes showed significant hepato-protection as measured by reduction in apoptosis, LDH release, and improvement in liver functions. Transplantation of differentiated oval cells like cells in fibrotic livers exhibited enhanced homing, reduced liver fibrosis, and improved liver functions by augmenting hepatic microenvironment by improved liver functions. This preconditioning strategy to differentiate BMSCs into oval cell leads to improved survival and homing of transplanted cells. In addition, reduction in fibrosis and functional improvement in mice with CCl 4 -induced liver fibrosis was achieved. © 2016 International Federation for Cell Biology.

  6. Alleviative effects from boswellic acid on acetaminophen-induced hepatic injury - Corrected and republished from: Biomedicine (Taipei). 2016 Jun; 6 (2): 9. doi: 10.7603/s40681-016-0009-1PMCID: PMC4864770.

    PubMed

    Chen, Lung-Che; Hu, Li-Hong; Yin, Mei-Chin

    2017-06-01

    Protective effects of boswellic acid (BA) against acetaminophen (APAP)-induced hepatotoxicity in Balb/ cA mice were examined. BA, at 0.05 or 0.1%, was supplied for 4 weeks. Acute liver injury was induced by APAP treatment. Results showed that BA intake increased hepatic BA bioavailability. APAP treatment decreased glutathione (GSH) level, increased reactive oxygen species (ROS) and oxidized glutathione (GSSG) production; and lowered activity and protein expression of glutathione reductase (GR) and heme oxygenase (HO)-1 in liver. BA intake at both doses alleviated subsequent APAP-induced oxidative stress by retaining GSH content, decreasing ROS and GSSG formations, reserving activity and expression of GR and HO-1 in liver, and lowering hepatic cytochrome P450 2E1 activity and expression. APAP treatment enhanced hepatic levels of interleukin-6, tumor necrosis factor-alpha and monocyte chemoattractant protein-1. BA pre-intake diminished APAP-induced release of those inflammatory cytokines and chemokines. APAP up-regulated hepatic protein expression of toll-like receptor (TLR)-3, TLR-4, MyD88, nuclear factor kappa B (NF-κB) p50, NF-κB p65 and JNK. BA pre-intake at both doses suppressed the expression of NF-κB p65 and p-JNK, and only at 0.1% down-regulated hepatic TLR-3, TLR-4 and MyD88 expression. APAP led to obvious foci of inflammatory cell infiltration in liver, determined by H&E stain. BA intake at both doses attenuated hepatic inflammatory infiltration. These findings support that boswellic acid is a potent hepato-protective agent. © Author(s) 2017. This article is published with open access by China Medical University.

  7. [Ketoconazole-induced hepatitis. Case report].

    PubMed

    Henning, H; Kasper, B; Lüders, C J

    1983-12-01

    Since Oct. 1981 a new systemic antifungal drug Ketoconazole is available in the Federal Republic of Germany that has proven effective even in severe cases with fungal infections. This case-study will call attention on a rare but important side effect, namely Ketoconazole induced hepatitis. As an acute icteric viral hepatitis, type Non-A-Non-B-hepatitis possibly misdiagnosed only a carefully compiled history of the recent intake of drugs points at the real cause of hepatitis. In our case-report we observed a considerable increase in serum enzymes, especially GOT, GPT and GLDH after a drug-challenge with two tablets. We recommend so-called liver functions tests 2 to 3 weeks after beginning of therapy and further-on in monthly intervals. Histologically at that time toxic hydropic changes of the liver cells and a mesenchymal reaction with portal and intralobular mainly eosinophilic infiltration could be established. The serum enzymes came to normal only after 12 weeks.

  8. Albendazole Induced Recurrent Acute Toxic Hepatitis: A Case Report.

    PubMed

    Bilgic, Yilmaz; Yilmaz, Cengiz; Cagin, Yasir Furkan; Atayan, Yahya; Karadag, Nese; Harputluoglu, Murat Muhsin Muhip

    2017-01-01

    Drug induced acute toxic hepatitis can be idiosyncratic. Albendazole, a widely used broad spectrum antiparasitic drug is generally accepted as a safe drug. It may cause asymptomatic transient liver enzyme abnormalities but acute toxic hepatitis is very rare. Case Report : Herein, we present the case of 47 year old woman with recurrent acute toxic hepatitis after a single intake of albendazole in 2010 and 2014. The patient was presented with symptoms and findings of anorexia, vomiting and jaundice. For diagnosis, other acute hepatitis etiologies were excluded. Roussel Uclaf Causality Assessment Method (RUCAM) score was calculated and found to be 10, which meant highly probable drug hepatotoxicity. Within 2 months, all pathological findings came to normal. There are a few reported cases of albendazole induced toxic hepatitis, but at adults, there is no known recurrent acute toxic hepatitis due to albendazole at this certainty according to RUCAM score. Physicians should be aware of this rare and potentially fatal adverse effect of albendazole. © Acta Gastro-Enterologica Belgica.

  9. Aerobic capacity and hepatic mitochondrial lipid oxidation alters susceptibility for chronic high-fat diet-induced hepatic steatosis.

    PubMed

    Morris, E Matthew; Meers, Grace M E; Koch, Lauren G; Britton, Steven L; Fletcher, Justin A; Fu, Xiaorong; Shankar, Kartik; Burgess, Shawn C; Ibdah, Jamal A; Rector, R Scott; Thyfault, John P

    2016-10-01

    Rats selectively bred for high capacity running (HCR) or low capacity running (LCR) display divergence for intrinsic aerobic capacity and hepatic mitochondrial oxidative capacity, both factors associated with susceptibility for nonalcoholic fatty liver disease. Here, we tested if HCR and LCR rats display differences in susceptibility for hepatic steatosis after 16 wk of high-fat diets (HFD) with either 45% or 60% of kcals from fat. HCR rats were protected against HFD-induced hepatic steatosis, whereas only the 60% HFD induced steatosis in LCR rats, as marked by a doubling of liver triglycerides. Hepatic complete fatty acid oxidation (FAO) and mitochondrial respiratory capacity were all lower in LCR compared with HCR rats. LCR rats also displayed lower hepatic complete and incomplete FAO in the presence of etomoxir, suggesting a reduced role for noncarnitine palmitoyltransferase-1-mediated lipid catabolism in LCR versus HCR rats. Hepatic complete FAO and mitochondrial respiration were largely unaffected by either chronic HFD; however, 60% HFD feeding markedly reduced 2-pyruvate oxidation, a marker of tricarboxylic acid (TCA) cycle flux, and mitochondrial complete FAO only in LCR rats. LCR rats displayed lower levels of hepatic long-chain acylcarnitines than HCR rats but maintained similar levels of hepatic acetyl-carnitine levels, further supporting lower rates of β-oxidation, and TCA cycle flux in LCR than HCR rats. Finally, only LCR rats displayed early reductions in TCA cycle genes after the acute initiation of a HFD. In conclusion, intrinsically high aerobic capacity confers protection against HFD-induced hepatic steatosis through elevated hepatic mitochondrial oxidative capacity.

  10. Aerobic capacity and hepatic mitochondrial lipid oxidation alters susceptibility for chronic high-fat diet-induced hepatic steatosis

    PubMed Central

    Morris, E. Matthew; Meers, Grace M. E.; Koch, Lauren G.; Britton, Steven L.; Fletcher, Justin A.; Fu, Xiaorong; Shankar, Kartik; Burgess, Shawn C.; Ibdah, Jamal A.; Rector, R. Scott

    2016-01-01

    Rats selectively bred for high capacity running (HCR) or low capacity running (LCR) display divergence for intrinsic aerobic capacity and hepatic mitochondrial oxidative capacity, both factors associated with susceptibility for nonalcoholic fatty liver disease. Here, we tested if HCR and LCR rats display differences in susceptibility for hepatic steatosis after 16 wk of high-fat diets (HFD) with either 45% or 60% of kcals from fat. HCR rats were protected against HFD-induced hepatic steatosis, whereas only the 60% HFD induced steatosis in LCR rats, as marked by a doubling of liver triglycerides. Hepatic complete fatty acid oxidation (FAO) and mitochondrial respiratory capacity were all lower in LCR compared with HCR rats. LCR rats also displayed lower hepatic complete and incomplete FAO in the presence of etomoxir, suggesting a reduced role for noncarnitine palmitoyltransferase-1-mediated lipid catabolism in LCR versus HCR rats. Hepatic complete FAO and mitochondrial respiration were largely unaffected by either chronic HFD; however, 60% HFD feeding markedly reduced 2-pyruvate oxidation, a marker of tricarboxylic acid (TCA) cycle flux, and mitochondrial complete FAO only in LCR rats. LCR rats displayed lower levels of hepatic long-chain acylcarnitines than HCR rats but maintained similar levels of hepatic acetyl-carnitine levels, further supporting lower rates of β-oxidation, and TCA cycle flux in LCR than HCR rats. Finally, only LCR rats displayed early reductions in TCA cycle genes after the acute initiation of a HFD. In conclusion, intrinsically high aerobic capacity confers protection against HFD-induced hepatic steatosis through elevated hepatic mitochondrial oxidative capacity. PMID:27600823

  11. The Analysis of the Patterns of Radiation-Induced DNA Damage Foci by a Stochastic Monte Carlo Model of DNA Double Strand Breaks Induction by Heavy Ions and Image Segmentation Software

    NASA Technical Reports Server (NTRS)

    Ponomarev, Artem; Cucinotta, F.

    2011-01-01

    To create a generalized mechanistic model of DNA damage in human cells that will generate analytical and image data corresponding to experimentally observed DNA damage foci and will help to improve the experimental foci yields by simulating spatial foci patterns and resolving problems with quantitative image analysis. Material and Methods: The analysis of patterns of RIFs (radiation-induced foci) produced by low- and high-LET (linear energy transfer) radiation was conducted by using a Monte Carlo model that combines the heavy ion track structure with characteristics of the human genome on the level of chromosomes. The foci patterns were also simulated in the maximum projection plane for flat nuclei. Some data analysis was done with the help of image segmentation software that identifies individual classes of RIFs and colocolized RIFs, which is of importance to some experimental assays that assign DNA damage a dual phosphorescent signal. Results: The model predicts the spatial and genomic distributions of DNA DSBs (double strand breaks) and associated RIFs in a human cell nucleus for a particular dose of either low- or high-LET radiation. We used the model to do analyses for different irradiation scenarios. In the beam-parallel-to-the-disk-of-a-flattened-nucleus scenario we found that the foci appeared to be merged due to their high density, while, in the perpendicular-beam scenario, the foci appeared as one bright spot per hit. The statistics and spatial distribution of regions of densely arranged foci, termed DNA foci chains, were predicted numerically using this model. Another analysis was done to evaluate the number of ion hits per nucleus, which were visible from streaks of closely located foci. In another analysis, our image segmentaiton software determined foci yields directly from images with single-class or colocolized foci. Conclusions: We showed that DSB clustering needs to be taken into account to determine the true DNA damage foci yield, which helps to

  12. Suppressive role of hepatic dendritic cells in concanavalin A-induced hepatitis

    PubMed Central

    Tomiyama, C; Watanabe, H; Izutsu, Y; Watanabe, M; Abo, T

    2011-01-01

    Concanavalin A (Con A)-induced hepatitis is a mouse model of acute autoimmune hepatitis. The aim of this study was to investigate the role of hepatic dendritic cells (DC) in the immune modulation of tissue damage. Almost all hepatic DC were plasmacytoid DC (CD11c+ I-Alow B220+); however, conventional DC were CD11c+ I-Ahigh B220–. At an early stage (3–6 h) after Con A administration, the number of DC in both the liver and spleen decreased, increasing thereafter (12–24 h) in parallel with hepatic failure. The hepatic CD11c+ DC population contained many CD11b- cells, while the majority of splenic CD11c+ DC were CD11b+. After Con A administration, the proportion of I-A+ and CD11b+ cells within the CD11c+ DC population tended to increase in the liver, but not in the spleen. Similarly, expression of the activation markers CD80, CD86 and CD40 by CD11c+ DC increased in the liver, but not in the spleen. Next, adoptive transfer of DC isolated from the liver and spleen was performed 3 h after Con A administration to examine the immunomodulatory function of DC. Only hepatic DC had the ability to suppress hepatic failure. Analysis of cytokine production and subsequent identification of the effector cells showed that hepatic DC achieved this by suppressing the production of interleukin (IL)-12 and IL-2, rather than modulating effector cell function. PMID:21985372

  13. DNA DSB measurements and modelling approaches based on gamma-H2AX foci time evolution

    NASA Astrophysics Data System (ADS)

    Esposito, Giuseppe; Campa, Alessandro; Antonelli, Francesca; Mariotti, Luca; Belli, Mauro; Giardullo, Paola; Simone, Giustina; Antonella Tabocchini, Maria; Ottolenghi, Andrea

    DNA double strand breaks (DSBs) induced by ionising radiation are considered the main dam-age related to the deleterious consequences in the cells. Unrepaired or mis-repaired DSBs can cause mutations or loss of chromosome regions which can eventually lead to cell death or neo-plastic transformation. Quantification of the number and complexity of DSBs induced by low doses of radiation remains a complex problem. About ten years ago Rogakou et al. proposed an immunofluorescent technique able to detect even a single DSB per cell. This approach is based on the serine 139 phosphorylation of many molecules (up to 2000) of histone H2AX (γg-H2AX) following the induction of a DSB in the DNA. DSB can be visualized as foci by immunofluores-cence by using phospho-specific antibodies, so that enumeration of foci can be used to measure DSB induction and processing. It is still not completely clear how γ-H2AX dephosphorylation takes place; however it has been related with DSB repair, in particular with the efficiency of DSB repair. In this work we analyse the H2AX phosphorylation-dephosphorylation kinetics after irradiation of primary human fibroblasts (AG1522 cell line) with radiation of differing quality, that is γ-rays and α-particles (125 keV/µm), with the aim of comparing the time evolution of γ-H2AX foci. Our results show that, after a dose of 0.5 Gy, both γ-rays and α-particles induce the maximum number of γ-H2AX foci within 30 minutes from irradiation, that this number depends on the radiation type and is consistent with the number of track traversal in α-irradiated nuclei, that the dephosphorylation kinetics are very different, being the α-induced foci rate of disappearence slower than that of γ-induced foci. In this work a modellistic approach to estimate the number of DSB induced by γ-rays detectable by using the γ-H2AX assay is presented. The competing processes of appearance and disappearance of visible foci will be modeled taking into account the

  14. Vanadium inhibits DNA-protein cross-links and ameliorates surface level changes of aberrant crypt foci during 1,2-dimethylhydrazine induced rat colon carcinogenesis.

    PubMed

    Kanna, P Suresh; Saralaya, M G; Samanta, K; Chatterjee, M

    2005-01-01

    The trace mineral vanadium inhibits cancer development in a variety of experimental animal models. The present study was to gain insight into a putative anticancer effect of vanadium in a rat model of colon carcinogenesis. The in vivo study was intended to clarify the effect of vanadium on DNA-protein cross-links (DPC), surface level changes of aberrant crypt foci (ACF) and biotransformation status during 1,2-dimethylhydrazine (1,2-DMH) induced preneoplastic rat colon carcinogenesis. The comet assay showed statistically higher mean base values of DNA-protein mass (p<0.01) and mean frequencies of tailed cells (p<0.001) in the carcinogen-induced group after treatment with proteinase K. Treatment with vanadium in the form of ammonium monovanadate supplemented ad libitum in drinking water for the entire experimental period caused a significant (p<0.02) reduction (40%) in DNA-protein cross-links in colon cells. Further, the biotransformation status of vanadium was ascertained measuring the drug metabolising enzymes, glutathione S-transferase (GST) and cytochrome P-450 (Cyt P-450). Significantly, there was an increase in glutathione S-transferase and cytochrome P-450 levels (p<0.01 and p<0.02, respectively) in rats supplemented with vanadium as compared to their carcinogen controls. As an endpoint marker, we also evaluated the effect of vanadium on surface level changes of aberrant crypt foci induced by 1,2-DMH by scanning electron microscopy. Animals induced with 1,2-DMH and supplemented with vanadium showed a marked improvement in colonic architecture with less number of aberrant crypt foci in contrast to the animals induced with 1,2-DMH alone, thereby exhibiting its anti-carcinogenicity by modulating the markers studied herein.

  15. Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bai, Xupeng; Hong, Weipeng; Cai, Peiheng

    Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36),more » an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) – extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity. - Highlights: • VPA induced hepatic steatosis and modulated genes associated with lipid metabolism. • CD36-mediated fatty acid uptake contributed to VPA-induced lipid accumulation. • PA increased the

  16. Ursodeoxycholyl Lysophosphatidylethanolamide Protects Against CD95/FAS-Induced Fulminant Hepatitis.

    PubMed

    Utaipan, Tanyarath; Otto, Ann-Christin; Gan-Schreier, Hongying; Chunglok, Warangkana; Pathil, Anita; Stremmel, Wolfgang; Chamulitrat, Walee

    2017-08-01

    Increased activation of CD95/Fas by Fas ligand in viral hepatitis and autoimmunity is involved in pathogenesis of fulminant hepatitis and liver failure. We designed a bile-acid phospholipid conjugate ursodeoxycholyl lysophosphatidylethanolamide (UDCA-LPE with LPE containing oleate at the sn-1) as a hepatoprotectant that was shown to protect against fulminant hepatitis induced by endotoxin. We herein further assessed the ability of UDCA-LPE to prevent death receptor CD95/Fas-induced fulminant hepatitis. C57BL/6 mice were intravenously administered with CD95/Fas agonistic monoclonal antibody (Jo-2) with or without 1 h pretreatment with 50 mg/kg UDCA-LPE. Jo-2 administration caused massive hepatocyte damage as seen by histology, and this was associated with a significant decrease in hepatic phosphatidylcholine (PC), lysoPC, and lysophosphatidylethanolamine levels. By histology, UDCA-LPE pretreatment improved hepatocyte damage and restored the loss of these phospholipids in part by a mechanism involving an inhibition of cytosolic phospholipaseA2 expression. Accordingly, Jo-2 treatment increased hepatic expression of cleaved caspase 8, caspase 3, and poly (ADP-Ribose) polymerase-1, and on the other hand decreased that of anti-apoptotic cellular FLICE-inhibitory protein. UDCA-LPE pretreatment was able to reverse all these changes. Moreover, UDCA-LPE attenuated inflammatory response by lowering the levels of Jo-2-induced proinflammatory cytokines TNF-α, IL-6, and IL-1β in liver and serum. UDCA-LPE was also able to decrease the levels of stimulated Th1/Th17 cytokines in Jo-2-primed isolated splenocytes. Taken together, UDCA-LPE exhibited potent anti-inflammatory effects against CD95/Fas-induced fulminant hepatitis.

  17. Hepatic FGF21 mediates sex differences in high-fat high-fructose diet-induced fatty liver.

    PubMed

    Chukijrungroat, Natsasi; Khamphaya, Tanaporn; Weerachayaphorn, Jittima; Songserm, Thaweesak; Saengsirisuwan, Vitoon

    2017-08-01

    The role of gender in the progression of fatty liver due to chronic high-fat high-fructose diet (HFFD) has not been studied. The present investigation assessed whether HFFD induced hepatic perturbations differently between the sexes and examined the potential mechanisms. Male, female, and ovariectomized (OVX) Sprague-Dawley rats were fed either a control diet or HFFD for 12 wk. Indexes of liver damage and hepatic steatosis were analyzed biochemically and histologically together with monitoring changes in hepatic gene and protein expression. HFFD induced a higher degree of hepatic steatosis in females, with significant increases in proteins involved in hepatic lipogenesis, whereas HFFD significantly induced liver injury, inflammation, and oxidative stress only in males. Interestingly, a significant increase in hepatic fibroblast growth factor 21 (FGF21) protein expression was observed in HFFD-fed males but not in HFFD-fed females. Ovarian hormone deprivation by itself led to a significant reduction in FGF21 with hepatic steatosis, and HFFD further aggravated hepatic fat accumulation in OVX rats. Importantly, estrogen replacement restored hepatic FGF21 levels and reduced hepatic steatosis in HFFD-fed OVX rats. Collectively, our results indicate that male rats are more susceptible to HFFD-induced hepatic inflammation and that the mechanism underlying this sex dimorphism is mediated through hepatic FGF21 expression. Our findings reveal sex differences in the development of HFFD-induced fatty liver and indicate the protective role of estrogen against HFFD-induced hepatic steatosis. Copyright © 2017 the American Physiological Society.

  18. Modulation of hepatic stellate cells and reversibility of hepatic fibrosis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Huang, Yu, E-mail: 1293363632@QQ.com; Deng, Xin, E-mail: Hendly@163.com; Liang, Jian, E-mail: lj99669@163.com

    Hepatic fibrosis (HF) is the pathological component of a variety of chronic liver diseases. Hepatic stellate cells (HSC) are the main collagen-producing cells in the liver and their activation promotes HF. If HSC activation and proliferation can be inhibited, HF occurrence and development can theoretically be reduced and even reversed. Over the past ten years, a number of studies have addressed this process, and here we present a review of HSC modulation and HF reversal. - Highlights: • We present a review of the modulation of hepatic stellate cells (HSC) and reversibility of hepatic fibrosis (HF). • HSC are themore » foci of HF occurrence and development, HF could be prevented and treated by modulating HSC. • If HSC activation and proliferation can be inhibited, HF could theoretically be inhibited and even reversed. • Prevention or reversal of HSC activation, or promotion of HSC apoptosis, immune elimination, and senescence may prevent, inhibit or reverse HF.« less

  19. Protective effects of L-carnosine on CCl4 -induced hepatic injury in rats.

    PubMed

    Alsheblak, Mehyar Mohammad; Elsherbiny, Nehal M; El-Karef, Amro; El-Shishtawy, Mamdouh M

    2016-03-01

    The present study was undertaken to investigate the possible protective effect of L-carnosine (CAR), an endogenous dipeptide of alanine and histidine, on carbon tetrachloride (CCl4)-induced hepatic injury. Liver injury was induced in male Sprague-Dawley rats by intraperitoneal (i.p.) injections of CCl4, twice weekly for six weeks. CAR was administered to rats daily, at dose of 250 mg/kg, i.p. At the end of six weeks, blood and liver tissue specimens were collected. Results show that CAR treatment attenuated the hepatic morphological changes, necroinflammation and fibrosis induced by CCl4, as indicated by hepatic histopathology scoring. In addition, CAR treatment significantly reduced the CCl4-induced elevation of liver-injury parameters in serum. CAR treatment also combatted oxidative stress; possibly by restoring hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) levels. Moreover, CAR treatment prevented the activation of hepatic stellate cells (HSCs), as indicated by reduced α-smooth muscle actin (α-SMA) expression in the liver, and decreased hepatic inflammation as demonstrated by a reduction in hepatic tumor necrosis factor-α (TNF-α) and restoration of interleukin-10 (IL-10) levels. In conclusion, CCl4-induced hepatic injury was alleviated by CAR treatment. The results suggest that these beneficial, protective effects are due, at least in part, to its anti-oxidant, anti-inflammatory and anti-fibrotic activities.

  20. Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-γ expression.

    PubMed

    Mwangi, Simon Musyoka; Peng, Sophia; Nezami, Behtash Ghazi; Thorn, Natalie; Farris, Alton B; Jain, Sanjay; Laroui, Hamed; Merlin, Didier; Anania, Frank; Srinivasan, Shanthi

    2016-01-15

    Glial cell line-derived neurotrophic factor (GDNF) protects against high-fat diet (HFD)-induced hepatic steatosis in mice, however, the mechanisms involved are not known. In this study we investigated the effects of GDNF overexpression and nanoparticle delivery of GDNF in mice on hepatic steatosis and fibrosis and the expression of genes involved in the regulation of hepatic lipid uptake and de novo lipogenesis. Transgenic overexpression of GDNF in liver and other metabolically active tissues was protective against HFD-induced hepatic steatosis. Mice overexpressing GDNF had significantly reduced P62/sequestosome 1 protein levels suggestive of accelerated autophagic clearance. They also had significantly reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) and CD36 gene expression and protein levels, and lower expression of mRNA coding for enzymes involved in de novo lipogenesis. GDNF-loaded nanoparticles were protective against short-term HFD-induced hepatic steatosis and attenuated liver fibrosis in mice with long-standing HFD-induced hepatic steatosis. They also suppressed the liver expression of steatosis-associated genes. In vitro, GDNF suppressed triglyceride accumulation in Hep G2 cells through enhanced p38 mitogen-activated protein kinase-dependent signaling and inhibition of PPAR-γ gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of nonalcoholic fatty liver disease.

  1. β-Cell Hyperplasia Induced by Hepatic Insulin Resistance

    PubMed Central

    Escribano, Oscar; Guillén, Carlos; Nevado, Carmen; Gómez-Hernández, Almudena; Kahn, C. Ronald; Benito, Manuel

    2009-01-01

    OBJECTIVE Type 2 diabetes results from a combination of insulin resistance and impaired insulin secretion. To directly address the effects of hepatic insulin resistance in adult animals, we developed an inducible liver-specific insulin receptor knockout mouse (iLIRKO). RESEARCH DESIGN AND METHODS Using this approach, we were able to induce variable insulin receptor (IR) deficiency in a tissue-specific manner (liver mosaicism). RESULTS iLIRKO mice presented progressive hepatic and extrahepatic insulin resistance without liver dysfunction. Initially, iLIRKO mice displayed hyperinsulinemia and increased β-cell mass, the extent of which was proportional to the deletion of hepatic IR. Our studies of iLIRKO suggest a cause-and-effect relationship between progressive insulin resistance and the fold increase of plasma insulin levels and β-cell mass. Ultimately, the β-cells failed to secrete sufficient insulin, leading to uncontrolled diabetes. We observed that hepatic IGF-1 expression was enhanced in iLIRKO mice, resulting in an increase of circulating IGF-1. Concurrently, the IR-A isoform was upregulated in hyperplastic β-cells of iLIRKO mice and IGF-1–induced proliferation was higher than in the controls. In mouse β-cell lines, IR-A, but not IR-B, conferred a proliferative capacity in response to insulin or IGF-1, providing a potential explanation for the β-cell hyperplasia induced by liver insulin resistance in iLIRKO mice. CONCLUSIONS Our studies of iLIRKO mice suggest a liver-pancreas endocrine axis in which IGF-1 functions as a liver-derived growth factor to promote compensatory pancreatic islet hyperplasia through IR-A. PMID:19136656

  2. Parvovirus B19 induced hepatic failure in an adult requiring liver transplantation

    PubMed Central

    Krygier, Darin S; Steinbrecher, Urs P; Petric, Martin; Erb, Siegfried R; Chung, Stephen W; Scudamore, Charles H; Buczkowski, Andrzej K; Yoshida, Eric M

    2009-01-01

    Parvovirus B19 induced acute hepatitis and hepatic failure have been previously reported, mainly in children. Very few cases of parvovirus induced hepatic failure have been reported in adults and fewer still have required liver transplantation. We report the case of a 55-year-old immunocompetent woman who developed fulminant hepatic failure after acute infection with Parvovirus B19 who subsequently underwent orthotopic liver transplantation. This is believed to be the first reported case in the literature in which an adult patient with fulminant hepatic failure associated with acute parvovirus B19 infection and without hematologic abnormalities has been identified prior to undergoing liver transplantation. This case suggests that Parvovirus B19 induced liver disease can affect adults, can occur in the absence of hematologic abnormalities and can be severe enough to require liver transplantation. PMID:19705505

  3. Reduced hepatic injury in Toll-like receptor 4-deficient mice following D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.

    PubMed

    Ben Ari, Ziv; Avlas, Orna; Pappo, Orit; Zilbermints, Veacheslav; Cheporko, Yelena; Bachmetov, Larissa; Zemel, Romy; Shainberg, Asher; Sharon, Eran; Grief, Franklin; Hochhauser, Edith

    2012-01-01

    Liver transplantation is the only therapy of proven benefit in fulminant hepatic failure (FHF). Lipopolysaccharide (LPS), D-galactosamine (GalN)-induced FHF is a well established model of liver injury in mice. Toll-Like Receptor 4 (TLR4) has been identified as a receptor for LPS. The aim of this study was to investigate the role of TLR4 in FHF induced by D-GalN/LPS administration in mice. Wild type (WT) and TLR4 deficient (TLR4ko) mice were studied in vivo in a fulminant model induced by GalN/LPS. Hepatic TLR4 expression, serum liver enzymes, hepatic and serum TNF-α and interleukin-1β levels were determined. Apoptotic cells were identified by immunohistochemistry for caspase-3. Nuclear factor-kappaβ (NF-κ β) and phosphorylated c-Jun hepatic expression were studied using Western blot analysis. All WT mice died within 24 hours after administration of GalN/LPS while all TLR4ko mice survived. Serum liver enzymes, interleukin-1β, TNF-α level, TLR4 mRNA expression, hepatic injury and hepatocyte apoptosis all significantly decreased in TLR4ko mice compared with WT mice. A significant decrease in hepatic c-Jun and IκB signaling pathway was noted in TLR4ko mice compared with WT mice. In conclusion, following induction of FHF, the inflammatory response and the liver injury in TLR4ko mice was significantly attenuated through decreased hepatic c-Jun and NF-κB expression and thus decreased TNF-α level. Down-regulation of TLR4 expression plays a pivotal role in GalN/LPS induced FHF. These findings might have important implications for the use of the anti TLR4 protein signaling as a potential target for therapeutic intervention in FHF. Copyright © 2012 S. Karger AG, Basel.

  4. Toxin-Induced Autoimmune Hepatitis Caused by Raw Cashew Nuts.

    PubMed

    Crismale, James F; Stueck, Ashley; Bansal, Meena

    2016-08-01

    A 64-year-old man with no past medical history presented with abnormally elevated liver enzymes 1 year after developing a diffuse rash thought to be related to eating large quantities of raw cashew nuts. Liver biopsy was performed, which revealed features concerning for drug- or toxin-induced autoimmune hepatitis. The patient began treatment with azathioprine and prednisone, and liver enzymes normalized. We describe a unique case of a toxin-induced autoimmune hepatitis precipitated not by a drug or dietary supplement but by a food product.

  5. Antioxidant and Hepatoprotective Efficiency of Selenium Nanoparticles Against Acetaminophen-Induced Hepatic Damage.

    PubMed

    Amin, Kamal Adel; Hashem, Khalid Shaban; Alshehri, Fawziah Saleh; Awad, Said T; Hassan, Mohammed S

    2017-01-01

    Overdoses of acetaminophen (APAP), a famous and widely used drug, may have hepatotoxic effects. Nanoscience is a novel scientific discipline that provides specific tools for medical science problems including using nano trace elements in hepatic diseases. Our study aimed to assess the hepatoprotective role of selenium nanoparticles (Nano-Se) against APAP-induced hepatic injury. Twenty-four male rats were classified into three equal groups: a control group that received 0.9 % NaCl, an APAP-treated group (oral administration), and a group treated with Nano-Se (10-20 nm, intraperitoneal (i.p.) injection) and APAP (oral administration). APAP overdose induced significant elevations in liver function biomarkers, hepatic lipid peroxidation, hepatic catalase, and superoxide dismutase (SOD), decreased the reduced glutathione (GSH) content and glutathione reductase (GR) activity, and stimulated significant DNA damage in hepatocytes, compared to control rats. Nano-Se administration improved the hepatic antioxidant protection mechanism and decreased cellular sensitivity to DNA fragmentation. Nano-Se exhibits a protective effect against APAP-induced hepatotoxicity through improved liver function and oxidative stress mediated by catalase, SOD, and GSH and decreases hepatic DNA fragmentation, a hepatic biomarker of cell death. Nano-Se could be a novel hepatoprotective strategy to inhibit oxidative stress.

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

    PubMed

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

    2014-01-01

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

  7. Tumor Induced Hepatic Myeloid Derived Suppressor Cells Can Cause Moderate Liver Damage

    PubMed Central

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

    2014-01-01

    Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage. PMID:25401795

  8. Metformin inhibits early stage diethylnitrosamine-induced hepatocarcinogenesis in rats

    PubMed Central

    JO, WOORI; YU, EUN-SIL; CHANG, MINSUN; PARK, HYUN-KYU; CHOI, HYUN-JI; RYU, JAE-EUN; JANG, SUNGWOONG; LEE, HYO-JU; JANG, JA-JUNE; SON, WOO-CHAN

    2016-01-01

    Antitumor effects of metformin have recently emerged despite its original use for type II diabetes. In the present study, the effects of metformin on the development and recurrence of hepatocellular carcinoma (HCC) were investigated using the diethylnitrosamine (DEN)-induced rat model of HCC. Tumor foci were characterized by gross examination and by histopathological characteristics, including proliferation, hepatic progenitor cell content and the expression of hepatocarcinoma-specific molecular markers. Potential target molecules of metformin were investigated to determine the molecular mechanism underlying the inhibitory effects of metformin on chemically induced liver tumorigenesis. The antitumor effects of metformin were increased by the reduction of surface nodules and decreased the incidence of altered hepatocellular foci, hepatocellular adenoma and carcinoma. Also, decreased expression levels of glutathione S-transferase placental form, proliferating cell nuclear antigen and cytokeratin 8 described the inhibitory effects of metformin on HCC. In the present study, Wistar rats receiving treatment with DEN were administered metformin for 16 weeks. In addition, metformin suppressed liver tumorigenesis via an AMPK-dependent pathway. These results suggested that metformin has promising effects on the early stage of HCC in rats. Therefore, metformin may be used for the prevention of HCC recurrence following primary chemotherapy for HCC and/or for high-risk patients, including chronic hepatitis and cirrhosis. PMID:26548419

  9. Ferret hepatitis E virus infection induces acute hepatitis and persistent infection in ferrets.

    PubMed

    Li, Tian-Cheng; Yang, Tingting; Yoshizaki, Sayaka; Ami, Yasushi; Suzaki, Yuriko; Ishii, Koji; Kishida, Noriko; Shirakura, Masayuki; Asanuma, Hideki; Takeda, Naokazu; Wakita, Takaji

    2016-02-01

    Ferret hepatitis E virus (HEV), a novel hepatitis E virus, has been identified in ferrets. However, the pathogenicity of ferret HEV remains unclear. In the present study, we compared the HEV RNA-positivity rates and alanine aminotransferase (ALT) levels of 63 ferrets between before and after import from the US to Japan. We found that the ferret HEV-RNA positivity rates were increased from 12.7% (8/63) to 60.3% (38/63), and ALT elevation was observed in 65.8% (25/38) of the ferret HEV RNA-positive ferrets, indicating that ferret HEV infection is responsible for liver damage. From long term-monitoring of ferret HEV infection we determined that this infection in ferrets exhibits three patterns: sub-clinical infection, acute hepatitis, and persistent infection. The ALT elevation was also observed in ferret HEV-infected ferrets in a primary infection experiment. These results indicate that the ferret HEV infection induced acute hepatitis and persistent infection in ferrets, suggesting that the ferrets are a candidate animal model for immunological as well as pathological studies of hepatitis E. Copyright © 2015 Elsevier B.V. All rights reserved.

  10. From Connectivity Models to Region Labels: Identifying Foci of a Neurological Disorder

    PubMed Central

    Venkataraman, Archana; Kubicki, Marek; Golland, Polina

    2014-01-01

    We propose a novel approach to identify the foci of a neurological disorder based on anatomical and functional connectivity information. Specifically, we formulate a generative model that characterizes the network of abnormal functional connectivity emanating from the affected foci. This allows us to aggregate pairwise connectivity changes into a region-based representation of the disease. We employ the variational expectation-maximization algorithm to fit the model and subsequently identify both the afflicted regions and the differences in connectivity induced by the disorder. We demonstrate our method on a population study of schizophrenia. PMID:23864168

  11. Improvement of Carbon Tetrachloride-Induced Acute Hepatic Failure by Transplantation of Induced Pluripotent Stem Cells without Reprogramming Factor c-Myc

    PubMed Central

    Chang, Hua-Ming; Liao, Yi-Wen; Chiang, Chih-Hung; Chen, Yi-Jen; Lai, Ying-Hsiu; Chang, Yuh-Lih; Chen, Hen-Li; Jeng, Shaw-Yeu; Hsieh, Jung-Hung; Peng, Chi-Hsien; Li, Hsin-Yang; Chien, Yueh; Chen, Szu-Yu; Chen, Liang-Kung; Huo, Teh-Ia

    2012-01-01

    The only curative treatment for hepatic failure is liver transplantation. Unfortunately, this treatment has several major limitations, as for example donor organ shortage. A previous report demonstrated that transplantation of induced pluripotent stem cells without reprogramming factor c-Myc (3-genes iPSCs) attenuates thioacetamide-induced hepatic failure with minimal incidence of tumorigenicity. In this study, we investigated whether 3-genes iPSC transplantation is capable of rescuing carbon tetrachloride (CCl4)-induced fulminant hepatic failure and hepatic encephalopathy in mice. Firstly, we demonstrated that 3-genes iPSCs possess the capacity to differentiate into hepatocyte-like cells (iPSC-Heps) that exhibit biological functions and express various hepatic specific markers. 3-genes iPSCs also exhibited several antioxidant enzymes that prevented CCl4-induced reactive oxygen species production and cell death. Intraperitoneal transplantation of either 3-genes iPSCs or 3-genes iPSC-Heps significantly reduced hepatic necrotic areas, improved hepatic functions, and survival rate in CCl4-treated mice. CCl4-induced hepatic encephalopathy was also improved by 3-genes iPSC transplantation. Hoechst staining confirmed the successful engraftment of both 3-genes iPSCs and 3-genes iPSC-Heps, indicating the homing properties of these cells. The most pronounced hepatoprotective effect of iPSCs appeared to originate from the highest antioxidant activity of 3-gene iPSCs among all transplanted cells. In summary, our findings demonstrated that 3-genes iPSCs serve as an available cell source for the treatment of an experimental model of acute liver diseases. PMID:22489170

  12. Selective inhibition of iNOS attenuates trauma-hemorrhage/resuscitation-induced hepatic injury.

    PubMed

    Kan, Wen-Hong; Hsu, Jun-Te; Schwacha, Martin G; Choudhry, Mashkoor A; Raju, Raghavan; Bland, Kirby I; Chaudry, Irshad H

    2008-10-01

    Although trauma-hemorrhage produces tissue hypoxia, systemic inflammatory response and organ dysfunction, the mechanisms responsible for these alterations are not clear. Using a potent selective inducible nitric oxide (NO) synthase inhibitor, N-[3-(aminomethyl) benzyl]acetamidine (1400W), and a nonselective NO synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), we investigated whether inducible NO synthase plays any role in producing hepatic injury, inflammation, and changes of protein expression following trauma-hemorrhage. To investigate this, male Sprague-Dawley rats were subjected to midline laparotomy and hemorrhagic shock (mean blood pressure 35-40 mmHg for approximately 90 min) followed by fluid resuscitation. Animals were treated with either vehicle (DMSO) or 1400W (10 mg/kg body wt ip), or L-NAME (30 mg/kg iv), 30 min before resuscitation and killed 2 h after resuscitation. Trauma-hemorrhage/resuscitation induced a marked hypotension and increase in markers of hepatic injury (i.e., plasma alpha-glutathione S-transferase, tissue myeloperoxidase activity, and nitrotyrosine formation). Hepatic expression of iNOS, hypoxia-inducible factor-1alpha, ICAM-1, IL-6, TNF-alpha, and neutrophil chemoattractant (cytokine-induced neutrophil chemoattractant-1 and macrophage inflammatory protein-2) protein levels were also markedly increased following trauma-hemorrhage/resuscitation. Administration of the iNOS inhibitor 1400W significantly attenuated hypotension and expression of these mediators of hepatic injury induced by trauma-hemorrhage/resuscitation. However, administration of L-NAME could not attenuate hepatic dysfunction and tissue injury mediated by trauma-hemorrhage, although it improved mean blood pressure as did 1400W. These results indicate that increased expression of iNOS following trauma-hemorrhage plays an important role in the induction of hepatic damage under such conditions.

  13. Alteration of hepatic structure and oxidative stress induced by intravenous nanoceria

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Tseng, Michael T., E-mail: mttsen01@louisville.edu; Lu, Xiaoqin, E-mail: x0lu0003@louisville.edu; Duan, Xiaoxian, E-mail: x0duan02@louisville.edu

    2012-04-15

    Beyond the traditional use of ceria as an abrasive, the scope of nanoceria applications now extends into fuel cell manufacturing, diesel fuel additives, and for therapeutic intervention as a putative antioxidant. However, the biological effects of nanoceria exposure have yet to be fully defined, which gave us the impetus to examine its systemic biodistribution and biological responses. An extensively characterized nanoceria (5 nm) dispersion was vascularly infused into rats, which were terminated 1 h, 20 h or 30 days later. Light and electron microscopic tissue characterization was conducted and hepatic oxidative stress parameters determined. We observed acute ceria nanoparticle sequestrationmore » by Kupffer cells with subsequent bioretention in parenchymal cells as well. The internalized ceria nanoparticles appeared as spherical agglomerates of varying dimension without specific organelle penetration. In hepatocytes, the agglomerated nanoceria frequently localized to the plasma membrane facing bile canaliculi. Hepatic stellate cells also sequestered nanoceria. Within the sinusoids, sustained nanoceria bioretention was associated with granuloma formations comprised of Kupffer cells and intermingling CD3{sup +} T cells. A statistically significant elevation of serum aspartate aminotransferase (AST) level was seen at 1 and 20 h, but subsided by 30 days after ceria administration. Further, elevated apoptosis was observed on day 30. These findings, together with increased hepatic protein carbonyl levels on day 30, indicate ceria-induced hepatic injury and oxidative stress, respectively. Such observations suggest a single vascular infusion of nanoceria can lead to persistent hepatic retention of particles with possible implications for occupational and therapeutic exposures. -- Highlights: ► Time course study on nanoceria induced hepatic alterations in rats. ► Serum AST elevation indicated acute hepatotoxicity. ► Ceria is retained for up to 30 days in Kupffer

  14. CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism

    PubMed Central

    Peterson, Jonathan M.; Seldin, Marcus M.; Wei, Zhikui; Aja, Susan

    2013-01-01

    CTRP3 is a secreted plasma protein of the C1q family that helps regulate hepatic gluconeogenesis and is downregulated in a diet-induced obese state. However, the role of CTRP3 in regulating lipid metabolism has not been established. Here, we used a transgenic mouse model to address the potential function of CTRP3 in ameliorating high-fat diet-induced metabolic stress. Both transgenic and wild-type mice fed a high-fat diet showed similar body weight gain, food intake, and energy expenditure. Despite similar adiposity to wild-type mice upon diet-induced obesity (DIO), CTRP3 transgenic mice were strikingly resistant to the development of hepatic steatosis, had reduced serum TNF-α levels, and demonstrated a modest improvement in systemic insulin sensitivity. Additionally, reduced hepatic triglyceride levels were due to decreased expression of enzymes (GPAT, AGPAT, and DGAT) involved in triglyceride synthesis. Importantly, short-term daily administration of recombinant CTRP3 to DIO mice for 5 days was sufficient to improve the fatty liver phenotype, evident as reduced hepatic triglyceride content and expression of triglyceride synthesis genes. Consistent with a direct effect on liver cells, recombinant CTRP3 treatment reduced fatty acid synthesis and neutral lipid accumulation in cultured rat H4IIE hepatocytes. Together, these results establish a novel role for CTRP3 hormone in regulating hepatic lipid metabolism and highlight its protective function and therapeutic potential in attenuating hepatic steatosis. PMID:23744740

  15. Ciliary neurotrophic factor analogue aggravates CCl4-induced acute hepatic injury in rats.

    PubMed

    Cui, Ming-Xia; Jiang, Jun-Feng; Min, Guang-Ning; Han, Wei; Wu, Yong-Jie

    2017-05-01

    Ciliary neurotrophic factor (CNTF) and CNTF analogs were reported to have hepatoprotective effect and ameliorate hepatic steatosis in db/db or high-fat-diet-fed mice. Because hepatic steatosis and injury are also commonly induced by hepatotoxin, the aim of the present study is to clarify whether CNTF could alleviate hepatic steatosis and injury induced by carbon tetrachloride (CCl 4 ). Unexpectedly, when combined with CCl 4 , CNTF aggravated hepatic steatosis and liver injury. The mechanism is associated with effects of CNTF that inhibited lipoprotein secretion and drastically impaired the ability of lipoproteins to act as transport vehicles for lipids from the liver to the circulation. While injected after CCl 4 cessation, CNTF could improve liver function. These data suggest that CNTF could be a potential hepatoprotective agent against CCl 4 -induced hepatic injury after the cessation of CCl 4 exposure. However, it is forbidden to combine recombinant mutant of human CNTF treatment with CCl 4 .

  16. Hepatitis C virus induces a prediabetic state by directly impairing hepatic glucose metabolism in mice.

    PubMed

    Lerat, Hervé; Imache, Mohamed Rabah; Polyte, Jacqueline; Gaudin, Aurore; Mercey, Marion; Donati, Flora; Baudesson, Camille; Higgs, Martin R; Picard, Alexandre; Magnan, Christophe; Foufelle, Fabienne; Pawlotsky, Jean-Michel

    2017-08-04

    Virus-related type 2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV); however, the underlying molecular mechanisms remain unknown. Our aim was to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes via deregulation of TNFα/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitant with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV protein-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce insulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a prediabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  17. Visualisation of γH2AX Foci Caused by Heavy Ion Particle Traversal; Distinction between Core Track versus Non-Track Damage

    PubMed Central

    Nakajima, Nakako Izumi; Brunton, Holly; Watanabe, Ritsuko; Shrikhande, Amruta; Hirayama, Ryoichi; Matsufuji, Naruhiro; Fujimori, Akira; Murakami, Takeshi; Okayasu, Ryuichi; Jeggo, Penny; Shibata, Atsushi

    2013-01-01

    Heavy particle irradiation produces complex DNA double strand breaks (DSBs) which can arise from primary ionisation events within the particle trajectory. Additionally, secondary electrons, termed delta-electrons, which have a range of distributions can create low linear energy transfer (LET) damage within but also distant from the track. DNA damage by delta-electrons distant from the track has not previously been carefully characterised. Using imaging with deconvolution, we show that at 8 hours after exposure to Fe (∼200 keV/µm) ions, γH2AX foci forming at DSBs within the particle track are large and encompass multiple smaller and closely localised foci, which we designate as clustered γH2AX foci. These foci are repaired with slow kinetics by DNA non-homologous end-joining (NHEJ) in G1 phase with the magnitude of complexity diminishing with time. These clustered foci (containing 10 or more individual foci) represent a signature of DSBs caused by high LET heavy particle radiation. We also identified simple γH2AX foci distant from the track, which resemble those arising after X-ray exposure, which we attribute to low LET delta-electron induced DSBs. They are rapidly repaired by NHEJ. Clustered γH2AX foci induced by heavy particle radiation cause prolonged checkpoint arrest compared to simple γH2AX foci following X-irradiation. However, mitotic entry was observed when ∼10 clustered foci remain. Thus, cells can progress into mitosis with multiple clusters of DSBs following the traversal of a heavy particle. PMID:23967070

  18. Obesity-induced hepatic hypoperfusion primes for hepatic dysfunction after resuscitated hemorrhagic shock.

    PubMed

    Matheson, Paul J; Hurt, Ryan T; Franklin, Glen A; McClain, Craig J; Garrison, R Neal

    2009-10-01

    Obese patients (BMI>35) after blunt trauma are at increased risk compared to non-obese for organ dysfunction, prolonged hospital stay, infection, prolonged mechanical ventilation, and mortality. Obesity and non-alcoholic fatty liver disease (NAFLD) produce a low grade systemic inflammatory response syndrome (SIRS) with compromised hepatic blood flow, which increases with body mass index. We hypothesized that obesity further aggravates liver dysfunction by reduced hepatic perfusion following resuscitated hemorrhagic shock (HEM). Age-matched Zucker rats (Obese, 314-519 g & Lean, 211-280 g) were randomly assigned to 4 groups (n = 10-12/group): (1) Lean-Sham; (2) Lean, HEM, and resuscitation (HEM/RES); (3) Obese-Sham; and (4) Obese-HEM/RES. HEM was 40% of mean arterial pressure (MAP) for 60 min; RES was return of shed blood/5 min and 2 volumes of saline/25 min. Hepatic blood flow (HBF) using galactose clearance, liver enzymes and complete metabolic panel were measured over 4 h after completion of RES. Obese rats had increased MAP, heart rate, and fasting blood glucose and BUN concentrations compared to lean controls, required less blood withdrawal (mL/g) to maintain 40% MAP, and RES did not restore BL MAP. Obese rats had decreased HBF at BL and during HEM/RES, which persisted 4 h post RES. ALT and BUN were increased compared to Lean-HEM/RES at 4 h post-RES. These data suggest that obesity significantly contributes to trauma outcomes through compromised vascular control or through fat-induced sinusoidal compression to impair hepatic blood flow after HEM/RES resulting in a greater hepatic injury. The pro-inflammatory state of NAFLD seen in obesity appears to prime the liver for hepatic ischemia after resuscitated hemorrhagic shock, perhaps intensified by insidious and ongoing hepatic hypoperfusion established prior to the traumatic injury or shock.

  19. Effect of vanadium on colonic aberrant crypt foci induced in rats by 1,2 Dimethyl hydrazine

    PubMed Central

    Kanna, P Suresh; Mahendrakumar, CB; Chakraborty, T; Hemalatha, P; Banerjee, Pratik; Chatterjee, M

    2003-01-01

    AIM: To investigate the chemo preventive effects of vanadium on rat colorectal carcinogenesis induced by 1,2-dimethylhydrazine (DMH). METHODS: Male Sprague-Dawley Rats were randomly divided into four groups. Rats in Group A received saline vehicle alone for 16 weeks. Rats in Group B were given DMH injection once a week intraperitoneally for 16 weeks; rats in Group C, with the same DMH treatment as in the Group B, but received 0.5-ppm vanadium in the form ammonium monovanadate ad libitum in drinking water. Rats in the Group D received vanadium alone as in the Group C without DMH injection. RESULTS: Aberrant crypt foci (ACF) were formed in animals in DMH-treated groups at the end of week 16. Compared to DMH group, vanadium treated group had less ACF (P < 0.001). At the end of week 32, all rats in DMH group developed large intestinal tumors. Rats treated with vanadium contained significantly few colonic adenomas and carcinomas (P < 0.05) compared to rats administered DMH only. In addition, a significant reduction (P < 0.05) in colon tumor burden (sum of tumor sizes per animal) was also evident in animals of Group C when compared to those in rats of carcinogen control Group B. The results also showed that vanadium significantly lowered PCNA index in ACF (P < 0.005). Furthermore, vanadium supplementation also elevated liver GST and Cyt P-450 activities (P < 0.001 and P < 0.02, respectively). CONCLUSION: Vanadium in the form of ammonium monovanadate supplemented in drinking water ad libitum has been found to be highly effective in reducing tumor incidence and preneoplastic foci on DMH-induced colorectal carcinogenesis. These findings suggest that vanadium administration can suppress colon carcinogenesis in rats. PMID:12717849

  20. Pro-Inflammatory Activated Kupffer Cells by Lipids Induce Hepatic NKT Cells Deficiency through Activation-Induced Cell Death

    PubMed Central

    Tang, Tongfang; Sui, Yongheng; Lian, Min; Li, Zhiping; Hua, Jing

    2013-01-01

    Background Dietary lipids play an important role in the progression of non-alcoholic fatty liver disease (NAFLD) through alternation of liver innate immune response. Aims The present study was to investigate the effect of lipid on Kupffer cells phenotype and function in vivo and in vitro. And further to investigate the impact of lipid on ability of Kupffer cell lipid antigen presentation to activate NKT cells. Methods Wild type male C57BL/6 mice were fed either normal or high-fat diet. Hepatic steatosis, Kupffer cell abundance, NKT cell number and cytokine gene expression were evaluated. Antigen presentation assay was performed with Kupffer cells treated with certain fatty acids in vitro and co-cultured with NKT cells. Results High-fat diet induced hepatosteatosis, significantly increased Kupffer cells and decreased hepatic NKT cells. Lipid treatment in vivo or in vitro induced increase of pro-inflammatory cytokines gene expression and toll-like receptor 4 (TLR4) expression in Kupffer cells. Kupffer cells expressed high levels of CD1d on cell surface and only presented exogenous lipid antigen to activate NKT cells. Ability of Kupffer cells to present antigen and activate NKT cells was enhanced after lipid treatment. In addition, pro-inflammatory activated Kupffer cells by lipid treatment induced hepatic NKT cells activation-induced apoptosis and necrosis. Conclusion High-fat diet increase Kupffer cells number and induce their pro-inflammatory status. Pro-inflammatory activated Kupfffer cells by lipid promote hepatic NKT cell over-activation and cell death, which lead to further hepatic NKT cell deficiency in the development of NAFLD. PMID:24312613

  1. Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient.

    PubMed

    Ates, İhsan; Kaplan, Mustafa; Yilmaz, Nisbet; Çiftçi, Filiz

    2015-01-01

    Acute hepatitis is a disorder that goes with liver cell necrosis and liver inflammation. Among the causes of acute hepatitis, the most common reasons are viral hepatitis. About 95% of the acute hepatitis generate because of hepatotropic viruses. Epstein-barr virus (EBV) and cytomegalovirus (CMV) are from the family of herpes viruses and rare causes of acute hepatitis. In this case report, acute hepatitis due to EBV and CMV coinfection will be described. Ates İ, Kaplan M, Yilmaz N, Çiftçi F. Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient. Euroasian J Hepato-Gastroenterol 2015;5(1):60-61.

  2. H2AX foci in late S/G2- and M-phase cells after hydroxyurea- and aphidicolin-induced DNA replication stress in Vicia.

    PubMed

    Rybaczek, Dorota; Bodys, Aleksandra; Maszewski, Janusz

    2007-09-01

    Immunocytochemistry using alpha-phospho-H2AX antibodies shows that hydroxyurea (HU), an inhibitor of ribonucleotide reductase, and aphidicolin (APH), an inhibitor of DNA-polymerases alpha and delta, may promote formation of phospho-H2AX foci in late S/G2-phase cells in root meristems of Vicia faba. Although fluorescent foci spread throughout the whole area of nucleoplasm, large phospho-H2AX aggregates in HU-treated cells allocate mainly in perinucleolar regions. A strong tendency of ATR/ATM-dependent phospho-Chk1S317 kinase to focus in analogous compartments, as opposed to phospho-Chk2T68 and to both effector kinases in APH-treated cells, may suggest that selected elements of the intra-S-phase cell cycle checkpoints share overlapping locations with DNA repair factors known to concentrate in phospho-H2AX aggregates. APH-induced phosphorylation of H2AX exhibits little or no overlap with the areas positioned close to nucleoli. Following G2-M transition of the HU- and APH-pretreated cells, altered chromatin structures are still discernible as large phospho-H2AX foci in the vicinity of chromosomes. Both in HU- and APH-treated roots, immunofluorescence analysis revealed a dominant fraction of small foci and a less frequent population of large phospho-H2AX aggregates, similar to those observed in animal cells exposed to ionizing radiation. The extent of H2AX phosphorylation has been found considerably reduced in root meristem cells treated with HU and caffeine. The frequencies of phospho-H2AX foci observed during mitosis and caffeine-mediated premature chromosome condensation (PCC) suggest that there may be functional links between the checkpoint mechanisms that control genome integrity and those activities which operate throughout the unperturbed mitosis in plants.

  3. Fecal microbiota transplantation prevents hepatic encephalopathy in rats with carbon tetrachloride-induced acute hepatic dysfunction.

    PubMed

    Wang, Wei-Wei; Zhang, Yu; Huang, Xiao-Bing; You, Nan; Zheng, Lu; Li, Jing

    2017-10-14

    To investigate whether fecal microbiota transplantation (FMT) prevents hepatic encephalopathy (HE) in rats with carbon tetrachloride (CCl 4 )-induced acute hepatic dysfunction. A rat model of HE was established with CCl 4 . Rat behaviors and spatial learning capability were observed, and hepatic necrosis, intestinal mucosal barrier, serum ammonia levels and intestinal permeability were determined in HE rats receiving FMT treatment. Furthermore, the expression of tight junction proteins (Claudin-1, Claudin-6 and Occludin), Toll-like receptor (TLR) 4/TLR9, interleukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α was examined. FMT improved rat behaviors, HE grade and spatial learning capability. Moreover, FMT prevented hepatic necrosis and intestinal mucosal barrier damage, leading to hepatic clearance of serum ammonia levels and reduced intestinal permeability. The expression of TLR4 and TLR9, two potent mediators of inflammatory response, was significantly downregulated in the liver of rats treated with FMT. Consistently, circulating pro-inflammatory factors such as interleukin (IL)-1β, IL-6 and tumor necrosis factor-α were remarkably decreased, indicating that FMT is able to limit systemic inflammation by decreasing the expression of TLR4 and TLR9. Importantly, HE-induced loss of tight junction proteins (Claudin-1, Claudin-6 and Occludin) was restored in intestinal tissues of rats receiving FMT treatment. FMT enables protective effects in HE rats, and it improves the cognitive function and reduces the liver function indexes. FMT may cure HE by altering the intestinal permeability and improving the TLR response of the liver.

  4. Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice.

    PubMed

    Bijnen, Mitchell; Josefs, Tatjana; Cuijpers, Ilona; Maalsen, Constantijn J; van de Gaar, José; Vroomen, Maria; Wijnands, Erwin; Rensen, Sander S; Greve, Jan Willem M; Hofker, Marten H; Biessen, Erik A L; Stehouwer, Coen D A; Schalkwijk, Casper G; Wouters, Kristiaan

    2017-10-26

    Obesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c + proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development. vAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr -/- acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH. Transplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c + and CD11c - macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c + ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes. ATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise

  5. Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis.

    PubMed

    Bai, Xupeng; Hong, Weipeng; Cai, Peiheng; Chen, Yibei; Xu, Chuncao; Cao, Di; Yu, Weibang; Zhao, Zhongxiang; Huang, Min; Jin, Jing

    2017-06-01

    Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) - extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient

    PubMed Central

    Kaplan, Mustafa; Yilmaz, Nisbet; Çiftçi, Filiz

    2015-01-01

    Acute hepatitis is a disorder that goes with liver cell necrosis and liver inflammation. Among the causes of acute hepatitis, the most common reasons are viral hepatitis. About 95% of the acute hepatitis generate because of hepatotropic viruses. Epstein-barr virus (EBV) and cytomegalovirus (CMV) are from the family of herpes viruses and rare causes of acute hepatitis. In this case report, acute hepatitis due to EBV and CMV coinfection will be described. How to cite this article Ates İ, Kaplan M, Yilmaz N, Çiftçi F. Epstein-Barr Virus and Cytomegalovirus induced Acute Hepatitis in Young Female Patient. Euroasian J Hepato-Gastroenterol 2015;5(1):60-61. PMID:29201691

  7. Fenofibrate Does Not Affect Burn-Induced Hepatic Endoplasmic Reticulum Stress

    PubMed Central

    Hiyama, Yaeko; Marshall, Alexandra H.; Kraft, Robert; Arno, Anna; Jeschke, Marc G.

    2013-01-01

    Background Burn injury causes major metabolic derangements such as hypermetabolism, hyperlipidemia, and insulin resistance and is associated with liver damage, hepatomegaly, and hepatic endoplasmic reticulum (ER) stress. Although the physiological consequences of such derangements have been delineated, the underlying molecular mechanisms remain unknown. Previously, it was shown that fenofibrate improves patient outcome by attenuating post-burn stress responses. Methods Fenofibrate, a peroxisome proliferator-activated receptor (PPAR)-α agonist, regulates liver lipid metabolism and has been used to treat hypertriglyceridemia and hypercholesterolemia for many years. The aim of the present study is to determine the effects of fenofibrate on burn-induced hepatic morphologic and metabolic changes. We randomized rats to sham, burn injury, and burn injury plus fenofibrate. Animals were sacrificed and livers were assessed at 24 or 48 hours post-burn. Results Burn injury decreased albumin and increased alanine transaminase (p = 0.1 vs. sham), indicating liver injury. Fenofibrate administration did not restore albumin or decrease alanine transaminase. In addition, ER stress was significantly increased after burn injury both with and without fenofibrate (p < 0.05 vs. sham). Burn injury increased fatty acid metabolism gene expression (p < 0.05 vs. sham), downstream of PPARα. Fenofibrate treatment increased fatty acid metabolism further, which reduced post-burn hepatic steatosis (burn vs. sham p < 0.05, burn+fenofibrate vs. sham not significant). Conclusions Fenofibrate did not alleviate thermal injury induced hepatic ER stress and dysfunction but reduced hepatic steatosis by modulating hepatic genes related to fat metabolism. PMID:23866789

  8. Lysine Acetylation of CREBH Regulates Fasting-Induced Hepatic Lipid Metabolism

    PubMed Central

    Kim, Hyunbae; Mendez, Roberto; Chen, Xuequn; Fang, Deyu

    2015-01-01

    Cyclic AMP-responsive element-binding protein 3-like 3, hepatocyte specific (CREBH), is a hepatic transcription factor that functions as a key regulator of energy homeostasis. Here, we defined a regulatory CREBH posttranslational modification process, namely, lysine-specific acetylation, and its functional involvement in fasting-induced hepatic lipid metabolism. Fasting induces CREBH acetylation in mouse livers in a time-dependent manner, and this event is critical for CREBH transcriptional activity in regulating hepatic lipid homeostasis. The histone acetyltransferase PCAF-mediated acetylation and the deacetylase sirtuin-1-mediated deacetylation coexist to maintain CREBH acetylation states under fasting conditions. Site-directed mutagenesis and functional analyses revealed that the lysine (K) residue at position 294 (K294) within the bZIP domain of the CREBH protein is the site where fasting-induced acetylation/deacetylation occurs. Introduction of the acetylation-deficient (K294R) or acetylation-mimicking (K294Q) mutation inhibited or enhanced CREBH transcriptional activity, respectively. Importantly, CREBH acetylation at lysine 294 was required for the interaction and synergy between CREBH and peroxisome proliferator-activated receptor α (PPARα) in activating their target genes upon fasting or glucagon stimulation. Introduction of the CREBH lysine 294 mutation in the liver leads to hepatic steatosis and hyperlipidemia in animals under prolonged fasting. In summary, our study reveals a molecular mechanism by which fasting or glucagon stimulation modulates lipid homeostasis through acetylation of CREBH. PMID:26438600

  9. Hepatitis E-induced severe myositis.

    PubMed

    Mengel, Annerose M; Stenzel, Werner; Meisel, Andreas; Büning, Carsten

    2016-02-01

    Hepatitis E virus (HEV) is endemic in Asian and African countries but is rarely reported in Western countries. Although there are some prominent neurological manifestations, HEV is rarely recognized by neurologists. This is a case report of myositis induced by HEV. We report the life-threatening case of a 57-year-old man with flaccid tetraparesis due to myositis, acute hepatitis, and renal failure caused by HEV infection. Muscle biopsy revealed scattered myofiber necrosis with a diffuse, mild lymphomonocytic infiltrate in the endomysium and perimysium. Because the patient suffered from an acute HEV infection with a rapidly progressive course of severe myopathy, we started ribavirin treatment. He recovered partially within 3 weeks and recovered fully within 6 months. This case highlights a neurological manifestation of endemic HEV infection with severe myositis in a patient with alcoholic chronic liver disease. Ribavirin treatment is effective in severe HEV infection and may also lead to rapid neurological recovery. © 2015 Wiley Periodicals, Inc.

  10. Induction and disappearance of γH2AX foci and formation of micronuclei after exposure of human lymphocytes to ⁶⁰Co γ-rays and p(66)+ Be(40) neutrons.

    PubMed

    Vandersickel, Veerle; Beukes, Philip; Van Bockstaele, Bram; Depuydt, Julie; Vral, Anne; Slabbert, Jacobus

    2014-02-01

    To investigate both the formation of micronuclei (MN) and the induction and subsequent loss of phosphorylated histone H2AX foci (γH2AX foci) after in vitro exposure of human lymphocytes to either (60)Co γ-rays or p(66)+ Be(40) neutrons. MN dose response (DR) curves were obtained by exposing isolated lymphocytes of 10 different donors to doses ranging from 0-4 Gy γ-rays or 0-2 Gy neutrons. Also, γH2AX foci DR curves were obtained following exposure to doses ranging from 0-0.5 Gy of either γ-rays or neutrons. Foci kinetics for lymphocytes for a single donor exposed to 0.5 Gy γ-rays or neutrons were studied up to 24 hours post-irradiation. Micronuclei yields following neutron exposure were consistently higher compared to that from (60)Co γ-rays. All MN yields were over-dispersed compared to a Poisson distribution. Over-dispersion was higher after neutron irradiation for all doses > 0.1 Gy. Up to 4 hours post-irradiation lower yields of neutron-induced γH2AX foci were observed. Between 4 and 24 hours the numbers of foci from neutrons were consistently higher than that from γ-rays. The half-live of foci disappearance is only marginally longer for neutrons compared to that from γ-rays. Foci formations were more likely to be over-dispersed for neutron irradiations. Although neutrons are more effective to induce MN, the absolute number of induced γH2AX foci are less at first compared to γ-rays. With time neutron-induced foci are more persistent. These findings are helpful for using γH2AX foci in biodosimetry and to understand the repair of neutron-induced cellular damage.

  11. Drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy.

    PubMed

    Gheorghe, Liana; Cotruta, Bogdan; Trifu, Viorel; Cotruta, Cristina; Becheanu, Gabriel; Gheorghe, Cristian

    2008-09-01

    Pegylated interferon-alpha in combination with ribavirin currently represents the therapeutic standard for the hepatitis C virus infection. Interferon based therapy may be responsible for many cutaneous side effects. We report a case of drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy. To our knowledge, this is the first reported case of Sweet's syndrome in association with pegylated interferon-alpha therapy.

  12. Submassive hepatic necrosis induced by dichloropropanol.

    PubMed

    Haratake, J; Furuta, A; Iwasa, T; Wakasugi, C; Imazu, K

    1993-06-01

    A hitherto undescribed industrial liver injury of fulminant form induced by dichloropropanol is reported. Two middle-aged men developed severe hepatic injury just after cleaning a dichloropropanol tank at a plant producing dichloropropanol. They died from hepatic failure 4 and 11 days respectively, after carrying out the work. Liver specimens taken at autopsy from one of the cases showed submassive hepatic necrosis. This accident prompted us to undertake an experimental study in rats of intraperitoneal one-shot injection of two isomeric substances of dichloropropanol, that is, 2,3-dichloro-1-propanol (DC1P) and 1,3-dichloro-2-propanol (DC2P). Saline was injected into the control rats. One, two, four, six, 24, 48, 72 h, and 1 week after the injection, rats in each group were sacrificed. Neither control nor DC1P-injected rats showed significant biochemical or histopathological abnormalities. DC2P-injected rats revealed elevations of transaminase from 6 h after the injections, and submassive necrosis of the liver was observed in many rats. It was concluded that the severe liver injuries in both the human cases and rats in our study were caused by DC2P.

  13. Drug-induced hepatitis superimposed on the presence of anti-SLA antibody: a case report.

    PubMed

    Etxagibel, Aitziber; Julià, M Rosa; Brotons, Alvaro; Company, M Margarita; Dolz, Carlos

    2008-01-28

    Autoimmune hepatitis is a necroinflammatory disorder of unknown etiology characterized by the presence of circulating antibodies, hypergammaglobulinemia, and response to immunosuppression. It has the histological features of chronic hepatitis. The onset is usually insidious, but in some patients the presentation may be acute and occasionally severe. Certain drugs can induce chronic hepatitis mimicking autoimmune hepatitis. Different autoantibodies have been associated with this process but they are not detectable after drug withdrawal and clinical resolution. We describe a case of drug-induced acute hepatitis associated with antinuclear, antisoluble liver-pancreas and anti-smooth muscle autoantibodies in a 66-year-old woman. Abnormal clinical and biochemical parameters resolved after drug withdrawal, but six months later anti-soluble liver-pancreas antibodies remained positive and liver biopsy showed chronic hepatitis and septal fibrosis. Furthermore, our patient has a HLA genotype associated with autoimmune hepatitis. Patient follow-up will disclose whether our patient suffers from an autoimmune disease and if the presence of anti-soluble liver antigens could precede the development of an autoimmune hepatitis, as the presence of antimitochondrial antibodies can precede primary biliary cirrhosis.

  14. Trivalent Chromium Supplementation Ameliorates Oleic Acid-Induced Hepatic Steatosis in Mice.

    PubMed

    Wang, Song; Wang, Jian; Liu, Yajing; Li, Hui; Wang, Qiao; Huang, Zhiwei; Liu, Wenbin; Shi, Ping

    2018-05-24

    Trivalent chromium [Cr(III)] is recognized as an essential trace element for human health, whereas its effect on hepatic lipid metabolism has not yet been fully understood. This study aimed to investigate the beneficial effects and potential mechanisms of Cr(III) on hepatic steatosis in an oleic acid (OA) induced mice model. Mice were fed with high OA for 12 weeks to induce lipid accumulation, and co-administrated with Cr(III) supplementation. Indexes of liver lipid accumulation, associated lipid genes expression, fatty acids (FAs) profile and inflammatory cytokines were analyzed. The data showed that Cr(III) supplementation could attenuate disease progress of hepatic steatosis and protect liver from high OA. After Cr(III) supplementation, elevated body weight and liver injury in steatosis mice were reversed, excessive lipid accumulation and FAs were also reduced. The up-regulation of cluster of differentiation 36 (CD36) and diacylglycerol acyltransferase 2 (DGAT2) following steatosis induction were inhibited by Cr(III). Cr(III) reduced the content of pro-inflammatory cytokines (IL-1β and TNF-α, IL-12) and restored the level of anti-inflammatory cytokine (IL-10) to the control values. Our results suggest that Cr(III) supplementation is a novel strategy for alleviating OA-induced hepatic steatosis.

  15. Liver-specific loss of Perilipin 2 alleviates diet-induced hepatic steatosis, inflammation, and fibrosis

    PubMed Central

    Najt, Charles P.; Senthivinayagam, Subramanian; Aljazi, Mohammad B.; Fader, Kelly A.; Olenic, Sandra D.; Brock, Julienne R. L.; Lydic, Todd A.; Jones, A. Daniel

    2016-01-01

    Hepatic inflammation and fibrosis are key elements in the pathogenesis of nonalcoholic steatohepatitis (NASH), a progressive liver disease initiated by excess hepatic lipid accumulation. Lipid droplet protein Perilipin 2 (Plin2) alleviates dietary-induced hepatic steatosis when globally ablated; however, its role in the progression of NASH remains unknown. To investigate this further, we challenged Plin2 liver-specific knockout mice (designated L-KO) and their respective wild-type (WT) controls with a methionine-choline-deficient (MCD) diet for 15 days to induce a NASH phenotype of increased hepatic triglyceride levels through impaired phosphatidylcholine (PC) synthesis and very-low-density lipoprotein (VLDL) secretion. Results on liver weights, body weights, fat tissue mass, and histology in WT and L-KO mice fed the MCD diet revealed signs of hepatic steatosis, fibrosis, and inflammation; however, these effects were blunted in L-KO mice. In addition, levels of PC and VLDL were unchanged, and hepatic steatosis was reduced in L-KO mice fed the MCD diet, due in part to an increase in remodeling of PE to PC via the enzyme phosphatidylethanolamine N-methyltransferase (PEMT). These mice also exhibited decreased hepatic expression of proinflammatory markers cyclooxygenase 2, IL-6, TNF-α, IL-1β, and reduced expression of endoplasmic reticulum (ER) stress proteins C/EBP homologous protein and cleaved caspase-1. Taken together, these results suggest that Plin2 liver-specific ablation alleviates diet-induced hepatic steatosis and inflammation via a PEMT-mediated mechanism that involves compensatory changes in proteins involved in phospholipid remodeling, inflammation, and ER stress that work to alleviate diet-induced NASH. Overall, these findings support a role for Plin2 as a target for NASH therapy. PMID:26968211

  16. On the black hole lens and its foci

    NASA Technical Reports Server (NTRS)

    Eshleman, Von R.; Gurrola, Eric M.; Lindal, Gunnar F.

    1989-01-01

    Methods developed for radio occultation studies of planetary atmospheres are used to predict the electromagnetic focusing properties of a refracting lens representation of a Schwarzschild black hole. The infinity of foci are of three distinct types: a principal forward axial focus which is by far the strongest; higher-order forward axial foci; and backward conical foci with axial nulls.

  17. Hepatitis B Virus X Protein Induces Hepatic Steatosis by Enhancing the Expression of Liver Fatty Acid Binding Protein.

    PubMed

    Wu, Yun-Li; Peng, Xian-E; Zhu, Yi-Bing; Yan, Xiao-Li; Chen, Wan-Nan; Lin, Xu

    2016-02-15

    Hepatitis B virus (HBV) has been implicated as a potential trigger of hepatic steatosis although molecular mechanisms involved in the pathogenesis of HBV-associated hepatic steatosis still remain elusive. Our prior work has revealed that the expression level of liver fatty acid binding protein 1 (FABP1), a key regulator of hepatic lipid metabolism, was elevated in HBV-producing hepatoma cells. In this study, the effects of HBV X protein (HBx) mediated FABP1 regulation on hepatic steatosis and the underlying mechanism were determined. mRNA and protein levels of FABP1 were measured by quantitative RT-PCR (qPCR) and Western blotting. HBx-mediated FABP1 regulation was evaluated by luciferase assay, coimmunoprecipitation, and chromatin immunoprecipitation. Hepatic lipid accumulation was measured by using Oil-Red-O staining and the triglyceride level. It was found that expression of FABP1 was increased in HBV-producing hepatoma cells, the sera of HBV-infected patients, and the sera and liver tissues of HBV-transgenic mice. Ectopic overexpression of HBx resulted in upregulation of FABP1 in HBx-expressing hepatoma cells, whereas HBx abolishment reduced FABP1 expression. Mechanistically, HBx activated the FABP1 promoter in an HNF3β-, C/EBPα-, and PPARα-dependent manner, in which HBx increased the gene expression of HNF3β and physically interacted with C/EBPα and PPARα. On the other hand, knockdown of FABP1 remarkably blocked lipid accumulation both in long-chain free fatty acids treated HBx-expressing HepG2 cells and in a high-fat diet-fed HBx-transgenic mice. Therefore, FABP1 is a key driver gene in HBx-induced hepatic lipid accumulation via regulation of HNF3β, C/EBPα, and PPARα. FABP1 may represent a novel target for treatment of HBV-associated hepatic steatosis. Accumulating evidence from epidemiological and experimental studies has indicated that chronic HBV infection is associated with hepatic steatosis. However, the molecular mechanism underlying HBV-induced

  18. Postulated deficiency of hepatic heme and repair by hematin infusions in the "inducible" hepatic porphyrias.

    PubMed Central

    Watson, C J; Pierach, C A; Bossenmaier, I; Cardinal, R

    1977-01-01

    There is compelling, indirect evidence of hepatic heme deficiency due primarily to the respective genetic errors of the three inducible hepatic porphyrias, acute intermittent porphyria, porphyria variegata, and hereditary coproporphyria. The induction is enhanced by exogenous inducers such as barbiturate, estrogens and other "porphyrogenic" chemicals and factors, including glucose deprivation. The newer knowledge of the induction of delta-aminolevulinic acid synthetase [delta-aminolevulinate synthase; succinyl--CoA:glycine C-succinyltransferase (decarboxylating), EC 2.3.1.37] in relation to inadequate heme, and repression by heme, stimulated early trials of hematin infusions to overcome the acute relapse in the foregoing inducible porphyrias. Recently this experience has been considerably expanded, 143 infusions of hematin having been given in 22 cases. Studies of the effect on the serum concentrations of delta-aminolevulinic acid and porphobilinogen have shown a highly significant decline, often to 0, especially of delta-aminolevulinic acid. A distinct relationship to the clinical severity of the attack has been evident in the frequency and magnitude of decline of serum delta-aminolevulinic acid and porphobilinogen. This was regularly associated with objective clinical improvement. PMID:266732

  19. Drug-induced hepatitis superimposed on the presence of anti-SLA antibody: a case report

    PubMed Central

    Etxagibel, Aitziber; Julià, M Rosa; Brotons, Alvaro; Company, M Margarita; Dolz, Carlos

    2008-01-01

    Introduction Autoimmune hepatitis is a necroinflammatory disorder of unknown etiology characterized by the presence of circulating antibodies, hypergammaglobulinemia, and response to immunosuppression. It has the histological features of chronic hepatitis. The onset is usually insidious, but in some patients the presentation may be acute and occasionally severe. Certain drugs can induce chronic hepatitis mimicking autoimmune hepatitis. Different autoantibodies have been associated with this process but they are not detectable after drug withdrawal and clinical resolution. Case presentation We describe a case of drug-induced acute hepatitis associated with antinuclear, antisoluble liver-pancreas and anti-smooth muscle autoantibodies in a 66-year-old woman. Abnormal clinical and biochemical parameters resolved after drug withdrawal, but six months later anti-soluble liver-pancreas antibodies remained positive and liver biopsy showed chronic hepatitis and septal fibrosis. Furthermore, our patient has a HLA genotype associated with autoimmune hepatitis. Conclusion Patient follow-up will disclose whether our patient suffers from an autoimmune disease and if the presence of anti-soluble liver antigens could precede the development of an autoimmune hepatitis, as the presence of antimitochondrial antibodies can precede primary biliary cirrhosis. PMID:18226219

  20. Lack of promotional effects of groundwater contaminant mixtures on the induction of preneoplastic foci in rat liver.

    PubMed

    Benjamin, S A; Yang, R S; Tessari, J D; Chubb, L W; Brown, M D; Dean, C E; Keefe, T J

    1999-10-01

    F344 rats were exposed to drinking water mixtures of seven of the most common groundwater contaminants associated with hazardous waste sites [arsenic, benzene, chloroform, chromium, lead, phenol, and trichloroethylene (TCE)] as the full mixture or submixtures of the organic and/or inorganic chemicals. The lowest concentrations (1x) of the individual chemicals were environmentally realistic and below what would be expected to induce significant short-term toxicity. This study was intended to determine if previously reported increases in localized hepatocellular proliferation in response to these chemicals might be correlated with increased risk for hepatocarcinogenesis. Rats were exposed via a drinking water solution to the full seven- chemical mixture (at 1x and 10x concentrations), submixtures of the organic or inorganic chemicals (at 10x concentrations), a mixture of TCE, lead, and chloroform (TLC submixture at 10x and 100x concentrations), or deionized water as a control. The rats were evaluated for promotion of placental glutathione-S-transferase (GST-P) positive preneoplastic liver cell foci after diethylnitrosamine (DEN) initiation and partial hepatectomy. Focus formation, cell proliferation, and apoptosis were evaluated after exposure to DEN or saline controls, the chemical mixtures or deionized water controls, or combinations of these treatments. The total number and area of GST-P positive foci in DEN-treated rats exposed to the full seven-chemical mixture was increased as compared with the DEN-water controls, but this was statistically significant only for total focus area in the 1x dose group. In DEN-treated rats, the inorganic or TLC submixtures resulted in a significant reduction in number and area of GST-P positive foci. Focus area also was decreased in the organic submixture-treated group, but not significantly. Hepatocellular proliferation was not significantly changed in the chemical mixture saline groups as compared with the mixture water controls

  1. [Hydroxyurea (hydroxycarbamide)-induced hepatic dysfunction confirmed by drug-induced lymphocyte stimulation test].

    PubMed

    Shimizu, Takayuki; Mori, Takehiko; Karigane, Daiki; Kikuchi, Taku; Koda, Yuya; Toyama, Takaaki; Nakajima, Hideaki; Okamoto, Shinichiro

    2014-01-01

    A 62-year-old man with refractory leukemia transformed from myelodysplastic syndrome was placed on hydroxyurea (hydroxycarbamide) at a daily dose of 500 mg. Because of insufficient cytoreductive efficacy, the dose was increased to 1,500 mg five days later. Eight days after the initiation of hydroxyurea, the patient started complaining of chills, fever, and vomiting. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly elevated to 5,098 and 3,880 IU/l from 44 and 59 IU/l in one day, respectively. Tests for hepatitis viruses were all negative. With the discontinuation of hydroxyurea, AST and ALT returned to their former levels within two weeks. A drug-induced lymphocyte stimulation test for hydroxyurea was positive with a stimulating index of 2.0. Hepatic dysfunction has been recognized as one of the side effects of hydroxyurea. However, there have been only a limited number of reports demonstrating drug allergy to have a role in hepatic dysfunction accompanied by fever and gastrointestinal symptoms. The findings of our case strongly suggest that all presentations could be explained by drug allergy. Physicians should be mindful of the potential for acute and severe hepatic dysfunction due to allergic reaction against hydroxyurea.

  2. Radon inhalation protects mice from carbon-tetrachloride-induced hepatic and renal damage.

    PubMed

    Kataoka, Takahiro; Nishiyama, Yuichi; Toyota, Teruaki; Yoshimoto, Masaaki; Sakoda, Akihiro; Ishimori, Yuu; Aoyama, Yutaka; Taguchi, Takehito; Yamaoka, Kiyonori

    2011-12-01

    We assessed whether radon inhalation provided protection from carbon tetrachloride (CCl4)-induced hepatic and renal damage in mice. Mice were subjected to intraperitoneal injection of CCl4 after inhaling approximately 18 kBq/m3 radon for 6 h. Radon inhalation significantly increased total glutathione (t-GSH) content and glutathione peroxidase (GPx) activity in the liver and kidney. Injection of CCl4 was associated with significantly higher levels of glutamic oxaloacetic transaminase (GOT) and alkaline phosphatase (ALP) activity and creatinine level in serum, and pretreatment with radon significantly decreased the GOT and ALP activity and creatinine level associated with CCl4 injection, suggesting that radon inhalation alleviates CCl4-induced hepatic and renal damage. The t-GSH contents and GPx activity in the liver and kidney of animals pretreated with radon were significantly higher than those of the CCl(4)-only group. These findings suggested that radon inhalation activated antioxidative functions and inhibited CCl4-induced hepatic and renal damage in mice.

  3. Probiotic Dahi containing Lactobacillus acidophilus and Bifidobacterium bifidum modulates the formation of aberrant crypt foci, mucin-depleted foci, and cell proliferation on 1,2-dimethylhydrazine-induced colorectal carcinogenesis in Wistar rats.

    PubMed

    Mohania, Dheeraj; Kansal, Vinod K; Kruzliak, Peter; Kumari, Archana

    2014-08-01

    Aberrant crypt foci (ACF) and mucin-depleted foci (MDF) are pre-neoplastic lesions identified in the colon of carcinogen-treated rodents and in humans at high risk for colon cancer. The present study was carried out to divulge the protective potential of the probiotic Dahi containing Lactobacillus acidophilus LaVK2 and Bifidobacterium bifidum BbVK3 alone or in combination with piroxicam (PXC) on the development of early biomarkers of colorectal carcinogenesis in male Wistar rats administered 1,2-dimethylhydrazine (DMH). DMH was injected subcutaneously at the rate of 40 mg/kg body weight per animal twice a week for 2 weeks. A total of 120 male Wistar rats were randomly allocated to five groups, each group having 24 animals. The rats were fed with buffalo milk or probiotic supplement (20 grams) alone or as an adjunct with PXC in addition to a basal diet ad libitum for 32 weeks. Group I was offered buffalo milk (BM) and served as the control group. Group II was administered DMH along with BM and served as the DMH-control group; group III was administered BM-DMH-PXC, in which besides administering BM-DMH, PXC was also offered. Group IV was offered probiotic LaBb Dahi and DMH, and group V was offered both probiotic LaBb Dahi and PXC along with DMH. The rats were euthanized at the 8(th), 16(th), and 32(nd) week of the experiment and examined for development of ACF, aberrant crypts per ACF (AC/ACF), mucin-depleted foci (MDF), large MDF, and proliferating cell nuclear antigen (PCNA) labeling index. Administration of DMH in rats induced pre-neoplastic lesions (ACF and MDF) and increased the PCNA index in colorectal tissue. A significant (p<0.05) reduction in the number of ACF, AC/ACF, MDF, large MDF, and PCNA labeling index were observed in the probiotic LaBb Dahi group compared with the DMH control group. Feeding rats with LaBb Dahi or treatment with PXC diminished the initiation and progression of DMH-induced pre-neoplastic lesions and the PCNA index, and treatment with

  4. To the solar foci

    NASA Technical Reports Server (NTRS)

    Sonnabend, D.

    1979-01-01

    Earlier authors showed that the sun is likely to act as a lens for gravitational radiation, with focui in the outer solar system. They suggested that missions to these foci have the potential of directly measuring the density structure of the sun. Other applications include gravitational wave astronomy and tests of general relativity. This idea is reexamined, concentrating on the engineering aspects of focal missions; primarily spacecraft design and performance. Other topics studied include solar optics, gravitational wave detectors, navigation, and the design of missions for different purposes. Specifically, it is shown that shuttle launched chemical rockets have a substantial capability for reaching some foci; and that all can be reached with large payloads using nuclear isotope-electric propulsion.

  5. FOCIS goes south: advances in translational and clinical immunology.

    PubMed

    Kalergis, Alexis M; Anegon, Ignacio; González, Pablo A

    2017-09-01

    FOCIS goes South: Advances in Translational and Clinical Immunology was the first Federation of Clinical Immunology Societies (FOCIS) ( www.focisnet.org ) meeting held in Latin America (May 15-17, 2017, Santiago de Chile, Chile). The meeting was organized as a 3-day workshop and was fostered by the Millennium Institute on Immunology and Immunotherapy, a recently nominated FOCIS Center of Excellence. The workshop brought together FOCIS associates, such as members of the FOCIS Board of Directors, Directors of different Centers of Excellence, regional speakers and 350 attendees. The Meeting covered aspects of immune regulation and modulation, as well as immunotherapy in areas of autoimmunity, transplantation, cancer and infectious diseases, among others. The activity also had a full-day immunology course and a day-long flow cytometry course.

  6. 2-heptyl-formononetin increases cholesterol and induces hepatic steatosis in mice.

    PubMed

    Andersen, Charlotte; Schjoldager, Janne G; Tortzen, Christian G; Vegge, Andreas; Hufeldt, Majbritt R; Skaanild, Mette T; Vogensen, Finn K; Kristiansen, Karsten; Hansen, Axel K; Nielsen, John

    2013-01-01

    Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice.

  7. 2-Heptyl-Formononetin Increases Cholesterol and Induces Hepatic Steatosis in Mice

    PubMed Central

    Andersen, Charlotte; Schjoldager, Janne G.; Tortzen, Christian G.; Vegge, Andreas; Hufeldt, Majbritt R.; Skaanild, Mette T.; Vogensen, Finn K.; Kristiansen, Karsten; Hansen, Axel K.; Nielsen, John

    2013-01-01

    Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma level of total cholesterol. Supplementation with formononetin did not affect plasma cholesterol but increased plasma triglycerides levels. Supplementation with formononetin and C7F induced hepatic steatosis. However, formononetin decreased markers of inflammation and liver injury. The development of hepatic steatosis was associated with deregulated expression of hepatic genes involved in lipid and lipoprotein metabolism. In conclusion, supplementation with formononetin and C7F to a cholesterol-enriched diet adversely affected lipid and lipoprotein metabolism in C57BL/6J mice. PMID:23738334

  8. Histone Deacetylase 6 (HDAC6) Is an Essential Modifier of Glucocorticoid-Induced Hepatic Gluconeogenesis

    PubMed Central

    Winkler, Robin; Benz, Verena; Clemenz, Markus; Bloch, Mandy; Foryst-Ludwig, Anna; Wardat, Sami; Witte, Nicole; Trappiel, Manuela; Namsolleck, Pawel; Mai, Knut; Spranger, Joachim; Matthias, Gabriele; Roloff, Tim; Truee, Oliver; Kappert, Kai; Schupp, Michael; Matthias, Patrick; Kintscher, Ulrich

    2012-01-01

    In the current study, we investigated the importance of histone deacetylase (HDAC)6 for glucocorticoid receptor–mediated effects on glucose metabolism and its potential as a therapeutic target for the prevention of glucocorticoid-induced diabetes. Dexamethasone-induced hepatic glucose output and glucocorticoid receptor translocation were analyzed in wild-type (wt) and HDAC6-deficient (HDAC6KO) mice. The effect of the specific HDAC6 inhibitor tubacin was analyzed in vitro. wt and HDAC6KO mice were subjected to 3 weeks’ dexamethasone treatment before analysis of glucose and insulin tolerance. HDAC6KO mice showed impaired dexamethasone-induced hepatic glucocorticoid receptor translocation. Accordingly, dexamethasone-induced expression of a large number of hepatic genes was significantly attenuated in mice lacking HDAC6 and by tubacin in vitro. Glucose output of primary hepatocytes from HDAC6KO mice was diminished. A significant improvement of dexamethasone-induced whole-body glucose intolerance as well as insulin resistance in HDAC6KO mice compared with wt littermates was observed. This study demonstrates that HDAC6 is an essential regulator of hepatic glucocorticoid-stimulated gluconeogenesis and impairment of whole-body glucose metabolism through modification of glucocorticoid receptor nuclear translocation. Selective pharmacological inhibition of HDAC6 may provide a future therapeutic option against the prodiabetogenic actions of glucocorticoids. PMID:22210316

  9. Dietary aloe vera gel powder and extract inhibit azoxymethane- induced colorectal aberrant crypt foci in mice fed a high- fat diet.

    PubMed

    Chihara, Takeshi; Shimpo, Kan; Kaneko, Takaaki; Beppu, Hidehiko; Higashiguchi, Takashi; Sonoda, Shigeru; Tanaka, Miyuki; Yamada, Muneo; Abe, Fumiaki

    2015-01-01

    Aloe vera gel exhibits protective effects against insulin resistance as well as lipid-lowering and anti-diabetic effects. The anti-diabetic compounds in this gel were identified as Aloe-sterols. Aloe vera gel extract (AVGE) containing Aloe-sterols has recently been produced using a new procedure. We previously reported that AVGE reduced large-sized intestinal polyps in Apc-deficient Min mice fed a high fat diet (HFD), suggesting that Aloe vera gel may protect against colorectal cancer. In the present study, we examined the effects of Aloe vera gel powder (AVGP) and AVGE on azoxymethane-induced colorectal preneoplastic aberrant crypt foci (ACF) in mice fed a HFD. Male C57BL/6J mice were given a normal diet (ND), HFD, HFD containing 0.5% carboxymethyl cellulose solution, which was used as a solvent for AVGE (HFDC), HFD containing 3% or 1% AVGP, and HFDC containing 0.0125% (H-) or 0.00375% (L-) AVGE. The number of ACF was significantly lower in mice given 3% AVGP and H-AVGE than in those given HFD or HFDC alone. Moreover, 3% AVGP, H-AVGE and L-AVGE significantly decreased the mean Ki-67 labeling index, assessed as a measure of cell proliferation in the colonic mucosa. In addition, hepatic phase II enzyme glutathione S-transferase mRNA levels were higher in the H-AVGE group than in the HFDC group. These results suggest that both AVGP and AVGE may have chemopreventive effects on colorectal carcinogenesis under the HFD condition. Furthermore, the concentration of Aloe-sterols was similar between 3% AVGP and H-AVGE, suggesting that Aloe-sterols were the main active ingredients in this experiment.

  10. Betaine attenuates chronic alcohol‑induced fatty liver by broadly regulating hepatic lipid metabolism.

    PubMed

    Yang, Wenjuan; Huang, Luming; Gao, Jinhang; Wen, Shilei; Tai, Yang; Chen, Meng; Huang, Zhiyin; Liu, Rui; Tang, Chengwei; Li, Jing

    2017-10-01

    Betaine has previously been demonstrated to protect the liver against alcohol‑induced fat accumulation. However, the mechanism through which betaine affects alcohol‑induced hepatic lipid metabolic disorders has not been extensively studied. The present study aimed to investigate the effect of betaine on alcoholic simple fatty liver and hepatic lipid metabolism disorders. A total of 36 rats were randomly divided into control, ethanol and ethanol + betaine groups. Liver function, morphological alterations, lipid content and tumor necrosis factor (TNF)‑α levels were determined. Hepatic expression levels of diacylglycerol acyltransferase (DGAT) 1, DGAT2, sterol regulatory element binding protein (SREBP)‑1c, SREBP‑2, fatty acid synthase (FAS), 3‑hydroxy‑3‑methyl‑glutaryl (HMG)‑CoA reductase, peroxisome proliferator-activated receptor λ coactivator (PGC)‑1α, adiponectin receptor (AdipoR) 1 and AdipoR2 were quantified. Serum and adipose tissue adiponectin levels were assessed using an enzyme‑linked immunoassay. The results demonstrated that alcohol‑induced ultramicrostructural alterations in hepatocytes, including the presence of lipid droplets and swollen mitochondria, were attenuated by betaine. Hepatic triglyceride, free fatty acid, total cholesterol and cholesterol ester contents and the expression of DGAT1, DGAT2, SREBP‑1c, SREBP‑2, FAS and HMG‑CoA reductase were increased following ethanol consumption, however were maintained at control levels following betaine supplementation. Alcohol‑induced decreases in hepatic PGC‑1α mRNA levels and serum and adipose tissue adiponectin concentrations were prevented by betaine. The downregulation of hepatic AdipoR1 which resulted from alcohol exposure was partially attenuated by betaine. No significant differences in liver function, TNF‑α, phospholipid and AdipoR2 levels were observed among the control, ethanol and ethanol + betaine groups. Overall, these results indicated that

  11. Inducing a visceral organ to protect a peripheral capillary bed: stabilizing hepatic HIF-1α prevents oxygen-induced retinopathy.

    PubMed

    Hoppe, George; Lee, Tamara J; Yoon, Suzy; Yu, Minzhong; Peachey, Neal S; Rayborn, Mary; Zutel, M Julieta; Trichonas, George; Au, John; Sears, Jonathan E

    2014-06-01

    Activation of hypoxia-inducible factor (HIF) can prevent oxygen-induced retinopathy in rodents. Here we demonstrate that dimethyloxaloylglycine (DMOG)-induced retinovascular protection is dependent on hepatic HIF-1 because mice deficient in liver-specific HIF-1α experience hyperoxia-induced damage even with DMOG treatment, whereas DMOG-treated wild-type mice have 50% less avascular retina (P < 0.0001). Hepatic HIF stabilization protects retinal function because DMOG normalizes the b-wave on electroretinography in wild-type mice. The localization of DMOG action to the liver is further supported by evidence that i) mRNA and protein erythropoietin levels within liver and serum increased in DMOG-treated wild-type animals but are reduced by 60% in liver-specific HIF-1α knockout mice treated with DMOG, ii) triple-positive (Sca1/cKit/VEGFR2), bone-marrow-derived endothelial precursor cells increased twofold in DMOG-treated wild-type mice (P < 0.001) but are unchanged in hepatic HIF-1α knockout mice in response to DMOG, and iii) hepatic luminescence in the luciferase oxygen-dependent degradation domain mouse was induced by subcutaneous and intraperitoneal DMOG. These findings uncover a novel endocrine mechanism for retinovascular protection. Activating HIF in visceral organs such as the liver may be a simple strategy to protect capillary beds in the retina and in other peripheral tissues. Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  12. Modeling Inborn Errors of Hepatic Metabolism Using Induced Pluripotent Stem Cells.

    PubMed

    Pournasr, Behshad; Duncan, Stephen A

    2017-11-01

    Inborn errors of hepatic metabolism are because of deficiencies commonly within a single enzyme as a consequence of heritable mutations in the genome. Individually such diseases are rare, but collectively they are common. Advances in genome-wide association studies and DNA sequencing have helped researchers identify the underlying genetic basis of such diseases. Unfortunately, cellular and animal models that accurately recapitulate these inborn errors of hepatic metabolism in the laboratory have been lacking. Recently, investigators have exploited molecular techniques to generate induced pluripotent stem cells from patients' somatic cells. Induced pluripotent stem cells can differentiate into a wide variety of cell types, including hepatocytes, thereby offering an innovative approach to unravel the mechanisms underlying inborn errors of hepatic metabolism. Moreover, such cell models could potentially provide a platform for the discovery of therapeutics. In this mini-review, we present a brief overview of the state-of-the-art in using pluripotent stem cells for such studies. © 2017 American Heart Association, Inc.

  13. Edaravone prevents lung injury induced by hepatic ischemia-reperfusion.

    PubMed

    Uchiyama, Munehito; Tojo, Kentaro; Yazawa, Takuya; Ota, Shuhei; Goto, Takahisa; Kurahashi, Kiyoyasu

    2015-04-01

    Lung injury is a major clinical concern after hepatic ischemia-reperfusion (I/R), due to the production of reactive oxygen species in the reperfused liver. We investigated the efficacy of edaravone, a potent free-radical scavenger, for attenuating lung injury after hepatic I/R. Adult male Sprague-Dawley rats were assigned to sham + normal saline (NS), I/R + NS, or I/R + edaravone group. Rats in the I/R groups were subjected to 90 min of partial hepatic I/R. Five minutes before reperfusion, 3 mg/kg edaravone was administered to the I/R + edaravone group. After 6 h of reperfusion, we evaluated lung histopathology and wet-to-dry ratio. We also measured malondialdehyde (MDA), an indicator of oxidative stress, in the liver and the lung, as well as cytokine messenger RNA expressions in the reperfused liver and plasma cytokine concentrations. Histopathology revealed lung damages after 6 h reperfusion of partial ischemic liver. Moreover, a significant increase in lung wet-to-dry ratio was observed. MDA concentration increased in the reperfused liver, but not in the lungs. Edaravone administration attenuated the lung injury and the increase of MDA in the reperfused liver. Edaravone also suppressed the reperfusion-induced increase of interleukin-6 messenger RNA expressions in the liver and plasma interleukin-6 concentrations. Edaravone administration before reperfusion of the ischemic liver attenuates oxidative stress in the reperfused liver and the subsequent lung injury. Edaravone may be beneficial for preventing lung injury induced by hepatic I/R. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Synergistic protective effect of picrorhiza with honey in acetaminophen induced hepatic injury.

    PubMed

    Gupta, Prashant; Tripathi, Alok; Agrawal, Tripti; Narayan, Chandradeo; Singh, B M; Kumar, Mohan; Kumar, Arvind

    2016-08-01

    Rhizome of picrorhiza along with honey prevents hepatic damage and cure the acetaminophen (paracetamol) induced hepatotoxicity by modulating the activity of hepatic enzymes. Here, we studied the in vivo effects of Picrorhiza kurroa and honey on acetaminophen induced hepatotoxicity Balb/c mice model. Hepatic histopathological observations of acetaminophen fed (day-6) group showed more congestion, hemorrhage, necrosis, distorted hepatic architecture and nuclear inclusion. Such damages were recompensed to normal by picrorhiza or honey alone or both in combinations. We observed increased activity of SGPT and SGOT in injured liver tissues, and that too was compensated to normal with picrorhiza or honey alone or both in combinations. We observed 1.27 and 1.23-fold enhanced activity of SGPT in serum and liver lysate, respectively while SGOT showed 1.66 and 1.11 fold enhanced activity. These two enzymes are signature enzymes of liver damage. Thus, our results support that honey may be used with drug picrorhiza due to its synergistic role to enhance hepatoprotective and hepatoregenerative ability along with allopathic drugs to mitigate the hepatotoxic effects.

  15. Superoxide produced by Kupffer cells is an essential effector in concanavalin A-induced hepatitis in mice.

    PubMed

    Nakashima, Hiroyuki; Kinoshita, Manabu; Nakashima, Masahiro; Habu, Yoshiko; Shono, Satoshi; Uchida, Takefumi; Shinomiya, Nariyoshi; Seki, Shuhji

    2008-12-01

    Although concanavalin A (Con-A)-induced experimental hepatitis is thought to be induced by activated T cells, natural killer T (NKT) cells, and cytokines, precise mechanisms are still unknown. In the current study, we investigated the roles of Kupffer cells, NKT cells, FasL, tumor necrosis factor (TNF), and superoxide in Con-A hepatitis in C57BL/6 mice. Removal of Kupffer cells using gadolinium chloride (GdCl(3)) from the liver completely inhibited Con-A hepatitis, whereas increased serum TNF and IFN-gamma levels were not inhibited at all. Unexpectedly, anti-FasL antibody pretreatment did not inhibit Con-A hepatitis, whereas it inhibited hepatic injury induced by a synthetic ligand of NKT cells, alpha-galactosylceramide. Furthermore, GdCl(3) pretreatment changed neither the activation-induced down-regulation of NK1.1 antigens as well as T cell receptors of NKT cells nor the increased expression of the CD69 activation antigen of hepatic T cells. CD68(+) Kupffer cells greatly increased in proportion in the early phase after Con-A injection; this increase was abrogated by GdCl(3) pretreatment. Anti-TNF antibody (Ab) pretreatment did not inhibit the increase of Kupffer cells, but it effectively suppressed superoxide/reactive oxygen production from Kupffer cells and the resulting hepatic injury. Conversely, depletion of NKT cells in mice by NK1.1 Ab pretreatment did suppress both the increase of CD68(+) Kupffer cells and Con-A hepatitis. Consistently, the diminution of oxygen radicals produced by Kupffer cells by use of free radical scavengers greatly inhibited Con-A hepatitis without suppressing cytokine production. However, adoptive transfer experiments also indicate that a close interaction/cooperation of Kupffer cells with NKT cells is essential for Con-A hepatitis. Superoxide produced by Kupffer cells may be the essential effector in Con-A hepatitis, and TNF and NKT cells support their activation and superoxide production.

  16. Long-term administration of Salvia miltiorrhiza ameliorates carbon tetrachloride-induced hepatic fibrosis in rats.

    PubMed

    Lee, Tzung-Yan; Wang, Guei-Jane; Chiu, Jen-Hwey; Lin, Han-Chieh

    2003-11-01

    Carbon tetrachloride (CCl4) is metabolized by cytochrome P450 to form a reactive trichloromethyl radical that triggers a chain of lipid peroxidation. These changes lead to cell injury, and chronic liver injury leads to excessive deposition of collagen in liver, resulting in liver fibrosis. The aim of this study was to evaluate the effects of long-term Salvia miltiorrhiza administration in CCl4-induced hepatic injury in rats. Salvia miltiorrhiza (10, 25 or 50 mg kg(-1) twice a day) was given for 9 weeks, beginning at the same time as the injections of CCl4. Rats receiving CCl4 alone showed a decreased hepatic glutathione level and an increased glutathione-S-transferase content. The hepatic thiobarbituratic acid-reactive substance levels were increased. CCl4 also caused a prominent collagen deposition in liver histology that was further supported by the increased hepatic mRNA expression of transforming growth factor-beta1, tissue inhibitor of metalloproteinase-1 and procollagen I. Salvia miltiorrhiza administration led to a dose-dependent increase in hepatic glutathione levels and a decrease in peroxidation products. Additionally, it reduced the mRNA expression of markers for hepatic fibrogenesis. In conclusion, long-term administration of Salvia miltiorrhiza in rats ameliorated the CCl4-induced hepatic injury that probably related to a reduced oxidant stress and degree of hepatic fibrosis.

  17. Positive Foci of Glutathione S‐Transferase Placental Form in the Liver of Rats Given Furfural by Oral Administration

    PubMed Central

    Shimizu, Akio; Nakamura, Yoshiyasu; Harada, Masaoki; Ono, Tetsuo; Sato, Kiyomi; Inoue, Tohru; Kanisawa, Masayoshi

    1989-01-01

    We observed GST‐P‐positive liver foci in rats during the course of developing liver cirrhosis by oral administration of furfural, an organic solvent. Male Wistar rats were given furfural‐containing diet (20–30 rag/kg diet) for 15–150 days, and killed 14 days after terminating furfural feeding. Immuno‐histochemical investigation of GST‐P‐positive liver foci which appeared in rats fed furfural for more than 30 days revealed an increase in number and size of the foci in proportion to the duration of furfural administration. Since furfural is known not to be carcinogenic in rats, this finding will be helpful to understand the enhancing effect of furfural‐induced cirrhosis on chemical hepatocarcino‐genesis. PMID:2507483

  18. Impaired Cardiolipin Biosynthesis Prevents Hepatic Steatosis and Diet-Induced Obesity

    PubMed Central

    Cole, Laura K.; Mejia, Edgard M.; Vandel, Marilyne; Sparagna, Genevieve C.; Claypool, Steven M.; Dyck-Chan, Laura; Klein, Julianne

    2016-01-01

    Mitochondria are the nexus of energy metabolism, and consequently their dysfunction has been implicated in the development of metabolic complications and progression to insulin resistance and type 2 diabetes. The unique tetra-acyl phospholipid cardiolipin (CL) is located in the inner mitochondrial membrane, where it maintains mitochondrial integrity. Here we show that knockdown of Tafazzin (TAZ kd), a CL transacylase, in mice results in protection against the development of obesity, insulin resistance, and hepatic steatosis. We determined that hypermetabolism protected TAZ kd mice from weight gain. Unexpectedly, the large reduction of CL in the heart and skeletal muscle of TAZ kd mice was not mirrored in the liver. As a result, TAZ kd mice exhibited normal hepatic mitochondrial supercomplex formation and elevated hepatic fatty acid oxidation. Collectively, these studies identify a key role for hepatic CL remodeling in regulating susceptibility to insulin resistance and as a novel therapeutic target for diet-induced obesity. PMID:27495222

  19. Quality of life in childhood epilepsy with lateralized epileptogenic foci.

    PubMed

    Mathiak, Krystyna A; Luba, Małgorzata; Mathiak, Klaus; Karzel, Katarzyna; Wolańczyk, Tomasz; Szczepanik, Elzbieta; Ostaszewski, Paweł

    2010-08-17

    Measuring quality of life (QOL) helps to delineate mechanisms underlying the interaction of disease and psychosocial factors. In adults, epileptic foci in the left temporal lobe led to lower QOL and higher depression and anxiety as compared to the right-sided foci. No study addressed the development of QOL disturbances depending on the lateralization of epileptogenic focus. The objective of our study was to examine QOL in children with lateralized epileptiform discharges. Thirty-one parents of children with epilepsy filled the Health-Related Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). Fifteen children had foci in the left hemisphere and sixteen in the right, as verified with Electroencephalography (EEG) examinations. We found a significant correlation between foci lateralization and reduced QOL (Spearman's rho = 0.361, p < 0.046). Children with right hemispheric foci exhibited lower overall QOL, particularly in five areas: anxiety, social-activities, stigma, general-health, and quality-of-life. We demonstrated for the first time that in children left- and right-hemispheric foci were associated with discordant QOL scores. Unlike in adults, foci in the right hemisphere led to worse emotional and social functioning demonstrating that seizures impact the brain differentially during development.

  20. Pharmacogenetics of ribavirin-induced anemia in hepatitis C.

    PubMed

    Ampuero, Javier; Romero-Gómez, Manuel

    2016-09-01

    Pharmacogenetics assesses inherited genetic differences in drug metabolic pathways and its role in medicine is growing. Ribavirin (RBV) and peginterferon were the standard of care therapy in hepatitis C virus infection during 15 years, with the addition of first-generation protease inhibitors at the beginning of 2010s. New direct-acting agents are the new standard of care, but RBV remains important in some scenarios. The main adverse effect of RBV is anemia, which requires dose reduction and even stopping treatment in some patients. Pharmacogenetics has identified ITPA and SLC28/29 genes to be closely related to RBV-induced anemia. The routine evaluation of these genes could help to identify those patients at risk of developing anemia during the hepatitis C virus treatment.

  1. Vitamin B12 supplement alleviates N'-nitrosodimethylamine-induced hepatic fibrosis in rats.

    PubMed

    Ahmad, Areeba; Afroz, Nishat; Gupta, Umesh D; Ahmad, Riaz

    2014-01-10

    Abstract Context: Altered vitamin B 12 levels have been correlated with hepatotoxicity; however, further evidence is required to establish its protective role. Objective: To evaluate the effects of vitamin B 12 supplement in protecting N'-nitrosodimethylamine (NDMA)-induced hepatic fibrosis in Wistar rats. Materials and methods: Hepatic fibrosis was induced by administering NDMA in doses of 10 mg/kg body weight thrice a week for 21 days. Another group received equal doses (10 mg/kg body weight) of vitamin B 12 subsequent to NDMA treatment. Animals from either group were sacrificed weekly from the start of the treatment along with their respective controls. Progression of hepatic fibrosis, in addition to the effect of vitamin B 12 , was assessed biochemically for liver function biomarkers, liver glycogen, hydroxyproline (HP) and B 12 reserves along with histopathologically by hematoxylin and eosin (H & E) as well immunohistochemical staining for α-SMA expression. Results and discussion: Elevation in the levels of aminotransferases, SALP, total bilirubin and HP was observed in NDMA treated rats, which was concomitant with remarkable depletion in liver glycogen and B 12 reserves (p < 0.05). Liver biopsies also demonstrated disrupted lobular architecture, collagen amassing and intense fibrosis by NDMA treatment. Immunohistochemical staining showed the presence of activated stellate cells that was dramatically increased up to day 21 in fibrotic rats. Following vitamin B 12 treatment, liver function biomarkers, glycogen contents and hepatic vitamin B 12 reserves were restored in fibrotic rats, significantly. Vitamin B 12 administration also facilitated restoration of normal liver architecture. Conclusion: These findings provide interesting new evidence in favor of protective role for vitamin B 12 against NDMA-induced hepatic fibrosis in rats.

  2. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis.

    PubMed

    Werawatganon, Duangporn; Linlawan, Sittikorn; Thanapirom, Kessarin; Somanawat, Kanjana; Klaikeaw, Naruemon; Rerknimitr, Rungsun; Siriviriyakul, Prasong

    2014-07-08

    An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. APAP overdose can cause liver injury. Our result indicate that Aloe vera attenuate APAP-induced

  3. Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo.

    PubMed

    Galbo, Thomas; Perry, Rachel J; Jurczak, Michael J; Camporez, João-Paulo G; Alves, Tiago C; Kahn, Mario; Guigni, Blas A; Serr, Julie; Zhang, Dongyan; Bhanot, Sanjay; Samuel, Varman T; Shulman, Gerald I

    2013-07-30

    Hepatic insulin resistance is a principal component of type 2 diabetes, but the cellular and molecular mechanisms responsible for its pathogenesis remain unknown. Recent studies have suggested that saturated fatty acids induce hepatic insulin resistance through activation of the toll-like receptor 4 (TLR-4) receptor in the liver, which in turn transcriptionally activates hepatic ceramide synthesis leading to inhibition of insulin signaling. In this study, we demonstrate that TLR-4 receptor signaling is not directly required for saturated or unsaturated fat-induced hepatic insulin resistance in both TLR-4 antisense oligonucleotide treated and TLR-4 knockout mice, and that ceramide accumulation is not dependent on TLR-4 signaling or a primary event in hepatic steatosis and impairment of insulin signaling. Further, we show that both saturated and unsaturated fats lead to hepatic accumulation of diacylglycerols, activation of PKCε, and impairment of insulin-stimulated IRS-2 signaling. These data demonstrate that saturated fat-induced insulin resistance is independent of TLR-4 activation and ceramides.

  4. Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo

    PubMed Central

    Galbo, Thomas; Perry, Rachel J.; Jurczak, Michael J.; Camporez‎, João-Paulo G.; Alves, Tiago C.; Kahn, Mario; Guigni, Blas A.; Serr, Julie; Zhang, Dongyan; Bhanot, Sanjay; Samuel, Varman T.; Shulman, Gerald I.

    2013-01-01

    Hepatic insulin resistance is a principal component of type 2 diabetes, but the cellular and molecular mechanisms responsible for its pathogenesis remain unknown. Recent studies have suggested that saturated fatty acids induce hepatic insulin resistance through activation of the toll-like receptor 4 (TLR-4) receptor in the liver, which in turn transcriptionally activates hepatic ceramide synthesis leading to inhibition of insulin signaling. In this study, we demonstrate that TLR-4 receptor signaling is not directly required for saturated or unsaturated fat-induced hepatic insulin resistance in both TLR-4 antisense oligonucleotide treated and TLR-4 knockout mice, and that ceramide accumulation is not dependent on TLR-4 signaling or a primary event in hepatic steatosis and impairment of insulin signaling. Further, we show that both saturated and unsaturated fats lead to hepatic accumulation of diacylglycerols, activation of PKCε, and impairment of insulin-stimulated IRS-2 signaling. These data demonstrate that saturated fat-induced insulin resistance is independent of TLR-4 activation and ceramides. PMID:23840067

  5. Tuberous Sclerosis Complex-1 Deficiency Attenuates Diet-Induced Hepatic Lipid Accumulation

    PubMed Central

    Kenerson, Heidi L.; Yeh, Matthew M.; Yeung, Raymond S.

    2011-01-01

    Non-alcoholic fatty liver disease (NAFLD) is causally linked to type 2 diabetes, insulin resistance and dyslipidemia. In a normal liver, insulin suppresses gluconeogenesis and promotes lipogenesis. In type 2 diabetes, the liver exhibits selective insulin resistance by failing to inhibit hepatic glucose production while maintaining triglyceride synthesis. Evidence suggests that the insulin pathway bifurcates downstream of Akt to regulate these two processes. Specifically, mTORC1 has been implicated in lipogenesis, but its role on hepatic steatosis has not been examined. Here, we generated mice with hepatocyte-specific deletion of Tsc1 to study the effects of constitutive mTORC1 activation in the liver. These mice developed normally but displayed mild hepatomegaly and insulin resistance without obesity. Unexpectedly, the Tsc1-null livers showed minimal signs of steatosis even under high-fat diet condition. This ‘resistant’ phenotype was reversed by rapamycin and could be overcome by the expression of Myr-Akt. Moreover, rapamycin failed to reduce hepatic triglyceride levels in models of steatosis secondary to Pten ablation in hepatocytes or high-fat diet in wild-type mice. These observations suggest that mTORC1 is neither necessary nor sufficient for steatosis. Instead, Akt and mTORC1 have opposing effects on hepatic lipid accumulation such that mTORC1 protects against diet-induced steatosis. Specifically, mTORC1 activity induces a metabolic shift towards fat utilization and glucose production in the liver. These findings provide novel insights into the role of mTORC1 in hepatic lipid metabolism. PMID:21479224

  6. Dentigenous infectious foci – a risk factor of infective endocarditis

    PubMed Central

    Wisniewska-Spychala, Beata; Sokalski, Jerzy; Grajek, Stefan; Jemielity, Marek; Trojnarska, Olga; Choroszy-Król, Irena; Sójka, Anna; Maksymiuk, Tomasz

    2012-01-01

    Summary Background Dentigenous, infectious foci are frequently associated with the development of various diseases. The role of such foci in the evolution of endocarditis still remains unclear. This article presents the concluding results of an interdisciplinary study verifying the influence of dentigenous, infectious foci on the development of infective endocarditis. Material/Methods The study subjects were 60 adult patients with history of infective endocarditis and coexistent acquired heart disease, along with the presence at least 2 odontogenic infectious foci (ie, 2 or more teeth with gangrenous pulp and periodontitis). The group had earlier been qualified for the procedure of heart valve replacement. Swabs of removed heart valve tissue with inflammatory lesions and blood were then examined microbiologically. Swabs of root canals and their periapical areas, of periodontal pockets, and of heart valves were also collected. Results Microbial flora, cultured from intradental foci, blood and heart valves, fully corresponded in 14 patients. This was accompanied in almost all cases by more advanced periodontitis (2nd degree, Scandinavian classification), irrespective of the bacterial co-occurrence mentioned. In the remaining patients, such consistency was not found. Conclusions Among various dentigenous, infectious foci, the intradental foci appear to constitute a risk factor for infective endocarditis. PMID:22293883

  7. Quality of life in childhood epilepsy with lateralized epileptogenic foci

    PubMed Central

    2010-01-01

    Background Measuring quality of life (QOL) helps to delineate mechanisms underlying the interaction of disease and psychosocial factors. In adults, epileptic foci in the left temporal lobe led to lower QOL and higher depression and anxiety as compared to the right-sided foci. No study addressed the development of QOL disturbances depending on the lateralization of epileptogenic focus. The objective of our study was to examine QOL in children with lateralized epileptiform discharges. Methods Thirty-one parents of children with epilepsy filled the Health-Related Quality of Life in Childhood Epilepsy Questionnaire (QOLCE). Fifteen children had foci in the left hemisphere and sixteen in the right, as verified with Electroencephalography (EEG) examinations. Results We found a significant correlation between foci lateralization and reduced QOL (Spearman's rho = 0.361, p < 0.046). Children with right hemispheric foci exhibited lower overall QOL, particularly in five areas: anxiety, social-activities, stigma, general-health, and quality-of-life. Conclusions We demonstrated for the first time that in children left- and right-hemispheric foci were associated with discordant QOL scores. Unlike in adults, foci in the right hemisphere led to worse emotional and social functioning demonstrating that seizures impact the brain differentially during development. PMID:20716372

  8. Serum from CCl4-induced acute rat injury model induces differentiation of ADSCs towards hepatic cells and reduces liver fibrosis.

    PubMed

    Baig, Maria Tayyab; Ali, Gibran; Awan, Sana Javaid; Shehzad, Umara; Mehmood, Azra; Mohsin, Sadia; Khan, Shaheen N; Riazuddin, Sheikh

    2017-10-01

    Cellular therapies hold promise to alleviate liver diseases. This study explored the potential of allogenic serum isolated from rat with acute CCl 4 injury to differentiate adipose derived stem cells (ADSCs) towards hepatic lineage. Acute liver injury was induced by CCl 4 which caused significant increase in serum levels of VEGF, SDF1α and EGF. ADSCs were preconditioned with 3% serum isolated from normal and acute liver injury models. ADSCs showed enhanced expression of hepatic markers (AFP, albumin, CK8 and CK19). These differentiated ADSCs were transplanted intra-hepatically in CCl 4 -induced liver fibrosis model. After one month of transplantation, fibrosis and liver functions (alkaline phosphatase, ALAT and bilirubin) showed marked improvement in acute injury group. Elevated expression of hepatic (AFP, albumin, CK 18 and HNF4a) and pro survival markers (PCNA and VEGF) and improvement in liver architecture as deduced from results of alpha smooth muscle actin, Sirius red and Masson's trichome staining was observed.

  9. Reversal of ethanol-induced hepatotoxicity by cinnamic and syringic acids in mice.

    PubMed

    Yan, Sheng-Lei; Wang, Zhi-Hong; Yen, Hsiu-Fang; Lee, Yi-Ju; Yin, Mei-Chin

    2016-12-01

    Ethanol was used to induce acute hepatotoxicity in mice. Effects of cinnamic acid (CA) and syringic acid (SA) post-intake for hepatic recovery from alcoholic injury was investigated. Ethanol treated mice were supplied by CA or SA at 40 or 80 mg/kg BW/day for 5 days. Results showed that ethanol stimulated protein expression of CYP2E1, p47 phox , gp91 phox , cyclooxygenase-2 and nuclear factor kappa B in liver. CA or SA post-intake restricted hepatic expression of these molecules. Ethanol suppressed nuclear factor erythroid 2-related factor (Nrf2) expression, and CA or SA enhanced Nrf2 expression in cytosolic and nuclear fractions. Ethanol increased the release of reactive oxygen species, oxidized glutathione, interleukin-6, tumor necrosis factor-alpha, nitric acid and prostaglandin E 2 . CA or SA lowered hepatic production of these oxidative and inflammatory factors. Histological data revealed that ethanol administration caused obvious foci of inflammatory cell infiltration, and CA or SA post-intake improved hepatic inflammatory infiltration. These findings support that cinnamic acid and syringic acid are potent nutraceutical agents for acute alcoholic liver disease therapy. However, potential additive or synergistic benefits of cinnamic and syringic acids against ethanol-induced hepatotoxicity need to be investigated. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. Prosteatotic genes are associated with unsaturated fat suppression of saturated fat-induced hepatic steatosis in C57BL/6 mice.

    PubMed

    Geng, Tuoyu; Xia, Lili; Russo, Sarah; Kamara, Davida; Cowart, Lauren Ashley

    2015-09-01

    Both high sugar and fat diets can induce prosteatotic genes, leading to obesity and obesity-associated diseases, including hepatic steatosis. Unsaturated fat/fatty acid (USFA) reduces high sugar-induced hepatic steatosis by inhibiting the induced prosteatotic genes. In contrast, it is still unclear how USFA ameliorates saturated fat/fatty acid (SFA)-induced hepatic steatosis. As sugar and fat have different transport and metabolic pathways, we hypothesized that USFA suppressed SFA-induced hepatic steatosis via a different set of prosteatotic genes. To test this, we implemented high SFA vs USFA diets and a control diet in C57BL/6 mice for 16 weeks. Severe hepatic steatosis was induced in mice fed the SFA diet. Among a nearly complete set of prosteatotic genes, only the stearoyl-coenzyme a desaturase 1 (Scd1), cluster of differentiation 36 (Cd36), and peroxisome proliferator-activated receptor γ (Pparγ) genes that were differentially expressed in the liver could contribute to SFA-induced steatosis or the alleviative effect of USFA. That is, the SFA diet induced the expression of Cd36 and Pparγ but not Scd1, and the USFA diet suppressed Scd1 expression and the induction of Cd36 and Pparγ. These findings were mainly recapitulated in cultured hepatocytes. The essential roles of SCD1 and CD36 were confirmed by the observation that the suppression of SCD1 and CD36 with small interfering RNA or drug treatment ameliorated SFA-induced lipid accumulation in hepatocytes. We thus concluded that SCD1, CD36, and PPARγ were essential to the suppression of SFA-induced hepatic steatosis by main dietary USFA, which may provide different therapeutic targets for reducing high-fat vs sugar-induced hepatic steatosis. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Chemopreventive efficacy of Andrographis paniculata on azoxymethane-induced aberrant colon crypt foci in vivo.

    PubMed

    Al-Henhena, Nawal; Ying, Rozaida Poh Yuen; Ismail, Salmah; Najm, Walaa; Najm, Wala; Khalifa, Shaden A M; El-Seedi, Hesham; Ameen Abdulla, Mahmood; Abdulla, Mahmood Ameen

    2014-01-01

    Andrographis paniculata is a grass-shaped medicinal herb, traditionally used in Southeast Asia. The aim of this study was to evaluate the chemoprotective effects of A. paniculata on colorectal cancer. A. paniculata ethanol extract was tested on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in vivo and in vitro. A. paniculata treated groups showed a significant reduction in the number of ACF of the treated rats. Microscopically, ACF showed remarkably elongated and stratified cells, and depletion of the submucosal glands of AOM group compared to the treated groups. Histologically, staining showed slightly elevated masses above the surrounding mucosa with oval or slit-like orifices. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) and β-catenin protein were down-regulated in the A. paniculata treated groups compared to the AOM group. When colon tissue was homogenized, malondialdehyde (MDA) and nitric oxide (NO) levels were significantly decreased, whereas superoxide dismutase (SOD) activity was increased in the treated groups compared to the AOM group. A. paniculata ethanol extract showed antioxidant and free radical scavenging activity, as elucidated by the measure of oxidative stress markers. Further, the active fractions were assessed against cell lines of CCD841 and HT29 colon cancer cells.

  12. Aloe vera attenuated liver injury in mice with acetaminophen-induced hepatitis

    PubMed Central

    2014-01-01

    Background An overdose of the acetaminophen causes liver injury. This study aims to examine the anti-oxidative, anti-inflammatory effects of Aloe vera in mice with acetaminophen induced hepatitis. Methods Male mice were randomly divided into three groups (n = 8 each). Control group were given orally distilled water (DW). APAP group were given orally N-acetyl-P-aminophenol (APAP) 400 mg/kg suspended in DW. Aloe vera-treated group were given orally APAP and Aloe vera (150 mg/kg) suspended in DW. Twenty-four hours later, the liver was removed to determine hepatic malondialdehyde (MDA), hepatic glutathione (GSH), the number of interleukin (IL)-12 and IL-18 positive stained cells (%) by immunohistochemistry method, and histopathological examination. Then, the serum was collected to determine transaminase (ALT). Results In APAP group, ALT, hepatic MDA and the number of IL-12 and IL-18 positive stained cells were significantly increased when compared to control group (1210.50 ± 533.86 vs 85.28 ± 28.27 U/L, 3.60 ± 1.50 vs 1.38 ± 0.15 nmol/mg protein, 12.18 ± 1.10 vs 1.84 ± 1.29%, and 13.26 ± 0.90 vs 2.54 ± 1.29%, P = 0.000, respectively), whereas hepatic GSH was significantly decreased when compared to control group (5.98 ± 0.30 vs 11.65 ± 0.43 nmol/mg protein, P = 0.000). The mean level of ALT, hepatic MDA, the number of IL-12 and IL-18 positive stained cells, and hepatic GSH in Aloe vera-treated group were improved as compared with APAP group (606.38 ± 495.45 vs 1210.50 ± 533.86 U/L, P = 0.024; 1.49 ± 0.64 vs 3.60 ± 1.50 nmol/mg protein, P = 0.001; 5.56 ± 1.25 vs 12.18 ± 1.10%, P = 0.000; 6.23 ± 0.94 vs 13.26 ± 0.90%, P = 0.000; and 10.02 ± 0.20 vs 5.98 ± 0.30 nmol/mg protein, P = 0.000, respectively). Moreover, in the APAP group, the liver showed extensive hemorrhagic hepatic necrosis at all zones while in Aloe vera-treated group, the liver architecture was improved histopathology. Conclusions APAP overdose can cause liver injury. Our result indicate

  13. Hypervitaminosis A-induced hepatic fibrosis in a cat.

    PubMed

    Guerra, Juliana M; Daniel, Alexandre G T; Aloia, Thiago P A; de Siqueira, Adriana; Fukushima, André R; Simões, Denise M N; Reche-Júior, Archivaldo; Cogliati, Bruno

    2014-03-01

    The excessive intake of vitamin A in the form of vitamin concentrate, supplement or vitamin-rich liver can result in hypervitaminosis A in man and animals. Although osteopathologies resulting from chronic vitamin A intoxication in cats are well characterized, no information is available concerning feline hypervitaminosis A-induced liver disease. We report the first case of hepatic stellate cell lipidosis and hepatic fibrosis in a domestic cat that had been fed a diet based on raw beef liver. Radiographic examination revealed exostoses and ankylosis between vertebrae C1 and T7, compatible with deforming cervical spondylosis. Necropsy showed a slightly enlarged and light yellow to bronze liver. Microscopic and ultrastructural analyses of liver tissues revealed diffuse and severe liver fibrosis associated with hepatic stellate cell hyperplasia and hypertrophy. These cells showed immunopositive staining for α-smooth muscle actin and desmin markers. The necropsy findings of chronic liver disease coupled with osteopathology supported the diagnosis of hypervitaminosis A. As in human hepatology, if there is dietary evidence to support increased intake of vitamin A, then hypervitaminosis A should be considered in the differential diagnosis of chronic liver disease in cats.

  14. Tangeretin Alleviates Cisplatin-Induced Acute Hepatic Injury in Rats: Targeting MAPKs and Apoptosis.

    PubMed

    Omar, Hany A; Mohamed, Wafaa R; Arab, Hany H; Arafa, El-Shaimaa A

    2016-01-01

    Despite its broad applications, cisplatin affords considerable nephro- and hepatotoxicity through triggering inflammatory and oxidative stress cascades. The aim of the current investigation was to study the possible protective effects of tangeretin on cisplatin-induced hepatotoxicity. The impact of tangeretin on cisplatin-evoked hepatic dysfunction and histopathologic changes along with oxidative stress, inflammatory and apoptotic biomarkers were investigated compared to silymarin. Tangeretin pre-treatment significantly improved liver function tests (ALT and AST), inhibited cisplatin-induced lipid profile aberrations (total cholesterol and triglycerides) and diminished histopathologic structural damage in liver tissues. Tangeretin also attenuated cisplatin-induced hepatic inflammatory events as indicated by suppression of tumor necrosis factor-α (TNF-α) and enhancement of interleukin-10 (IL-10). Meanwhile, it lowered malondialdehyde (MDA), nitric oxide (NO) and nuclear factor erythroid 2-related factor 2 (NRF-2) levels with restoration of glutathione (GSH), and glutathione peroxidase (GPx). Regarding mitogen-activated protein kinase (MAPK) pathway, tangeretin attenuated cisplatin-induced increase in phospho-p38, phospho-c-Jun N-terminal kinase (p-JNK) and phospho-extracellular signal-regulated kinase (p-ERK1/2) in liver tissues. In addition, tangeretin downregulated Bax expression with augmentation of Bcl-2 promoting liver cell survival. Our results highlight the protective effects of tangeretin against cisplatin-induced acute hepatic injury via the concerted modulation of inflammation, oxidative stress, MAPKs and apoptotic pathways.

  15. Bicyclol attenuates tetracycline-induced fatty liver associated with inhibition of hepatic ER stress and apoptosis in mice.

    PubMed

    Yao, Xiao-Min; Li, Yue; Li, Hong-Wei; Cheng, Xiao-Yan; Lin, Ai-Bin; Qu, Jun-Ge

    2016-01-01

    Endoplasmic reticulum (ER) stress is known to be involved in the development of several metabolic disorders, including non-alcoholic fatty liver disease (NAFLD). Tetracycline can cause hepatic steatosis, and ER stress may be involved in tetracycline-induced fatty liver. Our previous study showed that bicyclol has been proven to protect against tetracycline-induced fatty liver in mice, and ER stress may also be involved in bicyclol's hepatoprotective effect. Therefore, this study was performed to investigate the underlying mechanisms associated with ER stress and apoptosis, by which bicyclol attenuated tetracycline-induced fatty liver in mice. Bicyclol (300 mg/kg) was given to mice by gavage 3 times. Tetracycline (200 mg/kg, intraperitoneally) was injected at 1 h after the last dose of bicyclol. At 6 h and 24 h after single dose of tetracycline injection, serum ALT, AST, TG, CHO and hepatic histopathological examinations were performed to evaluate liver injuries. Hepatic steatosis was assessed by the accumulation of hepatic TG and CHO. Moreover, hepatic apoptosis and ER stress related markers were determined by TUNEL, real-time PCR, and western blot. As a result, bicyclol significantly protected against tetracycline-induced fatty liver as evidenced by the decrease of elevated serum transaminases and hepatic triglyceride, and the attenuation of histopathological changes in mice. In addition, bicyclol remarkably alleviated hepatic apoptosis and the gene expression of caspase-3, and increased the gene expression of XIAP. The gene expressions of ER stress-related markers, including CHOP, GRP78, IRE-1α, and ATF6, which were downregulated by bicyclol pretreatment in tetracycline-injected mice. These results suggested that bicyclol protected tetracycline-induced fatty liver partly due to its ability of anti-apoptosis associated with ER stress.

  16. Betaine reduces hepatic lipidosis induced by carbon tetrachloride in Sprague-Dawley rats.

    PubMed

    Junnila, M; Barak, A J; Beckenhauer, H C; Rahko, T

    1998-10-01

    Carbon tetrachloride-injected rats were given liquid diets with and without betaine for 7 d. Hepatic lipidosis was induced by 4 daily injections of carbon tetrachloride (CCl4). Animals were killed and their livers and blood taken for analysis of betaine, S-adenosylmethionine (SAM), betaine homocysteine methyltransferase (BHMT), triglyceride, alanine aminotransferase and aspartate aminotransferase. Liver samples were also processed and stained for histological examination. Supplemental betaine reduced triglyceride in the liver and centrilobular hepatic lipidosis induced by the CCl4 injections. In both the control and experimental groups receiving betaine, liver betaine, BHMT and SAM were significantly higher than in their respective groups not receiving betaine. This study provides evidence that betaine protects the liver against CCl4-induced lipidosis and may be a useful therapeutic and prophylactic agent in ameliorating the harmful effects of CCl4.

  17. Preventive Effect of the Korean Traditional Health Drink (Taemyeongcheong) on Acetaminophen-Induced Hepatic Damage in ICR Mice.

    PubMed

    Yi, Ruo-Kun; Song, Jia-Le; Lim, Yaung-Iee; Kim, Yong-Kyu; Park, Kun-Young

    2015-03-01

    This study was to investigate the preventive effect of taemyeongcheong (TMC, a Korean traditional health drink) on acetaminophen (APAP, 800 mg/kg BW)-induced hepatic damage in ICR mice. TMC is prepared from Saururus chinensis, Taraxacum officinale, Zingiber officinale, Cirsium setidens, Salicornia herbacea, and Glycyrrhizae. A high dose of TMC (500 mg/kg BW) was found to decrease APAP-induced increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase. TMC pretreatment also increased the hepatic levels of hepatic catalase, superoxide dismutase, glutathione peroxidase, and glutathione, and reduced serum levels of the inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in mice administered APAP (P<0.05). TMC (500 mg/kg BW) reduced hepatic mRNA levels of TNF-α, IL-1β, IL-6, COX-2, and iNOS by 87%, 84%, 89%, 85%, and 88%, respectively, in mice treated with APAP (P<0.05). Furthermore, histological observations suggested TMC pretreatment dose-dependently prevented APAP-induced hepatocyte damage. These results suggest that TMC could be used as a functional health drink to prevent hepatic damage.

  18. Osteomalacia induced by adefovir in patient with hepatitis B.

    PubMed

    Nathali Rivas Zavaleta, Mayra; Guayambuco Romero, Sonia; Calabozo Raluy, Marcelo; Pérez Ruiz, Fernando

    2014-01-01

    Osteomalacia is defined as a defect in mineralization of the bone matrix. We describe the case of a patient with chronic hepatitis B infection in whom treatment with adefovir induced renal phosphate loss with intense and sustained hypophosphatemia which derived in symptomatic osteomalacia. Copyright © 2012 Elsevier España, S.L. All rights reserved.

  19. Chemopreventive effect of selenium and Chinese medicinal herbs on N-nitrosobis(2-oxopropyl)amine-induced hepatocellular carcinoma in Syrian hamsters.

    PubMed

    Lee, Chang-Yin; Hsu, Yi-Chao; Wang, Jir-You; Chen, Chien-Chih; Chiu, Jen-Hwey

    2008-07-01

    Oxidative DNA damage by reactive oxygen species is involved in the process of liver carcinogenesis. To test the hypothesis that a remedy containing Scutellaria baicalensis Georgi (Sb) and Bupleurum scorzonerifolfium Willd (Bs) (Sb/Bs remedy) modulates hepatic neoplastic growth, BOP (N-nitrosobis(2-oxopropyl)amine)-induced liver cancers in hamsters were established. Parameters such as survival rate, tumour area, tumour foci, 8-hydroxydeoxyguanosine (8-OHdG), caspase-3, transforming growth factor (TGF-beta1) and tumour necrosis factor-alpha (TNF-alpha) were measured after Sb/Bs remedy treatment during BOP-induced carcinogenesis. The results showed that the Sb/Bs remedy and its constituents Sb and Bs suppressed the tumour area in BOP-induced liver tumours. Because selenium (Sel) is toxic at a high dose (10 mg/kg), with a low survival rate (0%), the combination of Sb/Bs remedy and low-dose Sel (1 mg/kg) was found to decrease the tumour area and the number of tumour foci while increasing serum TNF-alpha and TGF-beta1, but not IL-6 levels. Besides, the Sb/Bs remedy, when combined with low-dose Sel, not only decreased the expression of 8-OHdG and increased caspase-3 expression within the glutathione S-transferase placental form-positive tumour foci but also increased tumour apoptosis in BOP-induced hamsters. We conclude that low-dose Sel has a chemoprevention effect on BOP-induced liver tumours and such an effect was more enhanced when combined with Sb/Bs treatment.

  20. Epigallocatechin-3-gallate attenuates apoptosis and autophagy in concanavalin A-induced hepatitis by inhibiting BNIP3

    PubMed Central

    Li, Sainan; Xia, Yujing; Chen, Kan; Li, Jingjing; Liu, Tong; Wang, Fan; Lu, Jie; Zhou, Yingqun; Guo, Chuanyong

    2016-01-01

    Background Epigallocatechin-3-gallate (EGCG) is the most effective compound in green tea, and possesses a wide range of beneficial effects, including anti-inflammatory, antioxidant, antiobesity, and anticancer effects. In this study, we investigated the protective effects of EGCG in concanavalin A (ConA)-induced hepatitis in mice and explored the possible mechanisms involved in these effects. Methods Balb/C mice were injected with ConA (25 mg/kg) to induce acute autoimmune hepatitis, and EGCG (10 or 30 mg/kg) was administered orally twice daily for 10 days before ConA injection. Serum liver enzymes, proinflammatory cytokines, and other marker proteins were determined 2, 8, and 24 hours after the ConA administration. Results BNIP3 mediated cell apoptosis and autophagy in ConA-induced hepatitis. EGCG decreased the immunoreaction and pathological damage by reducing inflammatory factors, such as TNF-α, IL-6, IFN-γ, and IL-1β. EGCG also exhibited an antiapoptotic and antiautophagic effect by inhibiting BNIP3 via the IL-6/JAKs/STAT3 pathway. Conclusion EGCG attenuated liver injury in ConA-induced hepatitis by downregulating IL-6/JAKs/STAT3/BNIP3-mediated apoptosis and autophagy. PMID:26929598

  1. Hepatoprotective Effects of Grape Seed Procyanidin B2 in Rats With Carbon Tetrachloride-induced Hepatic Fibrosis.

    PubMed

    Wang, Zhenli; Zhang, Zemin; Du, Ning; Wang, Kai; Li, Lei

    2015-01-01

    Infectious hepatitis is a serious problem affecting millions of people worldwide, particularly in China and other developing countries, and it is the major risk factor for hepatic cirrhosis. To date, the pathogenesis of hepatic cirrhosis is complex and unclear. Traditional Chinese medicine (TCM) has long been used in its treatment; however, little is known to date about the effects of grape seed procyanidin B2 (GSPB2) on liver fibrosis. Using a rat model of carbon tetrachloride (CCl4)-induced hepatic fibrosis, the study intended to investigate the hepatoprotective effects of GSPB2 and to determine the possible pathway by which GSPB2 exerts its activities. Design • Thirty-six male, Sprague-Dawley rats were used in the study. Rats in a model (CCl4 only) group and the GSPB2 group were given CCl4 to induce hepatic fibrosis. Simultaneously, animals in the GSPB2 group were treated with GSPB2 by intragastric administration for 12 wk. In addition, the rat's Kupffer cells were cultured with CCl4 and GSPB2. The study took place at the central laboratory of Qilu Hospital at Shandong University in Jinan, China. The following parameters were investigated: (1) hepatic function; (2) the liver fibrosis index-serum hyaluronic acid (HA), laminin (LN), type 3 procollagen (PC-3), collagen 4, and hepatic hydroxyproline; (3) the expression in the liver of transforming growth factor β-1 (TGF-β1); (4) inflammatory cytokines in the liver and cell culture medium-tumor necrosis factor α (TNF-α), interleukin (IL) 1-β (IL-1β), IL-6, and IL-17; (5) oxidative stress markers in the liver and cell culture medium-malondialdehyde (MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), total superoxide dismutase (T-SOD), and total antioxidant capacity (T-AOC); and (6) levels of angiotensin 2 (Ang 2) in the liver. The CCl4 induced (1) significant hepatic-function damage; (2) elevated levels of the measures of the liver fibrosis index, TGF-β1, inflammatory cytokines, MDA, and 8-OHdG; (3) a reduction in

  2. Altered Hepatic Transport by Fetal Arsenite Exposure in Diet-Induced Fatty Liver Disease.

    PubMed

    Ditzel, Eric J; Li, Hui; Foy, Caroline E; Perrera, Alec B; Parker, Patricia; Renquist, Benjamin J; Cherrington, Nathan J; Camenisch, Todd D

    2016-07-01

    Non-alcoholic fatty liver disease can result in changes to drug metabolism and disposition potentiating adverse drug reactions. Furthermore, arsenite exposure during development compounds the severity of diet-induced fatty liver disease. This study examines the effects of arsenite potentiated diet-induced fatty liver disease on hepatic transport in male mice. Changes were detected for Mrp2/3/4 hepatic transporter gene expression as well as for Oatp1a4/2b1/1b2. Plasma concentrations of Mrp and Oatp substrates were increased in arsenic exposure groups compared with diet-only controls. In addition, murine embryonic hepatocytes and adult primary hepatocytes show significantly altered transporter expression after exposure to arsenite alone: a previously unreported phenomenon. These data indicate that developmental exposure to arsenite leads to changes in hepatic transport which could increase the risk for ADRs during fatty liver disease. © 2016 Wiley Periodicals, Inc.

  3. Subnuclear foci quantification using high-throughput 3D image cytometry

    NASA Astrophysics Data System (ADS)

    Wadduwage, Dushan N.; Parrish, Marcus; Choi, Heejin; Engelward, Bevin P.; Matsudaira, Paul; So, Peter T. C.

    2015-07-01

    Ionising radiation causes various types of DNA damages including double strand breaks (DSBs). DSBs are often recognized by DNA repair protein ATM which forms gamma-H2AX foci at the site of the DSBs that can be visualized using immunohistochemistry. However most of such experiments are of low throughput in terms of imaging and image analysis techniques. Most of the studies still use manual counting or classification. Hence they are limited to counting a low number of foci per cell (5 foci per nucleus) as the quantification process is extremely labour intensive. Therefore we have developed a high throughput instrumentation and computational pipeline specialized for gamma-H2AX foci quantification. A population of cells with highly clustered foci inside nuclei were imaged, in 3D with submicron resolution, using an in-house developed high throughput image cytometer. Imaging speeds as high as 800 cells/second in 3D were achieved by using HiLo wide-field depth resolved imaging and a remote z-scanning technique. Then the number of foci per cell nucleus were quantified using a 3D extended maxima transform based algorithm. Our results suggests that while most of the other 2D imaging and manual quantification studies can count only up to about 5 foci per nucleus our method is capable of counting more than 100. Moreover we show that 3D analysis is significantly superior compared to the 2D techniques.

  4. Biochanin A improves hepatic steatosis and insulin resistance by regulating the hepatic lipid and glucose metabolic pathways in diet-induced obese mice.

    PubMed

    Park, Hee-Sook; Hur, Haeng Jeon; Kim, Soon-Hee; Park, Su-Jin; Hong, Moon Ju; Sung, Mi Jeong; Kwon, Dae Young; Kim, Myung-Sunny

    2016-09-01

    Natural compounds that regulate peroxisome proliferator-activated receptor alpha (PPARα) have been reported to have beneficial effects in obesity-mediated metabolic disorders. In this study, we demonstrated that biochanin A (BA), an agonist of PPAR-α, improved hepatic steatosis and insulin resistance by regulating hepatic lipid and glucose metabolism. C57BL/6 mice were fed a normal chow diet, a high-fat diet (HFD), and an HFD supplemented with 0.05% BA for 12 weeks. Histological and biochemical examinations indicated that BA prevented obesity-induced hepatic steatosis and insulin resistance in HFD-fed mice. BA stimulated the transcriptional activation of PPAR-α in vitro and increased the expression of PPAR-α and its regulatory proteins in the liver. CE-TOF/MS analyses indicated that BA administration promoted the recovery of metabolites involved in phosphatidylcholine synthesis, lipogenesis, and beta-oxidation in the livers of obese mice. BA also suppressed the levels of gluconeogenesis-related metabolites and the expression of the associated enzymes, glucose 6-phosphatase and pyruvate kinase. Taken together, these results showed that BA ameliorated metabolic disorders such as hepatic steatosis and insulin resistance by modulating lipid and glucose metabolism in diet-induced obesity. Thus, BA may be a potential therapeutic agent for the prevention of obesity-mediated hepatic steatosis and insulin resistance. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Pretreatment Hepatoprotective Effect of the Marine Fungus Derived from Sponge on Hepatic Toxicity Induced by Heavy Metals in Rats

    PubMed Central

    Abdel-Monem, Nehad M.; Abdel-Azeem, Ahmed M.; El-Ashry, El-Sayed H.; Ghareeb, Doaa A.; Nabil-adam, Asmaa

    2013-01-01

    The aim of this study was to evaluate the pretreatment hepatoprotective effect of the extract of marine-derived fungus Trichurus spiralis Hasselbr (TS) isolated from Hippospongia communis sponge on hepatotoxicity. Twenty-eight male Sprague-Dawley rats were divided into four groups (n = 7). Group I served as −ve control, group II served as the induced group receiving subcutaneously for seven days 0.25 mg heavy metal mixtures, group III received (i.p.) TS extract of dose 40 mg for seven days, and group IV served as the protected group pretreated with TS extract for seven days as a protection dose, and then treated with the heavy metal-mixture. The main pathological changes within the liver after heavy-metal mixtures administrations marked hepatic damage evidenced by foci of lobular necrosis with neutrophilic infiltration, adjacent to dysplastic hepatocytes. ALT and AST measurements show a significant increase in group II by 46.20% and 45.12%, respectively. Total protein, elevated by about 38.9% in induction group compared to the −ve control group, in contrast to albumin, decreased as a consequence of metal administration with significant elevation on bilirubin level. The results prove that TS extract possesses a hepatoprotective property due to its proven antioxidant and free-radical scavenging properties. PMID:23484129

  6. Monocyte chemoattractant protein-induced protein 1 targets hypoxia-inducible factor 1α to protect against hepatic ischemia/reperfusion injury.

    PubMed

    Sun, Peng; Lu, Yue-Xin; Cheng, Daqing; Zhang, Kuo; Zheng, Jilin; Liu, Yupeng; Wang, Xiaozhan; Yuan, Yu-Feng; Tang, Yi-Da

    2018-05-09

    Sterile inflammation is an essential factor causing hepatic ischemia/reperfusion (I/R) injury. As a critical regulator of inflammation, the role of monocyte chemoattractant protein-induced protein 1 (MCPIP1) in hepatic I/R injury remains undetermined. In this study, we discovered that MCPIP1 downregulation was associated with hepatic I/R injury in liver transplant patients and a mouse model. Hepatocyte-specific Mcpip1 gene knockout (HKO) and transgenic (HTG) mice demonstrated that MCPIP1 functions to ameliorate liver damage, reduce inflammation, prevent cell death, and promote regeneration. A mechanistic study revealed that MCPIP1 interacted with and maintained hypoxia-inducible factor 1α (HIF-1α) expression by deubiquitinating HIF-1α. Notably, HIF-1α inhibitor reversed the protective effect of MCPIP1, while HIF-1α activator compensated for the detrimental effect of MCPIP1 deficiency. Thus, we identified the MCPIP1-HIF-1α axis as a critical pathway that may be a good target for intervention in hepatic I/R injury. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

  7. Protective effect of gastrodin on bile duct ligation-induced hepatic fibrosis in rats.

    PubMed

    Zhao, Shuangshuang; Li, Naren; Zhen, Yongzhan; Ge, Maoxu; Li, Yi; Yu, Bin; He, Hongwei; Shao, Rong-Guang

    2015-12-01

    Gastrodin has been showed to possess many beneficial physiological functions, including protection against inflammation and oxidation and apoptosis. Studies showed inflammation and oxidation play important roles in producing liver damage and initiating hepatic fibrogenesis. However, it has not been reported whether gastrodin has a protective effect against hepatic fibrosis or not. This is first ever made attempts to test gastrodin against liver fibrosis in bile duct ligation (BDL) rats. The aim of the present study is to evaluate the effect of gastrodin on BDL-induced hepatic fibrosis in rats. BDL rats were divided into two groups, BDL alone group, and BDL-gastrodin group treated with gastrodin (5 mg/ml in drinking water). The effects of gastrodin on BDL-induced hepatic injury and fibrosis in rats were estimated by assessing serum, urine, bile and liver tissue biochemistry followed by liver histopathology (using hematoxylin & eosin and sirius red stain) and hydroxyproline content measurement. The results showed that gastrodin treatment significantly reduced collagen content, bile duct proliferation and parenchymal necrosis after BDL. The serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) decreased with gastrodin treatment by 15.1 and 23.6 percent respectively in comparison to BDL group did not receive gastrodin. Gastrodin also significantly increased the level of serum high density lipoprotein (HDL) by 62.5 percent and down-regulated the elevated urine total bilirubin (TBIL) by 56.5 percent, but had no effect on total bile acid (TBA) in serum, bile and liver tissues. The immunohistochemical assay showed gastrodin remarkably reduced the expressions of CD68 and NF-κB in BDL rats. Hepatic SOD levels, depressed by BDL, were also increased by gastrodin by 8.4 percent. In addition, the increases of hepatic MDA and NO levels in BDL rats were attenuated by gastrodin by 31.3 and 38.7 percent separately. Our results indicate that gastrodin

  8. Activation of intestinal hypoxia-inducible factor 2α during obesity contributes to hepatic steatosis.

    PubMed

    Xie, Cen; Yagai, Tomoki; Luo, Yuhong; Liang, Xianyi; Chen, Tao; Wang, Qiong; Sun, Dongxue; Zhao, Jie; Ramakrishnan, Sadeesh K; Sun, Lulu; Jiang, Chunmei; Xue, Xiang; Tian, Yuan; Krausz, Kristopher W; Patterson, Andrew D; Shah, Yatrik M; Wu, Yue; Jiang, Changtao; Gonzalez, Frank J

    2017-11-01

    Nonalcoholic fatty liver disease is becoming the most common chronic liver disease in Western countries, and limited therapeutic options are available. Here we uncovered a role for intestinal hypoxia-inducible factor (HIF) in hepatic steatosis. Human-intestine biopsies from individuals with or without obesity revealed that intestinal HIF-2α signaling was positively correlated with body-mass index and hepatic toxicity. The causality of this correlation was verified in mice with an intestine-specific disruption of Hif2a, in which high-fat-diet-induced hepatic steatosis and obesity were substantially lower as compared to control mice. PT2385, a HIF-2α-specific inhibitor, had preventive and therapeutic effects on metabolic disorders that were dependent on intestine HIF-2α. Intestine HIF-2α inhibition markedly reduced intestine and serum ceramide levels. Mechanistically, intestine HIF-2α regulates ceramide metabolism mainly from the salvage pathway, by positively regulating the expression of Neu3, the gene encoding neuraminidase 3. These results suggest that intestinal HIF-2α could be a viable target for hepatic steatosis therapy.

  9. Hepatoprotective activity of Tridax procumbens against d-galactosamine/lipopolysaccharide-induced hepatitis in rats.

    PubMed

    Ravikumar, Vilwanathan; Shivashangari, Kanchi Subramanian; Devaki, Thiruvengadam

    2005-10-03

    The hepatoprotective activity of aerial parts of Tridax procumbens was investigated against d-Galactosamine/Lipopolysaccharide (d-GalN/LPS) induced hepatitis in rats. d-GalN/LPS (300 mg/kg body weight/30 microg/kg body weight)-induced hepatic damage was manifested by a significant increase in the activities of marker enzymes (aspartate transaminase, alanine transaminase, alkaline phosphatase, lactate dehydrogenase and gamma glutamyl transferase) and bilirubin level in serum and lipids both in serum and liver. Pretreatment of rats with a chloroform insoluble fraction from ethanolic extract of Tridax procumbens reversed these altered parameters to normal values. The biochemical observations were supplemented by histopathological examination of liver sections. Results of this study revealed that Tridax procumbens could afford a significant protection in the alleviation of d-GalN/LPS-induced hepatocellular injury.

  10. Prevention by zinc of cadmium-induced alterations in pancreatic and hepatic functions.

    PubMed Central

    Merali, Z; Singhal, R L

    1976-01-01

    Subacute cadmium treatment (CdCl2, 1 mg/kg twice daily for 7 days) in rats disturbs glucose homeostasis as shown by hyperglycemia and decreased glucose tolerance associated with suppression of insulin release, enhancement of hepatic gluconeogenic enzymes and decrease in hepatic glycogen content. 2 Exposure to cadmium increases hepatic cyclic adenosine 3',5'-monophosphate (cyclic AMP) and this is accompanied by stimulation of basal, adrenaline- as well as glucagon-stimulated form(s) of adenylate cyclase. 3 In contrast to cadmium, subacute administration of zinc (ZnCl2, 2 mg/kg twice daily for 7 days) fails to alter the activities of hepatic gluconeogenic enzymes, cyclic AMP synthesis, as well as glucose clearance and insulin release in response to a glucose load. 4 Zinc, when administered at the same time as cadmium, prevents the cadmium-induced lesions in both hepatic and pancreatic functions. 5 The results are discussed in relation to the possible mechanisms of cadmium toxicity and to the role of sulphydryl groups in the protection exercised by zinc. PMID:183849

  11. Preventive Effect of the Korean Traditional Health Drink (Taemyeongcheong) on Acetaminophen-Induced Hepatic Damage in ICR Mice

    PubMed Central

    Yi, Ruo-Kun; Song, Jia-Le; Lim, Yaung-Iee; Kim, Yong-Kyu; Park, Kun-Young

    2015-01-01

    This study was to investigate the preventive effect of taemyeongcheong (TMC, a Korean traditional health drink) on acetaminophen (APAP, 800 mg/kg BW)-induced hepatic damage in ICR mice. TMC is prepared from Saururus chinensis, Taraxacum officinale, Zingiber officinale, Cirsium setidens, Salicornia herbacea, and Glycyrrhizae. A high dose of TMC (500 mg/kg BW) was found to decrease APAP-induced increases in serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase. TMC pretreatment also increased the hepatic levels of hepatic catalase, superoxide dismutase, glutathione peroxidase, and glutathione, and reduced serum levels of the inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in mice administered APAP (P<0.05). TMC (500 mg/kg BW) reduced hepatic mRNA levels of TNF-α, IL-1β, IL-6, COX-2, and iNOS by 87%, 84%, 89%, 85%, and 88%, respectively, in mice treated with APAP (P<0.05). Furthermore, histological observations suggested TMC pretreatment dose-dependently prevented APAP-induced hepatocyte damage. These results suggest that TMC could be used as a functional health drink to prevent hepatic damage. PMID:25866750

  12. Atherogenic diet-induced hepatitis is partially dependent on murine TLR4

    USDA-ARS?s Scientific Manuscript database

    Diets high in cholesterol and cholate such as the Paigen diet have been used to study atherogenesis, lithogenesis, and proinflammatory microvascular changes induced by nutritional hypercholesterolemia. Although these diets lead to chronic hepatic inflammation and fibrosis, the early inflammatory cha...

  13. Phoenix dactylifera protects against oxidative stress and hepatic injury induced by paracetamol intoxication in rats.

    PubMed

    Salem, Gamal A; Shaban, Ahmed; Diab, Hussain A; Elsaghayer, Wesam A; Mjedib, Manal D; Hnesh, Aomassad M; Sahu, Ravi P

    2018-05-16

    The current studies were sought to determine effects of antioxidant potential of aqueous and methanolic extracts of Phoenix dactylifera leaves (PLAE and PLME) against the widely-used analgesic paracetamol (PCM) induced hepatotoxicity. Groups of rats were treated with or without PCM (1500 mg/kg), PLAE and PLME (300 mg/kg) and n-acetylcysteine (NAC, 50 mg/kg) followed by assessments of liver function tests, oxidative stress, antioxidant defenses, and hepatotoxicity. We observed that PCM significantly elevated serum liver markers, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), and bilirubin compared to control (untreated) group. These PCM-induced effects were associated with oxidative stress as demonstrated by increased levels of malondialdehyde (MDA) and reduced levels of hepatic antioxidant enzymes, glutathione peroxidase (GPx), catalase (CAT), and superoxide dismutase (SOD). Pretreatment of PLME decreased ALT and AST by 78.2% and tissue MDA by 54.1%, and increased hepatic GPx (3.5 folds), CAT (7 folds) and SOD (2.5 folds) compared to PCM group. These PLME-mediated effects were comparable to NAC pretreatment. Histological analysis demonstrates that PLME conserved hepatic tissues against lesions such as inflammation, centrilobular necrosis, and hemorrhages induced by PCM. In contrast, PLAE-mediated effects were less effective in reducing levels of liver function enzymes, oxidative stress, and liver histopathological profiles, and restoring antioxidant defenses against PCM-induced intoxication. These findings indicate that PLME exerts protective effects against PCM-induced hepatotoxicity via scavenging free radicals and restoring hepatic antioxidant enzymes. Thus, PLME and its bioactive components could further be evaluated for their pharmacological properties against drug-induced deleterious effects. Copyright © 2018. Published by Elsevier Masson SAS.

  14. Characterization of Aes nuclear foci in colorectal cancer cells

    PubMed Central

    Itatani, Yoshiro; Sonoshita, Masahiro; Kakizaki, Fumihiko; Okawa, Katsuya; Stifani, Stefano; Itoh, Hideaki; Sakai, Yoshiharu; Taketo, M. Mark

    2016-01-01

    Amino-terminal enhancer of split (Aes) is a member of Groucho/Transducin-like enhancer (TLE) family. Aes is a recently found metastasis suppressor of colorectal cancer (CRC) that inhibits Notch signalling, and forms nuclear foci together with TLE1. Although some Notch-associated proteins are known to form subnuclear bodies, little is known regarding the dynamics or functions of these structures. Here, we show that Aes nuclear foci in CRC observed under an electron microscope are in a rather amorphous structure, lacking surrounding membrane. Investigation of their behaviour during the cell cycle by time-lapse cinematography showed that Aes nuclear foci dissolve during mitosis and reassemble after completion of cytokinesis. We have also found that heat shock cognate 70 (HSC70) is an essential component of Aes foci. Pharmacological inhibition of the HSC70 ATPase activity with VER155008 reduces Aes focus formation. These results provide insight into the understanding of Aes-mediated inhibition of Notch signalling. PMID:26229111

  15. Chemopreventive Efficacy of Andrographis paniculata on Azoxymethane-Induced Aberrant Colon Crypt Foci In Vivo

    PubMed Central

    Al-Henhena, Nawal; Ying, Rozaida Poh Yuen; Ismail, Salmah; Najm, Wala; Khalifa, Shaden A. M.; El-Seedi, Hesham; Abdulla, Mahmood Ameen

    2014-01-01

    Andrographis paniculata is a grass-shaped medicinal herb, traditionally used in Southeast Asia. The aim of this study was to evaluate the chemoprotective effects of A. paniculata on colorectal cancer. A. paniculata ethanol extract was tested on azoxymethane (AOM)-induced aberrant crypt foci (ACF) in vivo and in vitro. A. paniculata treated groups showed a significant reduction in the number of ACF of the treated rats. Microscopically, ACF showed remarkably elongated and stratified cells, and depletion of the submucosal glands of AOM group compared to the treated groups. Histologically, staining showed slightly elevated masses above the surrounding mucosa with oval or slit-like orifices. Immunohistochemically, expression of proliferating cell nuclear antigen (PCNA) and β-catenin protein were down-regulated in the A. paniculata treated groups compared to the AOM group. When colon tissue was homogenized, malondialdehyde (MDA) and nitric oxide (NO) levels were significantly decreased, whereas superoxide dismutase (SOD) activity was increased in the treated groups compared to the AOM group. A. paniculata ethanol extract showed antioxidant and free radical scavenging activity, as elucidated by the measure of oxidative stress markers. Further, the active fractions were assessed against cell lines of CCD841 and HT29 colon cancer cells. PMID:25390042

  16. LKM3 autoantibodies in hepatitis C cirrhosis: a further phenomenon of the HCV-induced autoimmunity.

    PubMed

    Csepregi, A; Nemesánszky, E; Luettig, B; Obermayer-Straub, P; Manns, M P

    2001-03-01

    Chronic hepatitis C is frequently associated with laboratory markers-including LKM1 autoantibodies--of autoimmunity. A 62-yr-old woman with hepatitis C cirrhosis presented autoantibodies against liver and kidney microsomal proteins. By further evaluation of autoantibodies using ELISA and immunoblotting LKM1 and LKM3 autoantibodies could be revealed. The target antigen of LKM3 autoantibodies proved to be UGT-1.1 isoenzyme. In the absence of chronic hepatitis D infection or autoimmune hepatitis type 2, this is the first case that reports the occurrence of LKM3 autoantibodies in HCV-induced chronic liver disease.

  17. Perfluorooctane Sulfonate-Induced Hepatic Steatosis in Male Sprague Dawley Rats Is Not Attenuated by Dietary Choline Supplementation.

    PubMed

    Bagley, Bradford D; Chang, Shu-Ching; Ehresman, David J; Eveland, Alan; Zitzow, Jeremiah D; Parker, George A; Peters, Jeffrey M; Wallace, Kendall B; Butenhoff, John L

    2017-12-01

    Perfluorooctane sulfonate (PFOS) is an environmentally persistent chemical. Dietary 100 ppm PFOS fed to male mice and rats for 4 weeks caused hepatic steatosis through an unknown mechanism. Choline deficient diets can cause hepatic steatosis. A hepatic choline:PFOS ion complex was hypothesized to cause this effect in mice. This study tested whether dietary choline supplementation attenuates PFOS-induced hepatic steatosis in rats. Sprague Dawley rats (12/sex/group) were fed control, choline supplemented (CS), 100 ppm PFOS, or 100 ppm PFOS + CS diets for 3 weeks. Male rats fed both PFOS-containing diets had decreased serum cholesterol and triglycerides (TGs) on days 9, 16, and/or 23 and increased hepatic free fatty acids and TG (ie, steatosis). Female rats fed both PFOS diets had decreased serum cholesterol on days 9 and 16 and decreased hepatic free fatty acid and TG at termination (ie, no steatosis). Liver PFOS concentrations were similar for both sexes. Liver choline concentrations were increased in male rats fed PFOS (±CS), but the increase was lower in the PFOS + CS group. Female liver choline concentrations were not altered by any diet. These findings demonstrate a clear sex-related difference in PFOS-induced hepatic steatosis in the rat. Additional evaluated mechanisms (ie, nuclear receptor activation, mRNA upregulation, and choline kinase activity inhibition) did not appear to be involved in the hepatic steatosis. Dietary PFOS (100 ppm) induced hepatic steatosis in male, but not female, rats that was not attenuated by choline supplementation. The mechanism of lipid accumulation and the sex-related differences warrant further investigation. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. Effect of selective versus non-selective cyclooxygenase inhibitors on ischemia-reperfusion-induced hepatic injury in rats.

    PubMed

    Abdel-Gaber, Seham A; Ibrahim, Mohamed A; Amin, Entesar F; Ibrahim, Salwa A; Mohammed, Rehab K; Abdelrahman, Aly M

    2015-08-01

    Ischemia-reperfusion (IR) injury represents an important pathological process of liver injury during major hepatic surgery. The role of cyclooxygenase (COX) enzymes in the pathogenesis of ischemia-reperfusion (IR)-induced liver injury is not clear. This study investigated the effect of a selective COX-2 inhibitor, celecoxib, versus non-selective, indomethacin, on hepatic IR injury in rats. Hepatic IR was induced in adult male rats. The animals were divided into 4 groups: normal control (sham group), IR non-treated group; IR-indomethacin-treated group; and IR-celecoxib-treated group. Liver injury was evaluated by serum alanine aminotransferase (ALT) and a histopathological examination of liver tissues. Hepatic tissue content of oxidative stress parameters glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase, malondialdehyde (MDA), nitric oxide (NO) and the inflammatory marker, tumor necrosis factor-alpha, (TNF-α) were measured. Moreover, the immunohistochemical detection of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), and caspase-3 in the hepatic tissue was performed. Celecoxib, but not indomethacin, significantly attenuated hepatic IR injury as evidenced by reduction in serum ALT as well as by improvement in the histopathological scoring. Such effect was associated with attenuation in oxidative stress and TNF-α, along with modulation of immunohistochemical expression of eNOS, iNOS and caspase-3 in the hepatic tissue. The present study concluded that selective COX-2 inhibition (but not non-selective), is hepatoprotective against liver IR injury; indicating a differential role of COX-1 versus COX-2. Modulation of iNOS, eNOS and caspase-3 might participate in the protective effect of selective COX-2-inhibitors. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Concurrent clinical intraocular findings in horses with depigmented punctate chorioretinal foci.

    PubMed

    Mathes, Rachel L; Burdette, Erin L; Moore, Phillip A; Myrna, Kathern E

    2012-03-01

    To report concurrent clinical intraocular findings in horses with depigmented punctate chorioretinal foci and to document any correlation with equine recurrent uveitis (ERU). Records of 131 horses (241 eyes) examined at the University of Georgia Veterinary Teaching hospital from 2001 to 2010 were reviewed with either clinically normal fundi or depigmented punctate chorioretinal foci in the absence of other fundic pathology. Data collected included patient signalment, concurrent clinical ocular findings and follow-up information. Sex, presence of no other intraocular findings, presence of ERU, presence of cataracts, and presence of vitreal disease were compared between normal and foci groups using chi-squared analysis. Age and length of follow-up time were compared using a student's t-test. Ninety-one horses (167 eyes) with chorioretinal foci and forty horses (74 eyes) with clinically normal ocular fundi were examined. Fifty-eight (64%) horses with chorioretinal foci and 20 (50%) horses with clinically normal fundi had a normal intraocular examination. There was no significant difference in any of the criteria examined between groups. Horses with depigmented punctate chorioretinal foci, in the absence of other fundic pathology, are not more likely to have intraocular disease or ERU than horses with clinically normal ocular fundi. These findings suggest that depigmented punctate fundic foci in horses are not indicative of or associated with ERU. © 2011 American College of Veterinary Ophthalmologists.

  20. Bamboo salt attenuates CCl4-induced hepatic damage in Sprague-Dawley rats

    PubMed Central

    Zhao, Xin; Song, Jia-Le; Kil, Jeung-Ha

    2013-01-01

    Bamboo salt, a Korean folk medicine, is prepared with solar salt (sea salt) and baked several times at high temperatures in a bamboo case. In this study, we compared the preventive effects of bamboo salt and purified and solar salts on hepatic damage induced by carbon tetrachloride in Sprague-Dawley rats. Compared with purified and solar salts, bamboo salts prevented hepatic damage in rats, as evidenced by significantly reduced serum levels of aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase (P < 0.05). Bamboo salt (baked 9×) triggered the greatest reduction in these enzyme levels. In addition, it also reduced the levels of the proinflammatory cytokines interleukin (IL)-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. Histopathological sections of liver tissue demonstrated the protective effect of bamboo salt, whereas sections from animals treated with the other salt groups showed a greater degree of necrosis. We also performed reverse transcription-polymerase chain reaction and western blot analyses of the inflammation-related genes iNOS, COX-2, TNF-α, and IL-1β in rat liver tissues. Bamboo salt induced a significant decrease (~80%) in mRNA and protein expression levels of COX-2, iNOS, TNF-α, and IL-1β, compared with the other salts. Thus, we found that baked bamboo salt preparations could prevent CCl4-induced hepatic damage in vivo. PMID:23964314

  1. Pentoxifylline attenuates cytokine stress and Fas system in syngeneic liver proteins induced experimental autoimmune hepatitis.

    PubMed

    Hendawy, Nevien

    2017-08-01

    Apoptosis is a hallmark in the pathogenesis of autoimmune hepatitis (AIH). Cytokine stresses and extrinsic apoptotic pathway have been implicated in this type of hepatic injury. Pentoxifylline plays an important role in controlling inflammation and apoptosis in different autoimmune diseases. To assess the protective effect of pentoxifylline for 30days against pro-inflammatory cytokines as tumor necrosis factor-alpha (TNF-α), interferon-gamma (INF-γ) and mediators of extrinsic apoptotic pathway involving TNF receptor 1 (TNFR1) and its ligand TNF-α and Fas receptor and its ligand (FasL) in experimental autoimmune hepatitis (EAH) model. EAH was induced by intraperitoneal injection of syngeneic liver antigen emulsified in complete Freund's adjuvant (CFA) in male C57BL/6 mice. Five groups of mice were used: two control groups; Control PBS group and Control CFA group, EAH group and two EAH+pentoxifylline treated groups in doses (100 or 200mg/kg/d, given by oral gavage). Serum transaminase, pro-inflammatory cytokines (TNF-α and interferon-γ) and hepatic caspase-8 and 3 activities were evaluated. Signs of autoimmune hepatitis were confirmed by liver histology. In addition, hepatic TNFR1, Fas and FasL mRNA expression were assayed. Serum transaminase levels and signs of AIH observed in EAH mice were significantly reduced by pentoxifylline. Upregulated serum TNF-α, IFN-γ, hepatic caspase-8 and 3 activities and TNFR1, Fas and FasL mRNA expression in liver tissues in EAH group were significantly downregulated by pentoxifylline. Pentoxifylline protects against syngeneic liver antigen induced hepatitis and associating apoptosis through attenuating the exaggerated cytokine release and extrinsic apoptotic pathway. Thus, this may represent a new therapeutic strategy for hepatitis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. Protective effects of agmatine against D-galactosamine and lipopolysaccharide-induced fulminant hepatic failure in mice.

    PubMed

    El-Agamy, Dina S; Makled, Mirhan N; Gamil, Nareman M

    2014-06-01

    Fulminant hepatic failure (FHF) is a life-threatening syndrome characterized by massive hepatic necrosis and high mortality. There is no effective therapy for the disease other than liver transplantation. This study aimed to investigate the effect of agmatine, inducible nitric oxide synthase (iNOS) inhibitor, on D-galactosamine and lipopolysaccharide (GalN/LPS)-induced FHF in mice and explore its possible mechanism(s). Male Swiss albino mice were injected with a single dose agmatine (14 mg/kg, IP) 8 h prior to challenge with a single intraperitoneal injection of both GalN (800 mg/kg) and LPS (50 μg/kg). Agmatine significantly attenuated all GalN/LPS-induced biochemical and pathological changes in liver. It prevented the increase of serum transaminases and alkaline phosphatase (ALP). In addition, agmatine markedly attenuated GalN/LPS-induced necrosis and inflammation. Agmatine significantly reduced oxidative stress and enhanced antioxidant enzymes. Importantly, agmatine decreased total nitric oxide (NO) and pro-inflammatory cytokine, tumor necrosis factor-alpha (TNF-α). These findings reveal that agmatine has hepatoprotective effects against GalN/LPS-induced FHF in mice that may be related to its ability to suppress oxidative stress, NO synthesis and TNF-α production. Therefore, agmatine may serve as a novel therapeutic strategy for hepatic inflammatory diseases.

  3. Acute Liver Injury Induces Nucleocytoplasmic Redistribution of Hepatic Methionine Metabolism Enzymes

    PubMed Central

    Delgado, Miguel; Garrido, Francisco; Pérez-Miguelsanz, Juliana; Pacheco, María; Partearroyo, Teresa; Pérez-Sala, Dolores

    2014-01-01

    Abstract Aims: The discovery of methionine metabolism enzymes in the cell nucleus, together with their association with key nuclear processes, suggested a putative relationship between alterations in their subcellular distribution and disease. Results: Using the rat model of d-galactosamine intoxication, severe changes in hepatic steady-state mRNA levels were found; the largest decreases corresponded to enzymes exhibiting the highest expression in normal tissue. Cytoplasmic protein levels, activities, and metabolite concentrations suffered more moderate changes following a similar trend. Interestingly, galactosamine treatment induced hepatic nuclear accumulation of methionine adenosyltransferase (MAT) α1 and S-adenosylhomocysteine hydrolase tetramers, their active assemblies. In fact, galactosamine-treated livers showed enhanced nuclear MAT activity. Acetaminophen (APAP) intoxication mimicked most galactosamine effects on hepatic MATα1, including accumulation of nuclear tetramers. H35 cells that overexpress tagged-MATα1 reproduced the subcellular distribution observed in liver, and the changes induced by galactosamine and APAP that were also observed upon glutathione depletion by buthionine sulfoximine. The H35 nuclear accumulation of tagged-MATα1 induced by these agents correlated with decreased glutathione reduced form/glutathione oxidized form ratios and was prevented by N-acetylcysteine (NAC) and glutathione ethyl ester. However, the changes in epigenetic modifications associated with tagged-MATα1 nuclear accumulation were only prevented by NAC in galactosamine-treated cells. Innovation: Cytoplasmic and nuclear changes in proteins that regulate the methylation index follow opposite trends in acute liver injury, their nuclear accumulation showing potential as disease marker. Conclusion: Altogether these results demonstrate galactosamine- and APAP-induced nuclear accumulation of methionine metabolism enzymes as active oligomers and unveil the implication of

  4. Attenuation of CCl4-Induced Hepatic Fibrosis in Mice by Vaccinating against TGF-β1

    PubMed Central

    Li, Shuang; Lv, Yifei; Su, Houqiang; Jiang, Huiping; Hao, Zhiming

    2013-01-01

    Transforming growth factor β1 (TGF-β1) is the pivotal pro-fibrogenic cytokine in hepatic fibrosis. Reducing the over-produced expression of TGF-β1 or blocking its signaling pathways is considered to be a promising therapeutic strategy for hepatic fibrosis. In this study, we evaluated the feasibility of attenuating hepatic fibrosis by vaccination against TGF-β1 with TGF-β1 kinoids. Two TGF-β1 kinoid vaccines were prepared by cross-linking TGF-β1-derived polypeptides (TGF-β125–[41-65] and TGF-β130–[83-112]) to keyhole limpet hemocyanin (KLH). Immunization with the two TGF-β1 kinoids efficiently elicited the production of high-levels of TGF-β1-specific antibodies against in BALB/c mice as tested by enzyme-linked immunosorbent assay (ELISA) and Western blotting. The antisera neutralized TGF-β1-induced growth-inhibition on mink lung epithelial cells (Mv1Lu) and attenuated TGF-β1-induced Smad2/3 phosphorylation, α-SMA, collagen type 1 alpha 2 (COL1A2), plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1) expression in the rat hepatic stellate cell (HSC) line, HSC-T6. Vaccination against TGF-β1 with the kinoids significantly suppressed CCl4-induced collagen deposition and the expression of α-SMA and desmin, attenuated hepatocyte apoptosis and accelerated hepatocyte proliferation in BALB/c mice. These results demonstrated that immunization with the TGF-β1 kinoids efficiently attenuated CCl4-induced hepatic fibrosis and liver injury. Our study suggests that vaccination against TGF-β1 might be developed into a feasible therapeutic approach for the treatment of chronic fibrotic liver diseases. PMID:24349218

  5. Melatonin mitigates thioacetamide-induced hepatic fibrosis via antioxidant activity and modulation of proinflammatory cytokines and fibrogenic genes.

    PubMed

    Lebda, Mohamed A; Sadek, Kadry M; Abouzed, Tarek K; Tohamy, Hossam G; El-Sayed, Yasser S

    2018-01-01

    The potential antifibrotic effects of melatonin against induced hepatic fibrosis were explored. Rats were allocated into four groups: placebo; thioacetamide (TAA) (200mg/kg bwt, i.p twice weekly for two months); melatonin (5mg/kgbwt, i.p daily for a week before TAA and continued for an additional two months); and melatonin plus TAA. Hepatic fibrotic changes were evaluated biochemically and histopathologically. Hepatic oxidative/antioxidative indices were assessed. The expression of hepatic proinflammatory cytokines (tumor necrosis factor-α, and interleukin-1β), fibrogenic-related genes (transforming growth factor-1β, collagen I, collagen, III, laminin, and autotaxin) and an antioxidant-related gene (thioredoxin-1) were detected by qRT-PCR. In fibrotic rats, melatonin lowered serum aspartate aminotransferase, alanine aminotransferase, and autotaxin activities, bilirubin, hepatic hydroxyproline and plasma ammonia levels. Melatonin displayed hepatoprotective and antifibrotic potential as indicated by mild hydropic degeneration of some hepatocytes and mild fibroplasia. In addition, TAA induced the depletion of glutathione, glutathione s-transferase, glutathione peroxidase, superoxide dismutase, catalase, and paraoxonase-1 (PON-1), while inducing the accumulation of malondialdehyde, protein carbonyl (C=O) and nitric oxide (NO), and DNA fragmentation. These effects were restored by melatonin pretreatment. Furthermore, melatonin markedly attenuated the expression of proinflammatory cytokines and fibrogenic genes via the upregulation of thioredoxin-1 mRNA transcripts. Melatonin exhibits potent anti-inflammatory, antioxidant and fibrosuppressive activities against TAA-induced hepatic fibrogenesis via the suppression of oxidative stress, DNA damage, proinflammatory cytokines and fibrogenic gene transcripts. In addition, we demonstrate that the antifibrotic activity of melatonin is mediated by the induction of thioredoxin-1 with attenuation of autotaxin expressions

  6. A Chinese herbal medicine, jia-wei-xiao-yao-san, prevents dimethylnitrosamine-induced hepatic fibrosis in rats.

    PubMed

    Chien, Shu-Chen; Chang, Wei-Chiao; Lin, Pu-Hua; Chang, Wei-Pin; Hsu, Shih-Chung; Chang, Jung-Chen; Wu, Ya-Chieh; Pei, Jin-Kuo; Lin, Chia-Hsien

    2014-01-01

    Jia-wei-xiao-yao-san (JWXYS) is a traditional Chinese herbal medicine that is widely used to treat neuropsychological disorders. Only a few of the hepatoprotective effects of JWXYS have been studied. The aim of this study was to investigate the hepatoprotective effects of JWXYS on dimethylnitrosamine- (DMN-) induced chronic hepatitis and hepatic fibrosis in rats and to clarify the mechanism through which JWXYS exerts these effects. After the rats were treated with DMN for 3 weeks, serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were significantly elevated, whereas the albumin level decreased. Although DMN was continually administered, after the 3 doses of JWXYS were orally administered, the SGOT and SGPT levels significantly decreased and the albumin level was significantly elevated. In addition, JWXYS treatment prevented liver fibrosis induced by DMN. JWXYS exhibited superoxide-dismutase-like activity and dose-dependently inhibited DMN-induced lipid peroxidation and xanthine oxidase activity in the liver of rats. Our findings suggest that JWXYS exerts antifibrotic effects against DMN-induced chronic hepatic injury. The possible mechanism is at least partially attributable to the ability of JWXYS to inhibit reactive-oxygen-species-induced membrane lipid peroxidation.

  7. Protective effect of Piper betle leaf extract against cadmium-induced oxidative stress and hepatic dysfunction in rats

    PubMed Central

    Milton Prabu, S.; Muthumani, M.; Shagirtha, K.

    2012-01-01

    The present study was undertaken to examine the attenuative effect of Piper betle leaf extract (PBE) against cadmium (Cd) induced oxidative hepatic dysfunction in the liver of rats. Pre-oral supplementation of PBE (200 mg/kg BW) treated rats showed the protective efficacy against Cd induced hepatic oxidative stress. Oral administration of Cd (5 mg/kg BW) for four weeks to rats significantly (P > 0.05) elevated the level of serum hepatic markers such as serum aspartate transaminase (AST), serum alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), bilirubin (TBRNs), oxidative stress markers viz., thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), protein carbonyls (PC) and conjugated dienes (CD) and significantly (P > 0.05) reduced the enzymatic antioxidants viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) and non-enzymatic antioxidants Viz., reduced glutathione (GSH), total sulfhydryls (TSH), vitamin C and vitamin E in the liver. Pre-oral supplementation of PBE (200 mg/kg BW) in Cd intoxicated rats, the altered biochemical indices and pathological changes were recovered significantly (P > 0.05) which showed ameliorative effect of PBE against Cd induced hepatic oxidative stress. From the above findings, we suggested that the pre-administration of P. betle leaf extract exhibited remarkable protective effects against cadmium-induced oxidative hepatic injury in rats. PMID:23961183

  8. Protective effect of Piper betle leaf extract against cadmium-induced oxidative stress and hepatic dysfunction in rats.

    PubMed

    Milton Prabu, S; Muthumani, M; Shagirtha, K

    2012-04-01

    The present study was undertaken to examine the attenuative effect of Piper betle leaf extract (PBE) against cadmium (Cd) induced oxidative hepatic dysfunction in the liver of rats. Pre-oral supplementation of PBE (200 mg/kg BW) treated rats showed the protective efficacy against Cd induced hepatic oxidative stress. Oral administration of Cd (5 mg/kg BW) for four weeks to rats significantly (P > 0.05) elevated the level of serum hepatic markers such as serum aspartate transaminase (AST), serum alanine transaminase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGT), bilirubin (TBRNs), oxidative stress markers viz., thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH), protein carbonyls (PC) and conjugated dienes (CD) and significantly (P > 0.05) reduced the enzymatic antioxidants viz., superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), glutathione reductase (GR) and glucose-6-phosphate dehydrogenase (G6PD) and non-enzymatic antioxidants Viz., reduced glutathione (GSH), total sulfhydryls (TSH), vitamin C and vitamin E in the liver. Pre-oral supplementation of PBE (200 mg/kg BW) in Cd intoxicated rats, the altered biochemical indices and pathological changes were recovered significantly (P > 0.05) which showed ameliorative effect of PBE against Cd induced hepatic oxidative stress. From the above findings, we suggested that the pre-administration of P. betle leaf extract exhibited remarkable protective effects against cadmium-induced oxidative hepatic injury in rats.

  9. Spatiotemporal characterization of ionizing radiation induced DNA damage foci and their relation to chromatin organization

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Costes, Sylvain V; Chiolo, Irene; Pluth, Janice M.

    2009-09-15

    DNA damage sensing proteins have been shown to localize to the sites of DSB within seconds to minutes following ionizing radiation (IR) exposure, resulting in the formation of microscopically visible nuclear domains referred to as radiation-induced foci (RIF). This review characterizes the spatio-temporal properties of RIF at physiological doses, minutes to hours following exposure to ionizing radiation, and it proposes a model describing RIF formation and resolution as a function of radiation quality and nuclear densities. Discussion is limited to RIF formed by three interrelated proteins ATM (Ataxia telangiectasia mutated), 53BP1 (p53 binding protein 1) and ?H2AX (phosphorylated variant histonemore » H2AX). Early post-IR, we propose that RIF mark chromatin reorganization, leading to a local nuclear scaffold rigid enough to keep broken DNA from diffusing away, but open enough to allow the repair machinery. We review data indicating clear kinetic and physical differences between RIF emerging from dense and uncondensed regions of the nucleus. At later time post-IR, we propose that persistent RIF observed days following exposure to ionizing radiation are nuclear ?scars? marking permanent disruption of the chromatin architecture. When DNA damage is resolved, such chromatin modifications should not necessarily lead to growth arrest and it has been shown that persistent RIF can replicate during mitosis. Thus, heritable persistent RIF spanning over tens of Mbp may affect the transcriptome of a large progeny of cells. This opens the door for a non DNA mutation-based mechanism of radiation-induced phenotypes.« less

  10. Characterization of Aes nuclear foci in colorectal cancer cells.

    PubMed

    Itatani, Yoshiro; Sonoshita, Masahiro; Kakizaki, Fumihiko; Okawa, Katsuya; Stifani, Stefano; Itoh, Hideaki; Sakai, Yoshiharu; Taketo, M Mark

    2016-01-01

    Amino-terminal enhancer of split (Aes) is a member of Groucho/Transducin-like enhancer (TLE) family. Aes is a recently found metastasis suppressor of colorectal cancer (CRC) that inhibits Notch signalling, and forms nuclear foci together with TLE1. Although some Notch-associated proteins are known to form subnuclear bodies, little is known regarding the dynamics or functions of these structures. Here, we show that Aes nuclear foci in CRC observed under an electron microscope are in a rather amorphous structure, lacking surrounding membrane. Investigation of their behaviour during the cell cycle by time-lapse cinematography showed that Aes nuclear foci dissolve during mitosis and reassemble after completion of cytokinesis. We have also found that heat shock cognate 70 (HSC70) is an essential component of Aes foci. Pharmacological inhibition of the HSC70 ATPase activity with VER155008 reduces Aes focus formation. These results provide insight into the understanding of Aes-mediated inhibition of Notch signalling. © The Authors 2015. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.

  11. A Western diet induced NAFLD in LDLR(-/)(-) mice is associated with reduced hepatic glutathione synthesis.

    PubMed

    Li, Ling; Zhang, Guo-Fang; Lee, Kwangwon; Lopez, Rocio; Previs, Stephen F; Willard, Belinda; McCullough, Arthur; Kasumov, Takhar

    2016-07-01

    Oxidative stress plays a key role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Glutathione is the major anti-oxidant involved in cellular oxidative defense, however there are currently no simple non-invasive methods for assessing hepatic glutathione metabolism in patients with NAFLD. As a primary source of plasma glutathione, liver plays an important role in interorgan glutathione homeostasis. In this study, we have tested the hypothesis that measurements of plasma glutathione turnover could be used to assess the hepatic glutathione metabolism in LDLR(-/)(-) mice, a mouse model of diet-induced NAFLD. Mice were fed a standard low fat diet (LFD) or a high fat diet containing cholesterol (a Western type diet (WD)). The kinetics of hepatic and plasma glutathione were quantified using the (2)H2O metabolic labeling approach. Our results show that a WD leads to reduced fractional synthesis rates (FSR) of hepatic (25%/h in LFD vs. 18%/h in WD, P<0.05) and plasma glutathione (43%/h in LFD vs. 21%/h in WD, P<0.05), without any significant effect on their absolute production rates (PRs). WD-induced concordant changes in both hepatic and plasma glutathione turnover suggest that the plasma glutathione turnover measurements could be used to assess hepatic glutathione metabolism. The safety, simplicity, and low cost of the (2)H2O-based glutathione turnover approach suggest that this method has the potential for non-invasive probing of hepatic glutathione metabolism in patients with NAFLD and other diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Effect of thalidomide on endotoxin-induced decreases in activity and expression of hepatic cytochrome P450 3A2.

    PubMed

    Ueyama, Jun; Nadai, Masayuki; Zhao, Ying Lan; Kanazawa, Hiroaki; Takagi, Kenji; Kondo, Takaaki; Takagi, Kenzo; Wakusawa, Shinya; Abe, Fumie; Saito, Hiroko; Miyamoto, Ken-Ichi; Hasegawa, Takaaki

    2008-08-01

    Thalidomide has been reported to inhibit the production of tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) that are involved in the down-regulation of hepatic cytochrome P450 (CYP) induced by endotoxin. In the present study, we investigated the effects of thalidomide on endotoxin-induced decreases in the activity and expression of hepatic CYP3A2 in rats. Thalidomide (50 mg/kg) was administered orally 22 h and 2 h before intraperitoneal injection of endotoxin (1 mg/kg). Twenty-four hours after the injection of endotoxin, antipyrine clearance experiments were conducted, in which the rats were sacrificed and protein levels of hepatic CYP3A2 were measured. There were no significant differences in the histopathological changes in the liver between the endotoxin-treated and endotoxin plus thalidomide-treated rats. Thalidomide had no effect on the systemic clearance of antipyrine, which is a proper indicator for hepatic CYP3A2 activity, whereas it enhanced endotoxin-induced decrease in the systemic clearance of antipyrine. Western blot analysis revealed that thalidomide had no effect on the protein levels of hepatic CYP3A2, whereas it enhanced the down-regulation of hepatic CYP3A2 by endotoxin. However, there were no significant differences in the concentrations of TNF-alpha and NO in plasma between the endotoxin-treated and endotoxin plus thalidomide-treated rats. The present findings suggest that thalidomide enhances endotoxin-induced decreases in the activity and expression of hepatic CYP3A2.

  13. Berberine-induced activation of AMPK increases hepatic FGF21 expression via NUR77.

    PubMed

    Zhou, Feiye; Bai, Mengyao; Zhang, Yuqing; Zhu, Qin; Zhang, Linlin; Zhang, Qi; Wang, Shushu; Zhu, Kecheng; Liu, Yun; Wang, Xiao; Zhou, Libin

    2018-01-08

    Fibroblast growth factor 21 (FGF21), a hormone-like protein mainly derived from liver, exhibits multiple beneficial effect on energy metabolism. Similar to FGF21, berberine exerts anti-hyperglycemic and anti-dyslipidemic properties. Previous studies revealed that the beneficial metabolic effect of berberine was attributed to the activation of AMP-activated protein kinase (AMPK). Here we investigated the effect of berberine on FGF21 expression in primary mouse hepatocytes. As expected, berberine induced hepatic FGF21 expression in a dose-dependent and time-dependent manner, along with the increased expression of NUR77, a proved transcription factor of FGF21. Berberine stimulated the phosphorylations of AMPK and acetyl-CoA carboxylase in primary mouse hepatocytes. Adenovirus-mediated overexpression of constitutively active AMPK triggered hepatic FGF21 and NUR77 expressions. The inhibition of AMPK by compound C abolished berberine-stimulated FGF21 and NUR77 expressions. These results suggest that berberine-induced activation of AMPK may contribute to hepatic FGF21 expression via NUR77. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Hepatitis C Virus Induces the Mitochondrial Translocation of Parkin and Subsequent Mitophagy

    PubMed Central

    Kim, Seong-Jun; Syed, Gulam H.; Siddiqui, Aleem

    2013-01-01

    Hepatitis C Virus (HCV) induces intracellular events that trigger mitochondrial dysfunction and promote host metabolic alterations. Here, we investigated selective autophagic degradation of mitochondria (mitophagy) in HCV-infected cells. HCV infection stimulated Parkin and PINK1 gene expression, induced perinuclear clustering of mitochondria, and promoted mitochondrial translocation of Parkin, an initial event in mitophagy. Liver tissues from chronic HCV patients also exhibited notable levels of Parkin induction. Using multiple strategies involving confocal and electron microscopy, we demonstrated that HCV-infected cells display greater number of mitophagosomes and mitophagolysosomes compared to uninfected cells. HCV-induced mitophagy was evidenced by the colocalization of LC3 puncta with Parkin-associated mitochondria and lysosomes. Ultrastructural analysis by electron microscopy and immunoelectron microscopy also displayed engulfment of damaged mitochondria in double membrane vesicles in HCV-infected cells. The HCV-induced mitophagy occurred irrespective of genotypic differences. Silencing Parkin and PINK1 hindered HCV replication suggesting the functional relevance of mitophagy in HCV propagation. HCV-mediated decline of mitochondrial complex I enzyme activity was rescued by chemical inhibition of mitophagy or by Parkin silencing. Overall our results suggest that HCV induces Parkin-dependent mitophagy, which may have significant contribution in mitochondrial liver injury associated with chronic hepatitis C. PMID:23555273

  15. Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21.

    PubMed

    Li, Yu; Wong, Kimberly; Giles, Amber; Jiang, Jianwei; Lee, Jong Woo; Adams, Andrew C; Kharitonenkov, Alexei; Yang, Qin; Gao, Bin; Guarente, Leonard; Zang, Mengwei

    2014-02-01

    The hepatocyte-derived hormone fibroblast growth factor 21 (FGF21) is a hormone-like regulator of metabolism. The nicotinamide adenine dinucleotide-dependent deacetylase SIRT1 regulates fatty acid metabolism through multiple nutrient sensors. Hepatic overexpression of SIRT1 reduces steatosis and glucose intolerance in obese mice. We investigated mechanisms by which SIRT1 controls hepatic steatosis in mice. Liver-specific SIRT1 knockout (SIRT1 LKO) mice and their wild-type littermates (controls) were divided into groups that were placed on a normal chow diet, fasted for 24 hours, or fasted for 24 hours and then fed for 6 hours. Liver tissues were collected and analyzed by histologic examination, gene expression profiling, and real-time polymerase chain reaction assays. Human HepG2 cells were incubated with pharmacologic activators of SIRT1 (resveratrol or SRT1720) and mitochondrion oxidation consumption rate and immunoblot analyses were performed. FGF21 was overexpressed in SIRT1 LKO mice using an adenoviral vector. Energy expenditure was assessed by indirect calorimetry. Prolonged fasting induced lipid deposition in livers of control mice, but severe hepatic steatosis in SIRT1 LKO mice. Gene expression analysis showed that fasting up-regulated FGF21 in livers of control mice but not in SIRT1 LKO mice. Decreased hepatic and circulating levels of FGF21 in fasted SIRT1 LKO mice were associated with reduced hepatic expression of genes involved in fatty acid oxidation and ketogenesis, and increased expression of genes that control lipogenesis, compared with fasted control mice. Resveratrol or SRT1720 each increased the transcriptional activity of the FGF21 promoter (-2070/+117) and levels of FGF21 messenger RNA and protein in HepG2 cells. Surprisingly, SIRT1 LKO mice developed late-onset obesity with impaired whole-body energy expenditure. Hepatic overexpression of FGF21 in SIRT1 LKO mice increased the expression of genes that regulate fatty acid oxidation, decreased

  16. Elevated hepatic fatty acid elongase-5 activity corrects dietary fat-induced hyperglycemia in obese BL/6J mice[S

    PubMed Central

    Tripathy, Sasmita; Torres-Gonzalez, Moises; Jump, Donald B.

    2010-01-01

    Elevated hepatic fatty acid elongase-5 (Elovl5) activity lowers blood glucose in fasted chow-fed C57BL/6J mice. As high-fat diets induce hyperglycemia and suppress hepatic Elovl5 activity, we tested the hypothesis that elevated hepatic Elovl5 expression attenuates hyperglycemia in high-fat-diet-induced obese mice. Increasing hepatic Elovl5 activity by a recombinant adenoviral approach restored blood glucose and insulin, HOMA-IR, and glucose tolerance to normal values in obese mice. Elevated Elovl5 activity increased hepatic content of Elovl5 products (20:3,n-6, 22:4,n-6) and suppressed levels of enzymes (Pck1, G6Pc) and transcription factors (FoxO1 and PGC1α, but not CRTC2) involved in gluconeogenesis. Effects of Elovl5 on FoxO1 nuclear abundance correlated with increased phosphorylation of FoxO1, Akt, and the catalytic unit of PP2A, as well as a decline in cellular abundance of TRB3. Such changes are mechanistically linked to the regulation of FoxO1 nuclear abundance and gluconeogenesis. These results show that Elovl5 activity impacts the hepatic abundance and phosphorylation status of multiple proteins involved in gluconeogenesis. Our findings establish a link between fatty acid elongation and hepatic glucose metabolism and suggest a role for regulators of Elovl5 activity in the treatment of diet-induced hyperglycemia. PMID:20488798

  17. Understanding the Persistence of Plague Foci in Madagascar

    PubMed Central

    Andrianaivoarimanana, Voahangy; Kreppel, Katharina; Elissa, Nohal; Duplantier, Jean-Marc; Carniel, Elisabeth; Rajerison, Minoarisoa; Jambou, Ronan

    2013-01-01

    Plague, a zoonosis caused by Yersinia pestis, is still found in Africa, Asia, and the Americas. Madagascar reports almost one third of the cases worldwide. Y. pestis can be encountered in three very different types of foci: urban, rural, and sylvatic. Flea vector and wild rodent host population dynamics are tightly correlated with modulation of climatic conditions, an association that could be crucial for both the maintenance of foci and human plague epidemics. The black rat Rattus rattus, the main host of Y. pestis in Madagascar, is found to exhibit high resistance to plague in endemic areas, opposing the concept of high mortality rates among rats exposed to the infection. Also, endemic fleas could play an essential role in maintenance of the foci. This review discusses recent advances in the understanding of the role of these factors as well as human behavior in the persistence of plague in Madagascar. PMID:24244760

  18. Understanding the persistence of plague foci in Madagascar.

    PubMed

    Andrianaivoarimanana, Voahangy; Kreppel, Katharina; Elissa, Nohal; Duplantier, Jean-Marc; Carniel, Elisabeth; Rajerison, Minoarisoa; Jambou, Ronan

    2013-11-01

    Plague, a zoonosis caused by Yersinia pestis, is still found in Africa, Asia, and the Americas. Madagascar reports almost one third of the cases worldwide. Y. pestis can be encountered in three very different types of foci: urban, rural, and sylvatic. Flea vector and wild rodent host population dynamics are tightly correlated with modulation of climatic conditions, an association that could be crucial for both the maintenance of foci and human plague epidemics. The black rat Rattus rattus, the main host of Y. pestis in Madagascar, is found to exhibit high resistance to plague in endemic areas, opposing the concept of high mortality rates among rats exposed to the infection. Also, endemic fleas could play an essential role in maintenance of the foci. This review discusses recent advances in the understanding of the role of these factors as well as human behavior in the persistence of plague in Madagascar.

  19. [The results of serological studies in different foci of tropical and tertiary malaria].

    PubMed

    Suleĭmanov, G D; Doan, Kh N; Le, T T; Chan, B; Chan, T U

    1991-01-01

    Attempt was made to determine the value of serologic indices of malaria surveys. Following uniformed methodological and technical approaches 3 foci of P. vivax and 6 foci of P. falciparum malaria were surveyed in different endemic zones of Vietnam and the USSR. It was shown that the most objective criteria for a foci classification is its serologic mean geometric titre. The latter in its turn directly depends of transmission longevity in a foci.

  20. Overexpression of NRK1 ameliorates diet- and age-induced hepatic steatosis and insulin resistance.

    PubMed

    Fan, Rui; Cui, Jing; Ren, Feng; Wang, Qingzhi; Huang, Yanmei; Zhao, Bin; Wei, Lai; Qian, Xinlai; Xiong, Xiwen

    2018-06-02

    NAD + is a co-enzyme in redox reactions and a substrate required for activity of various enzyme families, including sirtuins and poly(ADP-ribose) polymerases. Dietary supplementation of NAD + precursors nicotinamide mononucleotide (NMN) or nicotinamide riboside (NR) protects against metabolic disease, neurodegenerative disorders and age-related physiological decline in mammals. Here we sought to identify the roles of nicotinamide riboside kinase 1 (NRK1) plays in regulating hepatic NAD + biosynthesis and lipid metabolism. Using adenovirus mediated gene transduction to overexpress or knockdown NRK1 in mouse liver, we have demonstrated that NRK1 is critical for maintaining hepatic NAD + levels and triglyceride content. We have further shown that the hepatic expression of Nmrk1 mRNA is significantly decreased either in mice treated with high-fat diet or in aged mice. However, adenoviral delivery of NRK1 in these diet- and age-induced mice elevates hepatic NAD + levels, reduces hepatic steatosis, and improves glucose tolerance and insulin sensitivity. Our results provide important insights in targeting NRK1 for treating hepatic steatosis. Copyright © 2018 Elsevier Inc. All rights reserved.

  1. Induced hypothermia reduces the hepatic inflammatory response in a swine multiple trauma model.

    PubMed

    Fröhlich, Matthias; Hildebrand, Frank; Weuster, Matthias; Mommsen, Philipp; Mohr, Juliane; Witte, Ingo; Raeven, Pierre; Ruchholtz, Steffen; Flohé, Sascha; van Griensven, Martijn; Pape, Hans-Christoph; Pfeifer, Roman

    2014-06-01

    Mild therapeutic hypothermia following trauma has been introduced in several studies to reduce the posttraumatic inflammation and organ injury. In this study, we analyzed the effects of induced mild hypothermia (34°C) on the inflammation of the shock organs liver and kidney. In a porcine model of multiple trauma including blunt chest trauma, liver laceration, and hemorrhagic shock followed by fluid resuscitation, the influence of induced hypothermia on hepatic and renal damage and organ-specific inflammation were evaluated. A total of 40 pigs were randomly assigned to four groups, which were sham (anesthesia only) or trauma groups receiving either hypothermia or normothermia. The parameters analyzed were laboratory parameters (aspartate transaminase [AST], lactate dehydrogenase, urea, creatinine) as well as hepatic and renal cytokine expression determined by real-time polymerase chain reaction (interleukin 6 [IL-6], IL-8). Blinded analysis of histologic changes in the liver and kidney was performed. Fifteen and a half hours following combined trauma, hepatic cytokine expression and liver damage were significantly increased in animals with normothermia compared with the respective sham group. Hypothermia, however, resulted in a fivefold reduced hepatic expression of IL-8 (mean ± SE, 2.4 ± 1.3; p = 0.01) when compared with the normothermic trauma group (IL-8, 12.8 ± 4.7). Accordingly, granulocyte infiltration and a histologic, semiquantitative score for liver injury were significantly higher in the normothermic trauma group. Serum AST levels raised significantly after trauma and normothermia compared with the respective sham group, while AST levels showed no difference from the sham groups in the hypothermic trauma group. In contrast, neither trauma nor hypothermia influenced the expression of IL-6 and IL-8 and tissue injury in the kidney. Therapeutic hypothermia seems to attenuate the hepatic inflammatory response and the associated liver injury after severe

  2. Hepatitis D virus replication is sensed by MDA5 and induces IFN-β/λ responses in hepatocytes.

    PubMed

    Zhang, Zhenfeng; Filzmayer, Christina; Ni, Yi; Sültmann, Holger; Mutz, Pascal; Hiet, Marie-Sophie; Vondran, Florian W R; Bartenschlager, Ralf; Urban, Stephan

    2018-07-01

    Hepatitis B virus (HBV) and D virus (HDV) co-infections cause the most severe form of viral hepatitis. HDV induces an innate immune response, but it is unknown how the host cell senses HDV and if this defense affects HDV replication. We aim to characterize interferon (IFN) activation by HDV, identify the responsible sensor and evaluate the effect of IFN on HDV replication. HDV and HBV susceptible hepatoma cell lines and primary human hepatocytes (PHH) were used for infection studies. Viral markers and cellular gene expression were analyzed at different time points after infection. Pattern recognition receptors (PRRs) required for HDV-mediated IFN activation and the impact on HDV replication were studied using stable knock-down or overexpression of the PRRs. Microarray analysis revealed that HDV but not HBV infection activated a broad range of interferon stimulated genes (ISGs) in HepG2 NTCP cells. HDV strongly activated IFN-β and IFN-λ in cell lines and PHH. HDV induced IFN levels remained unaltered upon RIG-I (DDX58) or TLR3 knock-down, but were almost completely abolished upon MDA5 (IFIH1) depletion. Conversely, overexpression of MDA5 but not RIG-I and TLR3 in HuH7.5 NTCP cells partially restored ISG induction. During long-term infection, IFN levels gradually diminished in both HepG2 NTCP and HepaRG NTCP cell lines. MDA5 depletion had little effect on HDV replication despite dampening HDV-induced IFN response. Moreover, treatment with type I or type III IFNs did not abolish HDV replication. Active replication of HDV induces an IFN-β/λ response, which is predominantly mediated by MDA5. This IFN response and exogenous IFN treatment have only a moderate effect on HDV replication in vitro indicating the adaption of HDV replication to an IFN-activated state. In contrast to hepatitis B virus, infection with hepatitis D virus induces a strong IFN-β/λ response in innate immune competent cell lines. MDA5 is the key sensor for the recognition of hepatitis D virus

  3. Chemoproteomics reveals baicalin activates hepatic CPT1 to ameliorate diet-induced obesity and hepatic steatosis.

    PubMed

    Dai, Jianye; Liang, Kai; Zhao, Shan; Jia, Wentong; Liu, Yuan; Wu, Hongkun; Lv, Jia; Cao, Chen; Chen, Tao; Zhuang, Shentian; Hou, Xiaomeng; Zhou, Shijie; Zhang, Xiannian; Chen, Xiao-Wei; Huang, Yanyi; Xiao, Rui-Ping; Wang, Yan-Ling; Luo, Tuoping; Xiao, Junyu; Wang, Chu

    2018-06-11

    Obesity and related metabolic diseases are becoming worldwide epidemics that lead to increased death rates and heavy health care costs. Effective treatment options have not been found yet. Here, based on the observation that baicalin, a flavonoid from the herbal medicine Scutellaria baicalensis , has unique antisteatosis activity, we performed quantitative chemoproteomic profiling and identified carnitine palmitoyltransferase 1 (CPT1), the controlling enzyme for fatty acid oxidation, as the key target of baicalin. The flavonoid directly activated hepatic CPT1 with isoform selectivity to accelerate the lipid influx into mitochondria for oxidation. Chronic treatment of baicalin ameliorated diet-induced obesity (DIO) and hepatic steatosis and led to systemic improvement of other metabolic disorders. Disruption of the predicted binding site of baicalin on CPT1 completely abolished the beneficial effect of the flavonoid. Our discovery of baicalin as an allosteric CPT1 activator opens new opportunities for pharmacological treatment of DIO and associated sequelae.

  4. Chardonnay Grape Seed Flour Ameliorates Hepatic Steatosis and Insulin Resistance via Altered Hepatic Gene Expression for Oxidative Stress, Inflammation, and Lipid and Ceramide Synthesis in Diet-Induced Obese Mice

    PubMed Central

    Seo, Kun-Ho; Bartley, Glenn E.; Tam, Christina; Kim, Hong-Seok; Kim, Dong-Hyeon; Chon, Jung-Whan; Yokoyama, Wallace

    2016-01-01

    To identify differentially expressed hepatic genes contributing to the improvement of high-fat (HF) diet-induced hepatic steatosis and insulin resistance following supplementation of partially defatted flavonoid-rich Chardonnay grape seed flour (ChrSd), diet-induced obese (DIO) mice were fed HF diets containing either ChrSd or microcrystalline cellulose (MCC, control) for 5 weeks. The 2-h insulin area under the curve was significantly lowered by ChrSd, indicating that ChrSd improved insulin sensitivity. ChrSd intake also significantly reduced body weight gain, liver and adipose tissue weight, hepatic lipid content, and plasma low-density lipoprotein (LDL)-cholesterol, despite a significant increase in food intake. Exon microarray analysis of hepatic gene expression revealed down-regulation of genes related to triglyceride and ceramide synthesis, immune response, oxidative stress, and inflammation and upregulation of genes related to fatty acid oxidation, cholesterol, and bile acid synthesis. In conclusion, the effects of ChrSd supplementation in a HF diet on weight gain, insulin resistance, and progression of hepatic steatosis in DIO mice were associated with modulation of hepatic genes related to oxidative stress, inflammation, ceramide synthesis, and lipid and cholesterol metabolism. PMID:27977712

  5. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism

    PubMed Central

    Shin, Andrew C.; Fasshauer, Martin; Filatova, Nika; Grundell, Linus A.; Zielinski, Elizabeth; Zhou, Jian-Ying; Scherer, Thomas; Lindtner, Claudia; White, Phillip J.; Lapworth, Amanda L.; Ilkayeva, Olga; Knippschild, Uwe; Wolf, Anna M.; Scheja, Ludger; Grove, Kevin L.; Smith, Richard D.; Qian, Wei-Jun; Lynch, Christopher J.; Newgard, Christopher B.; Buettner, Christoph

    2014-01-01

    Summary Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α keto-acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in non-human primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs, and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes. PMID:25307860

  6. The ameliorative effect of thymol against hydrocortisone-induced hepatic oxidative stress injury in adult male rats.

    PubMed

    Aboelwafa, Hanaa R; Yousef, Hany N

    2015-08-01

    The aim of the present study was to investigate whether hydrocortisone induces oxidative stress in hepatocytes and to evaluate the possible ameliorative effect of thymol against such hepatic injury. Twenty-four adult male rats were divided into control, thymol, hydrocortisone, and hydrocortisone+thymol groups. The 4 groups were treated daily for 15 days. Hydrocortisone significantly induced oxidative stress in the liver tissues, marked by increased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), total oxidative capacity (TOC), and tumor necrosis factor-alpha (TNF-α) accompanied by marked decline of serum levels of total protein, albumin, and total antioxidant capacity (TAC). Also, marked elevation in the levels of the thiobarbituric acid reactive substances (TBARS) and TNF-α, beside significant decrease in the level of glutathione (GSH) in hepatic tissues were recorded. These biochemical alterations were accompanied by histopathological changes marked by destruction of the normal hepatic architecture, in addition to ultrastructural alterations represented by degenerative features covering almost all the cytoplasmic organelles of the hepatocytes. Supplementation of hydrocortisone-treated rats with thymol reversed most of the biochemical, histological, and ultrastructural alterations. The results of our study confirm that thymol has strong ameliorative effect against hydrocortisone-induced oxidative stress injury in hepatic tissues.

  7. Persistence of γ-H2AX and 53BP1 foci in proliferating and non-proliferating human mammary epithelial cells after exposure to γ-rays or iron ions.

    PubMed

    Groesser, Torsten; Chang, Hang; Fontenay, Gerald; Chen, James; Costes, Sylvain V; Helen Barcellos-Hoff, Mary; Parvin, Bahram; Rydberg, Bjorn

    2011-07-01

    To investigate γ-H2AX (phosphorylated histone H2AX) and 53BP1 (tumour protein 53 binding protein No. 1) foci formation and removal in proliferating and non-proliferating human mammary epithelial cells (HMEC) after exposure to sparsely and densely ionising radiation under different cell culture conditions. HMEC cells were grown either as monolayers (2D) or in extracellular matrix to allow the formation of acinar structures in vitro (3D). Foci numbers were quantified by image analysis at various time points after exposure. Our results reveal that in non-proliferating cells under 2D and 3D cell culture conditions, iron-ion induced γ-H2AX foci were still present at 72 h after exposure, although 53BP1 foci returned to control levels at 48 h. In contrast in proliferating HMEC, both γ-H2AX and 53BP1 foci decreased to control levels during the 24-48 h time interval after irradiation under 2D conditions. Foci numbers decreased faster after γ-ray irradiation and returned to control levels by 12 h regardless of marker, cell proliferation status, and cell culture condition. The disappearance of radiation-induced γ-H2AX and 53BP1 foci in HMEC has different dynamics that depend on radiation quality and proliferation status. Notably, the general patterns do not depend on the cell culture condition (2D versus 3D). We speculate that the persistent γ-H2AX foci in iron-ion irradiated non-proliferating cells could be due to limited availability of double-strand break (DSB) repair pathways in G0/G1-phase, or that repair of complex DSB requires replication or chromatin remodelling.

  8. 3D-structured illumination microscopy reveals clustered DNA double-strand break formation in widespread γH2AX foci after high LET heavy-ion particle radiation

    PubMed Central

    Hagiwara, Yoshihiko; Niimi, Atsuko; Isono, Mayu; Yamauchi, Motohiro; Yasuhara, Takaaki; Limsirichaikul, Siripan; Oike, Takahiro; Sato, Hiro; Held, Kathryn D.; Nakano, Takashi; Shibata, Atsushi

    2017-01-01

    DNA double-strand breaks (DSBs) induced by ionising radiation are considered the major cause of genotoxic mutations and cell death. While DSBs are dispersed throughout chromatin after X-rays or γ-irradiation, multiple types of DNA damage including DSBs, single-strand breaks and base damage can be generated within 1–2 helical DNA turns, defined as a complex DNA lesion, after high Linear Energy Transfer (LET) particle irradiation. In addition to the formation of complex DNA lesions, recent evidence suggests that multiple DSBs can be closely generated along the tracks of high LET particle irradiation. Herein, by using three dimensional (3D)-structured illumination microscopy, we identified the formation of 3D widespread γH2AX foci after high LET carbon-ion irradiation. The large γH2AX foci in G2-phase cells encompassed multiple foci of replication protein A (RPA), a marker of DSBs undergoing resection during homologous recombination. Furthermore, we demonstrated by 3D analysis that the distance between two individual RPA foci within γH2AX foci was approximately 700 nm. Together, our findings suggest that high LET heavy-ion particles induce clustered DSB formation on a scale of approximately 1 μm3. These closely localised DSBs are considered to be a risk for the formation of chromosomal rearrangement after heavy-ion irradiation. PMID:29312614

  9. 3D-structured illumination microscopy reveals clustered DNA double-strand break formation in widespread γH2AX foci after high LET heavy-ion particle radiation.

    PubMed

    Hagiwara, Yoshihiko; Niimi, Atsuko; Isono, Mayu; Yamauchi, Motohiro; Yasuhara, Takaaki; Limsirichaikul, Siripan; Oike, Takahiro; Sato, Hiro; Held, Kathryn D; Nakano, Takashi; Shibata, Atsushi

    2017-12-12

    DNA double-strand breaks (DSBs) induced by ionising radiation are considered the major cause of genotoxic mutations and cell death. While DSBs are dispersed throughout chromatin after X-rays or γ-irradiation, multiple types of DNA damage including DSBs, single-strand breaks and base damage can be generated within 1-2 helical DNA turns, defined as a complex DNA lesion, after high Linear Energy Transfer (LET) particle irradiation. In addition to the formation of complex DNA lesions, recent evidence suggests that multiple DSBs can be closely generated along the tracks of high LET particle irradiation. Herein, by using three dimensional (3D)-structured illumination microscopy, we identified the formation of 3D widespread γH2AX foci after high LET carbon-ion irradiation. The large γH2AX foci in G 2 -phase cells encompassed multiple foci of replication protein A (RPA), a marker of DSBs undergoing resection during homologous recombination. Furthermore, we demonstrated by 3D analysis that the distance between two individual RPA foci within γH2AX foci was approximately 700 nm. Together, our findings suggest that high LET heavy-ion particles induce clustered DSB formation on a scale of approximately 1 μm 3 . These closely localised DSBs are considered to be a risk for the formation of chromosomal rearrangement after heavy-ion irradiation.

  10. Ameliorative effects of rutin on hepatic encephalopathy-induced by thioacetamide or gamma irradiation.

    PubMed

    Mansour, Somaya Z; El-Marakby, Seham M; Moawed, Fatma S M

    2017-07-01

    Hepatic encephalopathy (HE) is a syndrome resulting from acute or chronic liver failure. This study was designed to evaluate the effect of rutin on thioacetamide (TAA) or γ-radiation-induced HE model. Animals were received with TAA (200mg/kg, i.p.) twice weekly for four weeks or exposed to 6Gy of γ-radiation to induce HE then groups orally treated with rutin (50mg/kg b.wt.) for four weeks. At the end of experiment, blood, liver and brain samples were collected to assess biochemical and biophysical markers as well histopathological investigations. TAA or γ-radiation exposed rats experienced increases in serum activities of ALT, AST, ALP and ammonia level. Also an alteration in relative permeability and conductivity of erythrocytes was observed. Furthermore, cytokines levels and AChE activity were induced whereas the activities of HO-1 and neurotransmitters contents were depleted. TAA or γ-radiation caused distortion of hepatic and brain architecture as shown by histopathological examination. Treatment with rutin resulted in improvement in liver function by the decline in serum AST and ALT activities and reduction in serum ammonia level. In addition, the administration of rutin significantly modulated the alteration in cytokines levels and neurotransmitters content. Histopathological examinations of liver and brain tissues showed that administration of rutin has attenuate TAA or radiation-induced damage and improve tissue architecture. Consequently, rutin has been a powerful hepatoprotective effect to combat hepatic encephalopathy associated hyperammonemia and its consequential damage in liver and brain. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. From the Dance of the Foci to a Strophoid

    ERIC Educational Resources Information Center

    Jobbings, Andrew

    2011-01-01

    The intersection of a plane and a cone is a conic section and rotating the plane leads to a family of conics. What happens to the foci of these conics as the plane rotates? A classical result gives the locus of the foci as an oblique strophoid when the plane rotates about a tangent to the cone. The analogous curve when the plane intersects a…

  12. Physicochemical properties, antioxidant activities and protective effect against acute ethanol-induced hepatic injury in mice of foxtail millet (Setaria italica) bran oil.

    PubMed

    Pang, Min; He, Shujian; Wang, Lu; Cao, Xinmin; Cao, Lili; Jiang, Shaotong

    2014-08-01

    This study was designed to investigate physicochemical characterization of the oil extracted from foxtail millet bran (FMBO), and the antioxidant and hepatoprotective effects against acute ethanol-induced hepatic injury in mice. GC-MS analysis revealed that unsaturated fatty acids (UFAs) account for 83.76% of the total fatty acids; in particular, the linoleic acid (C18:2) is the predominant polyunsaturated fatty acid (PUFA), and the compounds of squalene and six phytosterols (or phytostanols) were identified in unsaponifiable matter of FMBO. The antioxidant activity examination of FMBO in vitro showed highly ferric-reducing antioxidant power and scavenging effects against DPPH· and HO· radicals. Furthermore, the protective effect of FMBO against acute hepatic injuries induced by ethanol was verified in mice. In this, intragastric administration with different dosages of FMBO in mice ahead of acute ethanol administration could observably antagonize the ethanol-induced increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), and the hepatic malondialdehyde (MDA) levels, respectively, along with enhanced hepatic superoxide dismutase (SOD) levels relative to the control. Hepatic histological changes were also observed and confirmed that FMBO is capable of attenuating ethanol-induced hepatic injury.

  13. ASMASE IS REQUIRED FOR CHRONIC ALCOHOL INDUCED HEPATIC ENDOPLASMIC RETICULUM STRESS AND MITOCHONDRIAL CHOLESTEROL LOADING

    PubMed Central

    Fernandez, Anna; Matias, Núria; Fucho, Raquel; Ribas, Vicente; Von Montfort, Claudia; Nuño, Natalia; Baulies, Anna; Martinez, Laura; Tarrats, Núria; Mari, Montserrat; Colell, Anna; Morales, Albert; Dubuquoy, Laurent; Mathurin, Philippe; Bataller, Ramón; Caballeria, Joan; Elena, Montserrat; Balsinde, Jesus; Kaplowitz, Neil; Garcia-Ruiz, Carmen; Fernandez-Checa, Jose C.

    2013-01-01

    Background & aims The pathogenesis of alcohol-induced liver disease (ALD) is poorly understood. Here, we examined the role of acid sphingomyelinase (ASMase) in alcohol induced hepatic endoplasmic reticulum (ER) stress, a key mechanism of ALD Methods We examined ER stress, lipogenesis, hyperhomocysteinemia, mitochondrial cholesterol (mChol) trafficking and susceptibility to LPS and concanavalin-A in ASMase−/− mice fed alcohol. Results Alcohol feeding increased SREBP-1c, DGAT-2 and FAS mRNA in ASMase+/+ but not in ASMase−/− mice. Compared to ASMase+/+ mice, ASMase−/− mice exhibited decreased expression of ER stress markers induced by alcohol, but the level of tunicamycin-mediated upregulation of ER stress markers and steatosis was similar in both types of mice. The increase in homocysteine levels induced by alcohol feeding was comparable in both ASMase+/+ mice and ASMase−/− mice. Exogenous ASMase, but not neutral SMase, induced ER stress by perturbing ER Ca2+ homeostasis. Moreover, alcohol-induced mChol loading and StARD1 overexpression were blunted in ASMase−/− mice. Tunicamycin upregulated StARD1 expression and this outcome was abrogated by tauroursodeoxycholic acid. Alcohol-induced liver injury and sensitization to LPS and concanavalin-A were prevented in ASMase−/− mice. These effects were reproduced in alcohol-fed TNFR1/R2−/− mice. Moreover, ASMase does not impair hepatic regeneration following partial hepatectomy. Of relevance, liver samples from patients with alcoholic hepatitis exhibited increased expression of ASMase, StARD1 and ER stress markers. Conclusion Our data indicate that ASMase is critical for alcohol-induced ER stress, and provide a rationale for further clinical investigation in ALD. PMID:23707365

  14. Fibre optic confocal imaging (FOCI) for subsurface microscopy of the colon in vivo.

    PubMed Central

    Delaney, P M; King, R G; Lambert, J R; Harris, M R

    1994-01-01

    Fibre optic confocal imaging (FOCI) is a new type of microscopy which has been recently developed (Delaney et al. 1993). In contrast to conventional light microscopy, FOCI and other confocal techniques allow clear imaging of subsurface structures within translucent objects. However, unlike conventional confocal microscopes which are bulky (because of a need for accurate alignment of large components) FOCI allows the imaging end to be miniaturised and relatively mobile. FOCI is thus particularly suited for clear subsurface imaging of structures within living animals or subjects. The aim of the present study was to assess the suitability of using FOCI for imaging of subsurface structures within the colon, both in vitro (human and rat biopsies) and in vivo (in rats). Images were obtained in fluorescence mode (excitation 488 nm, detection above 515 nm) following topical application of fluorescein. By this technique the glandular structure of the colon was imaged. FOCI is thus suitable for subsurface imaging of the colon in vivo. Images Fig. 2 Fig. 3 PMID:8157487

  15. Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice

    PubMed Central

    Avraham, Y; Grigoriadis, NC; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, EM

    2011-01-01

    BACKGROUND AND PURPOSE Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. EXPERIMENTAL APPROACH Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. KEY RESULTS Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. CONCLUSIONS AND IMPLICATIONS Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. PMID:21182490

  16. Differential involvement of IL-6 in the early and late phase of 1-methylnicotinamide (MNA) release in Concanavalin A-induced hepatitis.

    PubMed

    Sternak, Magdalena; Jakubowski, Andrzej; Czarnowska, Elzbieta; Slominska, Ewa M; Smolenski, Ryszard T; Szafarz, Malgorzata; Walczak, Maria; Sitek, Barbara; Wojcik, Tomasz; Jasztal, Agnieszka; Kaminski, Karol; Chlopicki, Stefan

    2015-09-01

    Exogenous 1-methylnicotinamide (MNA) displays anti-inflammatory activity. The aim of this work was to characterize the profile of release of endogenous MNA during the initiation and progression of murine hepatitis induced by Concanavalin A (ConA). In particular we aimed to clarify the role of interleukin-6 (IL-6) as well as the energy state of hepatocytes in MNA release in early and late phases of ConA-induced hepatitis in mice. Hepatitis was induced by ConA in IL-6(+/+) and IL-6(-/-) mice, and various parameters of liver inflammation and injury, as well as the energy state of hepatocytes, were analysed in relation to MNA release. The decrease in ATP/ADP and NADH/NAD ratios, cytokine release (IL-6, IFN-ɤ), acute phase response (e.g. haptoglobin) and liver injury (alanine aminotransaminase, ALT) were all blunted in ConA-induced hepatitis in IL-6(-/-) mice as compared to IL-6(+/+) mice. The release of MNA in response to Con A was also significantly blunted in IL-6(-/-) mice as compared to IL-6(+/+) mice in the early stage of ConA-induced hepatitis. In turn, nicotinamide N-methyltransferase (NNMT) and aldehyde oxidase (AO) activities were blunted in the liver and MNA plasma concentration was elevated to similar degree in the late stage after Concanavalin A in IL-6(+/+) and IL-6(-/-) mice. In conclusion, we demonstrated that in ConA-induced hepatitis, early, but not late MNA release was IL-6-dependent. Our results suggest that in the initiation and early hepatitis, MNA release is linked to the energy deficit/impaired redox status in hepatocytes, while in a later phase, MNA release is rather linked to the systemic inflammation. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Osthole ameliorates hepatic fibrosis and inhibits hepatic stellate cell activation.

    PubMed

    Liu, Ya-Wei; Chiu, Yung-Tsung; Fu, Shu-Ling; Huang, Yi-Tsau

    2015-08-01

    Hepatic fibrosis is a dynamic process which ultimately leads to cirrhosis in almost patients with chronic hepatic injury. However, progressive fibrosis is a reversible scarring response. Activation of hepatic stellate cells (HSCs) is the prevailing process during hepatic fibrosis. Osthole is an active component majorly contained in the fruit of Cnidium monnieri (L.) Cusson. This present study investigated the therapeutic effects of osthole on rat liver fibrosis and HSC activation. We established the thioacetamide (TAA)-model of Sprague-Dawley (SD) rats to induce hepatic fibrosis. Rats were divided into three groups: control, TAA, and TAA + osthole (10 mg/kg). In vivo, osthole significantly reduced liver injury by diminishing levels of plasma AST and ALT, improving histological architecture, decreasing collagen and α-SMA accumulation, and improving hepatic fibrosis scores. Additionally, osthole reduced the expression of fibrosis-related genes significantly. Osthole also suppressed the production of fibrosis-related cytokines and chemokines. Moreover, nuclear translocation of p65 was significantly suppressed in osthole-treated liver. Osthole also ameliorated TAA-induced injury through reducing cellular oxidation. Osthole showed inhibitory effects in inflammation-related genes and chemokines production as well. In vitro, we assessed osthole effects in activated HSCs (HSC-T6 and LX-2). Osthole attenuated TGF-β1-induced migration and invasion in HSCs. Furthermore, osthole decreased TNF-α-triggered NF-κB activities significantly. Besides, osthole alleviated TGF-β1- or ET-1-induced HSCs contractility. Our study demonstrated that osthole improved TAA-caused liver injury, fibrogenesis and inflammation in rats. In addition, osthole suppressed HSCs activation in vitro significantly.

  18. Dose response and repair kinetics of gamma-H2AX foci induced by in vitro irradiation of whole blood and T-lymphocytes with X- and gamma-radiation.

    PubMed

    Beels, Laurence; Werbrouck, Joke; Thierens, Hubert

    2010-09-01

    Dose response and repair kinetics of phosphorylated histone H2A isoform X (gamma-H2AX) foci in T-lymphocytes were investigated in the low-dose range after in vitro irradiation of whole blood and T-lymphocytes with 100 kVp X-rays and (60)Co gamma-rays. Whole blood or isolated T-lymphocytes were irradiated in vitro and gamma-H2AX foci were scored. Dose response was determined in the 0-500 mGy dose range. Foci kinetics were studied at doses of 5 and 200 mGy up to 24 h post-irradiation. After X-irradiation, the dose response for whole blood shows a biphasic behaviour with a low-dose hypersensitivity, which is less pronounced for isolated T-lymphocytes. In contrast, gamma-radiation shows a linear dose response for both irradiation conditions. Concerning repair kinetics, delayed repair was found after X-ray whole blood irradiation (5 and 200 mGy) with 40% of the foci persisting 24 h post-irradiation. This number of foci is reduced to 10% after irradiation of isolated T-lymphocytes with 200 mGy X-rays. On the contrary, gamma-H2AX foci are reduced to background levels 24 h post-irradiation with 200 mGy (60)Co gamma-rays. gamma-H2AX foci response and repair kinetics depend on irradiation conditions and radiation quality, possibly linked to Bystander response.

  19. MRI Evaluation of Non-Necrotic T2-Hyperintense Foci in Pediatric Diffuse Intrinsic Pontine Glioma.

    PubMed

    Clerk-Lamalice, O; Reddick, W E; Li, X; Li, Y; Edwards, A; Glass, J O; Patay, Z

    2016-05-19

    The conventional MR imaging appearance of diffuse intrinsic pontine glioma suggests intralesional histopathologic heterogeneity, and various distinct lesion components, including T2-hypointense foci, have been described. Here we report the prevalence, conventional MR imaging semiology, and advanced MR imaging features of non-necrotic T2-hyperintense foci in diffuse intrinsic pontine glioma. Twenty-five patients with diffuse intrinsic pontine gliomas were included in this study. MR imaging was performed at 3T by using conventional and advanced MR imaging sequences. Perfusion (CBV), vascular permeability (v e , K trans ), and diffusion (ADC) metrics were calculated and used to characterize non-necrotic T2-hyperintense foci in comparison with other lesion components, namely necrotic T2-hyperintense foci, T2-hypointense foci, peritumoral edema, and normal brain stem. Statistical analysis was performed by using Kruskal-Wallis and Wilcoxon rank sum tests. Sixteen non-necrotic T2-hyperintense foci were found in 12 tumors. In these foci, ADC values were significantly higher than those in either T2-hypointense foci (P = .002) or normal parenchyma (P = .0002), and relative CBV values were significantly lower than those in either T2-hypointense (P = .0002) or necrotic T2-hyperintense (P = .006) foci. Volume transfer coefficient values in T2-hyperintense foci were lower than those in T2-hypointense (P = .0005) or necrotic T2-hyperintense (P = .0348) foci. Non-necrotic T2-hyperintense foci are common, distinct lesion components within diffuse intrinsic pontine gliomas. Advanced MR imaging data suggest low cellularity and an early stage of angioneogenesis with leaky vessels resulting in expansion of the extracellular space. Because of the lack of biopsy validation, the underlying histoarchitectural and pathophysiologic changes remain unclear; therefore, these foci may correspond to a poorly understood biologic event in tumor evolution. © 2016 American Society of Neuroradiology.

  20. Glucosylceramide and Lysophosphatidylcholines as Potential Blood Biomarkers for Drug-Induced Hepatic Phospholipidosis

    PubMed Central

    Saito, Kosuke; Maekawa, Keiko; Ishikawa, Masaki; Senoo, Yuya; Urata, Masayo; Murayama, Mayumi; Nakatsu, Noriyuki; Yamada, Hiroshi; Saito, Yoshiro

    2014-01-01

    Drug-induced phospholipidosis is one of the major concerns in drug development and clinical treatment. The present study involved the use of a nontargeting lipidomic analysis with liquid chromatography-mass spectrometry to explore noninvasive blood biomarkers for hepatic phospholipidosis from rat plasma. We used three tricyclic antidepressants (clomipramine [CPM], imipramine [IMI], and amitriptyline [AMT]) for the model of phospholipidosis in hepatocytes and ketoconazole (KC) for the model of phospholipidosis in cholangiocytes and administered treatment for 3 and 28 days each. Total plasma lipids were extracted and measured. Lipid molecules contributing to the separation of control and drug-treated rat plasma in a multivariate orthogonal partial least squares discriminant analysis were identified. Four lysophosphatidylcholines (LPCs) (16:1, 18:1, 18:2, and 20:4) and 42:1 hexosylceramide (HexCer) were identified as molecules separating control and drug-treated rats in all models of phospholipidosis in hepatocytes. In addition, 16:1, 18:2, and 20:4 LPCs and 42:1 HexCer were identified in a model of hepatic phospholipidosis in cholangiocytes, although LPCs were identified only in the case of 3-day treatment with KC. The levels of LPCs were decreased by drug-induced phospholipidosis, whereas those of 42:1 HexCer were increased. The increase in 42:1 HexCer was much higher in the case of IMI and AMT than in the case of CPM; moreover, the increase induced by IMI was dose-dependent. Structural characterization determining long-chain base and hexose delineated that 42:1 HexCer was d18:1/24:0 glucosylceramide (GluCer). In summary, our study demonstrated that d18:1/24:0 GluCer and LPCs are potential novel biomarkers for drug-induced hepatic phospholipidosis. PMID:24980264

  1. Nilotinib counteracts thioacetamide-induced hepatic oxidative stress and attenuates liver fibrosis progression.

    PubMed

    Shaker, Mohamed E; Salem, Hatem A; Shiha, Gamal E; Ibrahim, Tarek M

    2011-04-01

    The aim of this study was to evaluate and compare the effects of imatinib and nilotinib to that of silymarin on established liver fibrosis and oxidative stress in a thioacetamide (TAA) rat model. Male Wistar rats received intraperitoneal (i.p.) injections of TAA (150mg/kg, twice weekly) for 12weeks. Daily treatments with imatinib (10mg/kg), nilotinib (10mg/kg), and silymarin (100mg/kg) were administered orally during the last 4weeks of TAA-administration. At the end of the study, hepatic damage was evaluated by analysis of liver function tests in serum. Hepatic histopathology and collagen content were employed to quantify liver fibrosis. Hepatic oxidative stress was assessed by measuring malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), total nitrate/nitrite (NOx), and reduced glutathione (GSH) contents, as well as myeloperoxidase (MPO) and superoxide dismutase (SOD) activities. Nilotinib, silymarin and, to a lesser extent, imatinib treatments ameliorated TAA-induced hepatic oxidative stress and damage as indicated by hepatic MDA, 4-HNE, NOx, GSH, MPO and SOD levels, as well as liver function tests. Hepatic histopathology results revealed that nilotinib, imatinib, and silymarin treatments decreased the mean score of fibrosis in TAA-treated rats by 24, 14, and 3%, respectively. However, nilotinib and silymarin, but not imatinib, treatments decreased hepatic collagen content in TAA-treated rats by 17 and 36%, respectively. In conclusion, we demonstrated for the first time that nilotinib not only protected against hepatic oxidative stress, but also slowed down liver fibrosis progression. Thus, we provide the first evidence that nilotinib might be a promising anti-fibrotic drug. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

  2. A Western diet induced NAFLD in LDLR−/− mice is associated with reduced hepatic glutathione synthesis

    PubMed Central

    Li, Ling; Zhang, Guo-Fang; Lee, Kwangwon; Lopez, Rocio; Previs, Stephen F.; Willard, Belinda; McCullough, Arthur; Kasumov, Takhar

    2017-01-01

    Oxidative stress plays a key role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Glutathione is the major anti-oxidant involved in cellular oxidative defense, however there are currently no simple non-invasive methods for assessing hepatic glutathione metabolism in patients with NAFLD. As a primary source of plasma glutathione, liver plays an important role in interorgan glutathione homeostasis. In this study, we have tested the hypothesis that measurements of plasma glutathione turnover could be used to assess the hepatic glutathione metabolism in LDLR−/− mice, a mouse model of diet-induced NAFLD. Mice were fed a standard low fat diet (LFD) or a high fat diet containing cholesterol (a Western type diet (WD)). The kinetics of hepatic and plasma glutathione were quantified using the 2H2O metabolic labeling approach. Our results show that a WD leads to reduced fractional synthesis rates (FSR) of hepatic (25%/h in LFD vs. 18%/h in WD, P < 0.05) and plasma glutathione (43%/h in LFD vs. 21%/h in WD, P <0.05), without any significant effect on their absolute production rates (PRs). WD-induced concordant changes in both hepatic and plasma glutathione turnover suggest that the plasma glutathione turnover measurements could be used to assess hepatic glutathione metabolism. The safety, simplicity, and low cost of the 2H2O-based glutathione turnover approach suggest that this method has the potential for non-invasive probing of hepatic glutathione metabolism in patients with NAFLD and other diseases. PMID:27036364

  3. Profiles of metabolites and gene expression in rats with chemically induced hepatic necrosis.

    PubMed

    Heijne, Wilbert H M; Lamers, Robert-Jan A N; van Bladeren, Peter J; Groten, John P; van Nesselrooij, Joop H J; van Ommen, Ben

    2005-01-01

    This study investigated whether integrated analysis of transcriptomics and metabolomics data increased the sensitivity of detection and provided new insight in the mechanisms of hepatotoxicity. Metabolite levels in plasma or urine were analyzed in relation to changes in hepatic gene expression in rats that received bromobenzene to induce acute hepatic centrilobular necrosis. Bromobenzene-induced lesions were only observed after treatment with the highest of 3 dose levels. Multivariate statistical analysis showed that metabolite profiles of blood plasma were largely different from controls when the rats were treated with bromobenzene, also at doses that did not elicit histopathological changes. Changes in levels of genes and metabolites were related to the degree of necrosis, providing putative novel markers of hepatotoxicity. Levels of endogenous metabolites like alanine, lactate, tyrosine and dimethylglycine differed in plasma from treated and control rats. The metabolite profiles of urine were found to be reflective of the exposure levels. This integrated analysis of hepatic transcriptomics and plasma metabolomics was able to more sensitively detect changes related to hepatotoxicity and discover novel markers. The relation between gene expression and metabolite levels was explored and additional insight in the role of various biological pathways in bromobenzene-induced hepatic necrosis was obtained, including the involvement of apoptosis and changes in glycolysis and amino acid metabolism. The complete Table 2 is available as a supplemental file online at http://taylorandfrancis.metapress.com/openurlasp?genre=journal&issn=0192-6233. To access the file, click on the issue link for 33(4), then select this article. A download option appears at the bottom of this abstract. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org.

  4. Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shaker, Mohamed E., E-mail: mshaker2222@yahoo.com; Zalata, Khaled R.; Mehal, Wajahat Z.

    2011-04-15

    Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl{sub 4}) rat model. Male Wistar rats received intraperitoneal injections of CCl{sub 4} twice weekly for 8 weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20 mg/kg), nilotinib (10 and 20 mg/kg) and silymarin (100 mg/kg) during the last 4 weeks of CCl{sub 4}-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stressmore » parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20 mg/kg) was the most effective treatment to counteract CCl{sub 4}-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10 mg/kg), nilotinib (20 mg/kg) and silymarin (100 mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl{sub 4}-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl{sub 4}-induced fibrosis was ameliorated significantly by nilotinib (20 mg/kg) and imatinib (20 mg/kg). Unlike nilotinib, imatinib (20 mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans. - Graphical abstract: Display Omitted Research Highlights: > The anti-fibrotic effects of imatinib, nilotinib and silymarin were

  5. Hypothermia can reverse hepatic oxidative stress damage induced by hypoxia in rats.

    PubMed

    Garnacho-Castaño, Manuel Vicente; Alva, Norma; Sánchez-Nuño, Sergio; Bardallo, Raquel G; Palomeque, Jesús; Carbonell, Teresa

    2016-12-01

    Our previous findings demonstrated that hypothermia enhances the reduction potential in the liver and helps to maintain the plasmatic antioxidant pool. Here, we aimed to elucidate if hypothermia protects against hypoxia-induced oxidative stress damage in rat liver. Several hepatic markers of oxidative stress were compared in three groups of animals (n = 8 in each group): control normothermic group ventilated with room air and two groups under extreme hypoxia (breathing 10 % O 2 ), one kept at normothermia (HN) (37 °C) and the other under deep hypothermia (HH) (central body temperature of 21-22 °C). Hypoxia in normothermia significantly increased the levels of hepatic nitric oxide, inducible nitric oxide synthase expression, protein oxidation, Carbonilated proteins, advanced oxidation protein products, 4-hydroxynonenal (HNE) protein adducts, and lipid peroxidation when compared to the control group (p < 0.05). However, when hypoxia was induced under hypothermia, results from the oxidative stress biomarker analyses did not differ significantly from those found in the control group. Indeed, 4-HNE protein adduct amounts were significantly lower in the HH versus HN group (p < 0.05). Therefore, hypothermia can mitigate hypoxia-induced oxidative stress damage in rat liver. These effects could help clarify the mechanisms of action of therapeutic hypothermia.

  6. Cordyceps sinensis prevents apoptosis in mouse liver with D-galactosamine/lipopolysaccharide-induced fulminant hepatic failure.

    PubMed

    Cheng, Yu-Jung; Cheng, Shiu-Min; Teng, Yi-Hsien; Shyu, Woei-Cherng; Chen, Hsiu-Ling; Lee, Shin-Da

    2014-01-01

    Cordyceps sinensis (C. sinensis) has long been considered to be an herbal medicine and has been used in the treatment of various inflammatory diseases. The present study examined the cytoprotective properties of C. sinensis on D(+)-galactosamine (GalN)/lipopolysaccharide (LPS)-induced fulminant hepatic failure. Mice were randomly assigned into control, GalN/LPS, CS 20 mg and CS 40 mg groups (C. sinensis, oral gavage, five days/week, four weeks). After receiving saline or C. sinensis, mice were intraperitoneally given GalN (800 mg/kg)/LPS (10 μg/kg). The effects of C. sinensis on TNF-α, IL-10, AST, NO, SOD, and apoptoticrelated proteins after the onset of endotoxin intoxication were determined. Data demonstrated that GalN/LPS increased hepatocyte degeneration, circulating AST, TNF-α, IL-10, and hepatic apoptosis and caspase activity. C. sinensis pre-treatment reduced AST, TNF-α, and NO and increased IL-10 and SOD in GalN/LPS induced fulminant hepatic failure. C. sinensis attenuated the apoptosis of hepatocytes, as evidenced by the TUNEL and capase-3, 6 activity analyses. In summary, C. sinensis alleviates GalN/LPS-induced liver injury by modulating the cytokine response and inhibiting apoptosis.

  7. Chronic inflammation aggravates metabolic disorders of hepatic fatty acids in high-fat diet-induced obese mice

    PubMed Central

    Zhao, Lei; Zhong, Shan; Qu, Haiyang; Xie, Yunxia; Cao, Zhennan; Li, Qing; Yang, Ping; Varghese, Zac; Moorhead, John F.; Chen, Yaxi; Ruan, Xiong Z.

    2015-01-01

    The prevalence of nonalcoholic fatty liver disease (NAFLD) increases with increasing body mass index (BMI). However, approximately 40–50% of obese adults do not develop hepatic steatosis. The level of inflammatory biomarkers is higher in obese subjects with NAFLD compared to BMI-matched subjects without hepatic steatosis. We used a casein injection in high-fat diet (HFD)-fed C57BL/6J mice to induce inflammatory stress. Although mice on a HFD exhibited apparent phenotypes of obesity and hyperlipidemia regardless of exposure to casein injection, only the HFD+Casein mice showed increased hepatic vacuolar degeneration accompanied with elevated inflammatory cytokines in the liver and serum, compared to mice on a normal chow diet. The expression of genes related to hepatic fatty acid synthesis and oxidation were upregulated in the HFD-only mice. The casein injection further increased baseline levels of lipogenic genes and decreased the levels of oxidative genes in HFD-only mice. Inflammatory stress induced both oxidative stress and endoplasmic reticulum stress in HFD-fed mice livers. We conclude that chronic inflammation precedes hepatic steatosis by disrupting the balance between fatty acid synthesis and oxidation in the livers of HFD-fed obese mice. This mechanism may operate in obese individuals with chronic inflammation, thus making them more prone to NAFLD. PMID:25974206

  8. White Pitaya (Hylocereus undatus) Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice.

    PubMed

    Song, Haizhao; Zheng, Zihuan; Wu, Jianan; Lai, Jia; Chu, Qiang; Zheng, Xiaodong

    2016-01-01

    Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ) on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis) in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed low-fat diet with free access to water or WPJ, or fed high-fat diet with free access to water or WPJ for 14 weeks. Our results showed that administration of WPJ improved high-fat diet-induced insulin resistance, hepatic steatosis and adipose hypertrophy, but it exerted no influence on body weight gain in mice. Hepatic gene expression analysis indicated that WPJ supplement not only changed the expression profile of genes involved in lipid and cholesterol metabolism (Srebp1, HMGCoR, Cpt1b, HL, Insig1 and Insig2) but also significantly increased the expression levels of FGF21-related genes (Klb, FGFR2, Egr1 and cFos). In conclusion, WPJ protected from diet-induced hepatic steatosis and insulin resistance, which was associated with the improved FGF21 resistance and lipid metabolism.

  9. Cytochrome P450 2E1 gene polymorphisms/haplotypes and anti-tuberculosis drug-induced hepatitis in a Chinese cohort.

    PubMed

    Tang, Shaowen; Lv, Xiaozhen; Zhang, Yuan; Wu, Shanshan; Yang, Zhirong; Xia, Yinyin; Tu, Dehua; Deng, Peiyuan; Ma, Yu; Chen, Dafang; Zhan, Siyan

    2013-01-01

    The pathogenic mechanism of anti-tuberculosis (anti-TB) drug-induced hepatitis is associated with drug metabolizing enzymes. No tagging single-nucleotide polymorphisms (tSNPs) of cytochrome P450 2E1(CYP2E1) in the risk of anti-TB drug-induced hepatitis have been reported. The present study was aimed at exploring the role of tSNPs in CYP2E1 gene in a population-based anti-TB treatment cohort. A nested case-control study was designed. Each hepatitis case was 14 matched with controls by age, gender, treatment history, disease severity and drug dosage. The tSNPs were selected by using Haploview 4.2 based on the HapMap database of Han Chinese in Beijing, and detected by using TaqMan allelic discrimination technology. Eighty-nine anti-TB drug-induced hepatitis cases and 356 controls were included in this study. 6 tSNPs (rs2031920, rs2070672, rs915908, rs8192775, rs2515641, rs2515644) were genotyped and minor allele frequencies of these tSNPs were 21.9%, 23.0%, 19.1%, 23.6%, 20.8% and 44.4% in the cases and 20.9%, 22.7%, 18.9%, 23.2%, 18.2% and 43.2% in the controls, respectively. No significant difference was observed in genotypes or allele frequencies of the 6 tSNPs between case group and control group, and neither of haplotypes in block 1 nor in block 2 was significantly associated with the development of hepatitis. Based on the Chinese anti-TB treatment cohort, we did not find a statistically significant association between genetic polymorphisms of CYP2E1 and the risk of anti-TB drug-induced hepatitis. None of the haplotypes showed a significant association with the development of hepatitis in Chinese TB population.

  10. The regulatory effects of fish oil and chitosan on hepatic lipogenic signals in high-fat diet-induced obese rats.

    PubMed

    Chiu, Chen-Yuan; Chang, Tien-Chia; Liu, Shing-Hwa; Chiang, Meng-Tsan

    2017-10-01

    The present study investigated the regulatory effects of fish oil and chitosan on the signals of hepatic lipid metabolism and the postulated mechanism in high-fat diet-induced obese rats. Diet supplementation of chitosan and fish oil efficiently suppressed the increased weights in body and livers of high-fat diet-fed rats. Supplementation of chitosan and fish oil significantly decreased the activities of hepatic lipid biosynthesis-related enzymes and efficiently regulated plasma lipoprotein homeostasis. Both chitosan and fish oil significantly ameliorated the alterations in the protein expressions of hepatic lipogenic transcription factors (LXRα and PPARα), and could also significantly regulate the downstream hepatic lipogenic genes (FAS, HMGCR, CYP7A1, FATP, FABP, AOX, and ABCA) expressions in high-fat diet-fed rats. These results suggest that both fish oil and chitosan exerts downregulative effects on hepatic lipid metabolism in high-fat diet-induced obese rats via the LXRα inhibition and PPARα activation, which further affect the expressions of hepatic lipogenesis-associated genes. Copyright © 2017. Published by Elsevier B.V.

  11. Recurrent Acute Liver Failure Because of Acute Hepatitis Induced by Organic Solvents: A Case Report.

    PubMed

    Ito, Daisuke; Tanaka, Tomohiro; Akamatsu, Nobuhisa; Ito, Kyoji; Hasegawa, Kiyoshi; Sakamoto, Yoshihiro; Nakagawa, Hayato; Fujinaga, Hidetaka; Kokudo, Norihiro

    2016-01-01

    The authors present a case of recurrent acute liver failure because of occupational exposure to organic solvents. A 35-year-old man with a 3-week history of worsening jaundice and flu-like symptoms was admitted to our hospital. Viral hepatitis serology and autoimmune factors were negative. The authors considered liver transplantation, but the patient's liver function spontaneously recovered. Liver biopsy revealed massive infiltration of neutrophils, but the cause of the acute hepatitis was not identified. Four months after discharge, the patient's liver function worsened again. The authors considered the possibility of antinuclear antibody-negative autoimmune hepatitis and initiated steroid treatment, which was effective. Four months after discharge, the patient was admitted for repeated liver injury. The authors started him on steroid pulse therapy, but this time it was not effective. Just before the first admission, he had started his own construction company where he was highly exposed to organic solvents, and thus the authors considered organic solvent-induced hepatitis. Although urine test results for organic solvents were negative, a second liver biopsy revealed severe infiltration of neutrophils, compatible with toxic hepatitis. Again, his liver function spontaneously improved. Based on the pathology and detailed clinical course, including the patient's high exposure to organic solvents since just before the first admission, and the spontaneous recovery of his liver damage in the absence of the exposure, he was diagnosed with toxic hepatitis. The authors strongly advised him to avoid organic solvents. Since then, he has been in good health without recurrence. This is the first report of recurrent acute liver failure because of exposure to organic solvents, which was eventually diagnosed through a meticulous medical history and successfully recovered by avoiding the causative agents. In acute liver failure with an undetermined etiology, clinicians should rule

  12. Effect of leaving chronic oral foci untreated on infectious complications during intensive chemotherapy

    PubMed Central

    Schuurhuis, J M; Span, L F R; Stokman, M A; van Winkelhoff, A J; Vissink, A; Spijkervet, F K L

    2016-01-01

    Background: Leukaemic patients receiving intensive chemotherapy and patients undergoing autologous stem-cell transplantation (ASCT) are routinely screened for oral foci of infection to reduce infectious complications that could occur during therapy. In this prospective study we assessed the effect of leaving chronic oral foci of infection untreated on the development of infectious complications in intensively treated haematological patients. Methods: We included and prospectively evaluated all intensively treated leukaemic patients and patients undergoing ASCT who were referred to our medical centre between September 2012 and May 2014, and who matched the inclusion/exclusion criteria. Acute oral foci of infection were removed before chemotherapy or ASCT, whereas chronic oral foci were left untreated. Results: In total 28 leukaemic and 35 ASCT patients were included. Acute oral foci of infection were found in 2 leukaemic (7%) and 2 ASCT patients (6%), and chronic oral foci of infection in 24 leukaemic (86%) and 22 ASCT patients (63%). Positive blood cultures with microorganisms potentially originating from the oral cavity occurred in 7 patients during treatment, but were uneventful on development of infectious complications. Conclusions: Our prospective study supports the hypothesis that chronic oral foci of infection can be left untreated as this does not increase infectious complications during intensive chemotherapy. PMID:27002936

  13. PCNA-dependent accumulation of CDKN1A into nuclear foci after ionizing irradiation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wiese, Claudia; Rudolph, Jeanette Heede; Jakob, Burkhard

    2012-03-26

    The cyclin-dependent kinase inhibitor CDKN1A/p21 confers cell-cycle arrest in response to DNA damage and inhibits DNA replication through its direct interaction with the proliferating cell nuclear antigen (PCNA) and cyclin/cyclin-dependent kinase complexes. Previously, we reported that in response to densely ionizing radiation CDKN1A rapidly is recruited to the sites of particle traversal, and that CDKN1A foci formation in response to heavy ions is independent of its transactivation by TP53. In this paper, we show that exposure of normal human fibroblasts to X-rays or to H 2O 2 also induces nuclear accumulations of CDKN1A. We find that CDKN1A foci formation inmore » response to radiation damage is dependent on its dephosphorylation and on its direct physical interaction with PCNA. Live cell imaging analyses of ectopically expressed EGFP-CDKN1A and dsRed-PCNA show rapid recruitment of both proteins into foci after radiation damage. Detailed dynamic measurements reveal a slightly delayed recruitment of CDKN1A compared to PCNA, which is best described by bi-exponential curve fitting, taking the preceding binding of PCNA to DNA into account. Finally, we propose a regulatory role for CDKN1A in mediating PCNA function after radiation damage, and provide evidence that this role is distinct from its involvement in nucleotide excision repair and unrelated to double-strand break repair.« less

  14. [Southern taiga combined natural foci of spirochetoses].

    PubMed

    Korenberg, E I; Anan'ina, Iu V; Gorelova, N B; Savel'eva, O V; Kovalevskiĭ, Iu V; Petrov, E M

    2011-01-01

    Study of possibility of existence of combined natural foci of spirochetoses (ixodes tick borrelioses and leptospiroses) in typical taiga forests, and their etiologic and reservoir-host structure. Small mammals of 19 species were captured in 1992-2010 at a station in low-mountain southern taiga forests of Chusov area of Perm region. Borreliae were isolated by seeding urinary bladder or aural bioptates into BSK II medium, leptospirae--by seeding a suspension of kidney tissue into Vervoort-Wolf medium. 1350 animals were studied by seeding for borrelia infection and 1077--for leptospira. 287 of those, small animals of 6 species, were simultaneously studied for borrelia and leptospira infection. Borrelia isolates were identified by using PCR and restriction fragment length polymorphism methods, and leptospirae--by using standard diagnostic agglutinating sera kit. Blood of 2893 rodents of 12 species and insectivorous of 7 species was studied in microagglutination reaction for the detection of antibodies against leptospirae. Infection by Borrelia garinii and Borrelia afzelii or Grippotyphosa serogroup leptospira was detected in 6 most numerous species of forest small mammals. 3 root voles and I bankvole were simultaneously infected by borreliae and leptospirae. B. garinii and Grippotyphosa serogroup leptospira were simultaneously isolated from 2 root voles, and B. garinii and Javanica serogroup Leptospira interrogans--from 1 root vole. A bank vole was infected by B. afzelii and Javanica serogroup leptospira. Mixed-infected animals composed 1.4% of all animals of background species studied in parallel. The data obtained indicate a presence of natural foci of leptospiroses in the southern taiga forest pre-Urals. The data confirm the conceptions regarding a predominant presence in European forest ecosystems of foci with Grippotyphosa serogroup L. interrogans pathogen, and the main carrier ofthese leptospirae being bank vole. Combined natural foci of spirochetoses of two

  15. Dietary fat sources differentially modulate intestinal barrier and hepatic inflammation in alcohol-induced liver injury in rats

    PubMed Central

    Zhong, Wei; Li, Qiong; Xie, Guoxiang; Sun, Xiuhua; Tan, Xiaobing; Sun, Xinguo; Jia, Wei

    2013-01-01

    Endotoxemia is a causal factor in the development of alcoholic liver injury. The present study aimed at determining the interactions of ethanol with different fat sources at the gut-liver axis. Male Sprague-Dawley rats were pair fed control or ethanol liquid diet for 8 wk. The liquid diets were based on a modified Lieber-DeCarli formula, with 30% total calories derived from corn oil (rich in polyunsaturated fatty acids). To test the effects of saturated fats, corn oil in the ethanol diet was replaced by either cocoa butter (CB, rich in long-chain saturated fatty acids) or medium-chain triglycerides (MCT, exclusively medium-chain saturated fatty acids). Ethanol feeding increased hepatic lipid accumulation and inflammatory cell infiltration and perturbed hepatic and serum metabolite profiles. Ethanol feeding with CB or MCT alleviated ethanol-induced liver injury and attenuated ethanol-induced metabolic perturbation. Both CB and MCT also normalized ethanol-induced hepatic macrophage activation, cytokine expression, and neutrophil infiltration. Ethanol feeding elevated serum endotoxin level, which was normalized by MCT but not CB. In accordance, ethanol-induced downregulations of intestinal occludin and zonula occludens-1 were normalized by MCT but not CB. However, CB normalized ethanol-increased hepatic endotoxin level in association with upregulation of an endotoxin detoxifying enzyme, argininosuccinate synthase 1 (ASS1). Knockdown ASS1 in H4IIEC3 cells resulted in impaired endotoxin clearance and upregulated cytokine expression. These data demonstrate that the protection of saturated fats against alcohol-induced liver injury occur via different actions at the gut-liver axis and are chain length dependent. PMID:24113767

  16. The Association of Viral Hepatitis and Acute Pancreatitis

    PubMed Central

    Geokas, Michael C.; Olsen, Harvey; Swanson, Virginia; Rinderknecht, Heinrich

    1972-01-01

    The histological features of 24 pancreases obtained from patients who died of causes other than hepatitis, pancreatitis or pancreatic tumors, included a variable degree of autolysis, rare foci of inflammatory reaction but no hemorrhagic fat necrosis or destruction of elastic tissue in vessel walls (elastolysis). Assays of elastase in extracts of these pancreases showed no free enzyme, but varying amounts of proelastase. A review of autopsy findings in 33 patients with fatal liver necrosis attributed to halothane anesthesia, demonstrated changes of acute pancreatitis only in two. On the other hand, a review of 16 cases of fulminant viral hepatitis revealed changes characteristic of acute pancreatitis in seven – interstitial edema, hemorrhagic fat necrosis, inflammatory reaction and frequently elastolysis in vessel walls. Determination of elastase in extracts of one pancreas showed the bulk of the enzyme in free form. Furthermore, assays of urinary amylase in 44 patients with viral hepatitis showed increased levels of this enzyme (2583 ± 398 mean value ± standard error, Somogyi units per 100 ml in 13, or 29.5 percent). The evidence suggests that acute pancreatitis may at times complicate viral hepatitis. Although direct proof of viral pancreatic involvement is not feasible at present, a rational hypothesis is advanced which underlines similar mechanisms of tissue involvement in both liver and pancreas that may be brought about by the hepatitis viruses. PMID:5070694

  17. Dimethylarginine Dimethylaminohydrolase 1 Protects Against High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance in Mice.

    PubMed

    Li, Tianhe; Feng, Run; Zhao, Chenyang; Wang, Yue; Wang, Jian; Liu, Shasha; Cao, Jianwei; Wang, Hongyun; Wang, Ting; Guo, Yuting; Lu, Zhongbing

    2017-04-10

    High plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are associated with hepatic dysfunction in patients with nonalcoholic fatty liver disease (NAFLD). However, it is unknown whether ADMA is involved in the pathogenesis of NAFLD. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an enzyme that degrades ADMA. In this study, we used Ddah1 -/- mice to investigate the effects of the ADMA/DDAH1 pathway on high-fat diet (HFD)-induced hepatic steatosis. After HFD feeding for 20 weeks, Ddah1 -/- mice were more obese and had developed more severe hepatic steatosis and worse insulin resistance compared with wild-type (WT) mice. In the livers of HFD-fed mice, loss of DDAH1 resulted in higher levels of lipogenic genes, lower expression of β-oxidation genes, and greater induction of oxidative stress, endoplasmic reticulum stress, and inflammation than in the WT livers. Furthermore, ADMA treatment in HepG2 cells led to oxidative stress and steatosis, whereas overexpression of DDAH1 attenuated palmitic acid-induced steatosis, oxidative stress, and inflammation. Innovation and Conclusion: Our results provide the first direct evidence that the ADMA/DDAH1 pathway has a marked effect on hepatic lipogenesis and steatosis induced by HFD feeding. Our findings suggest that strategies to increase DDAH1 activity in hepatocytes may provide a novel approach to attenuate NAFLD development. Antioxid. Redox Signal. 26, 598-609.

  18. Hepatoprotective role of Ricinus communis leaf extract against d-galactosamine induced acute hepatitis in albino rats.

    PubMed

    Babu, Pappithi Ramesh; Bhuvaneswar, Cherukupalle; Sandeep, Gandham; Ramaiah, Chintha Venkata; Rajendra, Wudayagiri

    2017-04-01

    Ricinus communis (RC) is a traditional medicinal plant which has been used by Chenchu and Yerukula tribes for treating their liver ailments. The present work is aimed to explore the hepatoprotective efficacy of Ricinus communis against d-galactosamine (D-GalN) induced hepatitis rat model and its therapeutic potential compared with standard drug, silymarin (100mg/kg.bw). In vitro antioxidant activity of Methanolic extract of Ricinus communis leaves (MERCL) was assayed through DPPH and H 2 O 2 free radical scavenging activity. Qualitative and quantitative analysis of MERCL using HPLC, demonstrated that Rutin was found to be predominant bioactive compound in the extract. Hepatitis was induced by treating the rats with D-GalN at a single intraperitoneal dose of 800mg/kg.bw. Serum markers viz, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP) and Malondialdehyde (MDA) levels were significantly increased and the activity levels of antioxidant enzymes such as Superoxide dismutase (SOD),Catalase (CAT), Glutathione reductase (GR), Glutathione peroxidase (GPx), non-enzymatic antioxidant Glutathione (GSH) levels were decreased in the liver of hepatitis induced rats when compared to controls. Pre and post treatment with MERCL significantly altered the enzyme activities, GSH and MDA to normal levels. Histopathological observations also showed protective and curative effects of MERCL against D-GalN intoxication. These results demonstrated that MERCL significantly protected the liver from d-galactosamine induced hepatitis, improved the curative effect in the liver and hence, MERCL can be used as a potent hepatoprotective drug in future. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  19. High-fructose corn syrup-induced hepatic dysfunction in rats: improving effect of resveratrol.

    PubMed

    Sadi, Gokhan; Ergin, Volkan; Yilmaz, Guldal; Pektas, M Bilgehan; Yildirim, O Gokhan; Menevse, Adnan; Akar, Fatma

    2015-09-01

    The increased consumption of high-fructose corn syrup (HFCS) may contribute to the worldwide epidemic of fatty liver. In this study, we have investigated whether HFCS intake (20% beverages) influences lipid synthesis and accumulation in conjunction with insulin receptor substrate-1/2 (IRS-1; IRS-2), endothelial nitric oxide synthase (eNOS), sirtuin 1 (SIRT1) and inducible NOS (iNOS) expressions in liver of rats. Resveratrol was tested for its potential efficacy on changes induced by HFCS. Animals were randomly divided into four groups as control, resveratrol, HFCS and resveratrol plus HFCS (resveratrol + HFCS). HFCS was given as 20% solutions in drinking water. Feeding of all rats was maintained by a standard diet that enriched with or without resveratrol for 12 weeks. Dietary HFCS increased triglyceride content and caused mild microvesicular steatosis in association with up-regulation of fatty acid synthase and sterol regulatory element binding protein (SREBP)-1c in liver of rats. Moreover, HFCS feeding impaired hepatic expression levels of IRS-1, eNOS and SIRT1 mRNA/proteins, but did not change iNOS level. Resveratrol promoted IRS, eNOS and SIRT1, whereas suppressed SREBP-1c expression in rats fed with HFCS. Resveratrol supplementation considerably restored hepatic changes induced by HFCS. The improvement of hepatic insulin signaling and activation of SIRT1 by resveratrol may be associated with decreased triglyceride content and expression levels of the lipogenic genes of the liver.

  20. Gap Junction Inhibition Prevents Drug-induced Liver Toxicity and Fulminant Hepatic Failure

    PubMed Central

    Patel, Suraj J; Milwid, Jack M; King, Kevin R; Bohr, Stefan; Iracheta, Arvin; Li, Matthew; Vitalo, Antonia; Parekkadan, Biju; Jindal, Rohit; Yarmush, Martin L

    2013-01-01

    Drug-induced liver injury (DILI) limits the development and utilization of numerous therapeutic compounds, and consequently presents major challenges to the pharmaceutical industry and clinical medicine1, 2. Acetaminophen (APAP) containing compounds are among the most frequently prescribed drugs, and also the most common cause of DILI3. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and APAP-induced hepatotoxicity. We report that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation, and death. We identified a small molecule inhibitor of Cx32 as a novel hepatoprotectant that achieves the same result in wildtype mice when coadministered with known hepatotoxic drugs. These findings demonstrate that gap junction inhibition is an effective therapy for limiting DILI, and suggest a novel pharmaceutical strategy to improve drug safety. PMID:22252509

  1. Rebamipide retards CCl4-induced hepatic fibrosis in rats: Possible role for PGE2.

    PubMed

    Zakaria, Sherin; El-Sisi, Alaa

    2016-07-01

    Prostaglandin E2 (PGE2) is a potent physiological suppressor of liver fibrosis. Because the anti-ulcer drug rebamipide can induce the formation of endogenous PGE2, this study investigated the potential effects of rebamipide on development of a hepatic fibrosis that was inducible by carbon tetrachloride (CCl4). Groups of Wistar rats received intraperitoneal (IP) injections of CCl4 (0.45 ml/kg [0.72 g CCl4/kg]) over the course of for 4 weeks. Sub-sets of CCl4-treated rats were also treated concurrently with rebamipide at 60 or 100 mg/kg. At 24 h after the final treatments, liver function and oxidative stress were indirectly assessed. The extent of hepatic fibrosis was evaluated using two fibrotic markers, hyaluronic acid (HA) and pro-collagen-III (Procol-III); isolated liver tissues underwent histology and were evaluated for interleukin (IL)-10 and PGE2 content. The results indicated that treatment with rebamipide significantly inhibited CCl4-induced increases in serum ALT and AST and also reduced oxidative stress induced by CCl4. Fibrotic marker assays revealed that either dose of rebamipide decreased the host levels of Procol-III and HA that had become elevated due to the CCl4. At the higher dose tested, rebamipide appeared to be able to permit the hosts to have a normal liver histology and to minimize any CCl4-induced collagen precipitation in the liver. Lastly, the use of rebamipide was seen to be associated with significant increases in liver levels of both PGE2 and the anti-inflammatory cytokine IL-10. Based on these findings, it is concluded that rebamipide can retard hepatic fibrosis induced by CCl4 and that this effect may, in part, be mediated by an induction of PGE2 and IL-10 in the liver itself.

  2. [Premature assembly of nucleolus-derived foci induced by a reversible hypotonic shock in metaphase CV1 and HeLa cells].

    PubMed

    Zharskaia, O O; Zatsepina, O V

    2005-01-01

    The assembly of nucleolus-derived foci (NDF) in the cytoplasm of telophase cells is an early stage of nucleolus reassembly during mitosis. In current literature, significant attention is paid to the molecular composition of NDF and their participation in reassembly of the mature nucleolus. However, very little is known about mechanisms controlling the NDF formation. The authors have demonstrated for the first time that a reversible action of low ionic strength buffers (lypotonic shock treatment) on living mitotic human HeLa and green monkey CV1 cells triggers a premature assembly of NDF at metaphase. Like the true NDF, i. e., those assembled in telophase mitosis, NDF prematurally induced at metaphase contain RNA and proteins required for rRNA processing (fibrillarin, B23/nucliophosmin, C23/nucleolin), but lack UBF, an auxiliary factor of RNA polymerase I. We have assumed that a reversible action of hypotonic shock on metaphase cells may result in temporal increase in intracellular [Ca2+](i) that, in its turn, may induce a premature assembly of NDF under isotonic conditions. The structural integrity of the mitotic spindle apparently plays an essential role in the response of metaphase cells to hypotonic shock treatments.

  3. Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice.

    PubMed

    Avraham, Y; Grigoriadis, Nc; Poutahidis, T; Vorobiev, L; Magen, I; Ilan, Y; Mechoulam, R; Berry, Em

    2011-04-01

    Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure. We investigated the effects of cannabidiol, a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT(1A) , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide. Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes. In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration. Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  4. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism.

    PubMed

    Shin, Andrew C; Fasshauer, Martin; Filatova, Nika; Grundell, Linus A; Zielinski, Elizabeth; Zhou, Jian-Ying; Scherer, Thomas; Lindtner, Claudia; White, Phillip J; Lapworth, Amanda L; Ilkayeva, Olga; Knippschild, Uwe; Wolf, Anna M; Scheja, Ludger; Grove, Kevin L; Smith, Richard D; Qian, Wei-Jun; Lynch, Christopher J; Newgard, Christopher B; Buettner, Christoph

    2014-11-04

    Circulating branched-chain amino acid (BCAA) levels are elevated in obesity/diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of hepatic protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway. Selective induction of hypothalamic insulin signaling in rats and genetic modulation of brain insulin receptors in mice demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Short-term overfeeding impairs the ability of brain insulin to lower BCAAs in rats. High-fat feeding in nonhuman primates and obesity and/or diabetes in humans is associated with reduced BCKDH protein in liver. These findings support the concept that decreased hepatic BCKDH is a major cause of increased plasma BCAAs and that hypothalamic insulin resistance may account for impaired BCAA metabolism in obesity and diabetes. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Lactoferrin Dampens High-Fructose Corn Syrup-Induced Hepatic Manifestations of the Metabolic Syndrome in a Murine Model

    PubMed Central

    Li, Yi-Chieh; Hsieh, Chang-Chi

    2014-01-01

    Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome. PMID:24816278

  6. Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

    PubMed

    Li, Yi-Chieh; Hsieh, Chang-Chi

    2014-01-01

    Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

  7. Tumor-induced CD11b(+) Gr-1(+) myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner.

    PubMed

    Kapanadze, Tamar; Medina-Echeverz, José; Gamrekelashvili, Jaba; Weiss, Jonathan M; Wiltrout, Robert H; Kapoor, Veena; Hawk, Nga; Terabe, Masaki; Berzofsky, Jay A; Manns, Michael P; Wang, Ena; Marincola, Francesco M; Korangy, Firouzeh; Greten, Tim F

    2015-04-01

    Immunosuppressive CD11b(+) Gr-1(+) myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing (TB) mice. We studied hepatic MDSCs in two murine models of immune-mediated hepatitis. Unexpectedly, treatment of TB mice with Concanavalin A (Con A) or α-galactosylceramide resulted in increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels in comparison to tumor-free mice. Adoptive transfer of hepatic MDSCs into naïve mice exacerbated Con A induced liver damage. Hepatic CD11b(+) Gr-1(+) cells revealed a polarized proinflammatory gene signature after Con A treatment. An IFN-γ-dependent upregulation of CD40 on hepatic CD11b(+) Gr-1(+) cells along with an upregulation of CD80, CD86, and CD1d after Con A treatment was observed. Con A treatment resulted in a loss of suppressor function by tumor-induced CD11b(+) Gr-1(+) MDSCs as well as enhanced reactive oxygen species (ROS)-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Con A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40(-/-) tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased ROS production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as proinflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

  8. Diosmin Attenuates Methotrexate-Induced Hepatic, Renal, and Cardiac Injury: A Biochemical and Histopathological Study in Mice

    PubMed Central

    Khalifa, Hesham A.; Al-Quraishy, Saleh A.

    2017-01-01

    The current study was designed to investigate the beneficial role of diosmin, a biologically active flavonoid, against methotrexate- (MTX-) induced hepatic, renal, and cardiac injuries in mice. Male Swiss albino mice received a single intraperitoneal injection of MTX (at 20 mg/kg, body weight) either alone or in combination with oral diosmin (at 50 or 100 mg/kg body weight, for 10 days). Serum was used to evaluate tissue injury markers, while hepatic, renal, and cardiac tissue samples were obtained for determination of antioxidant activity as well as histopathological examination. Diosmin treatment ameliorated the MTX-induced elevation of serum alkaline phosphatase, aminotransferases, urea, creatinine, lactate dehydrogenase, and creatine kinases as well as plasma proinflammatory cytokines (interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha). Additionally, both diosmin doses significantly reduced tissue levels of malondialdehyde and nitric oxide and increased those of glutathione, glutathione peroxidase, glutathione reductase, glutathione S-transferase, superoxide dismutase, and catalase, compared to the MTX-intoxicated group. Histopathological examination showed that diosmin significantly minimized the MTX-induced histological alterations and nearly restored the normal architecture of hepatic, renal, and cardiac tissues. Based on these findings, diosmin may be a promising agent for protection against MTX-induced cytotoxicity in patients with cancer and autoimmune diseases. PMID:28819543

  9. Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

    PubMed Central

    Ivanov, Alexander V.; Valuev-Elliston, Vladimir T.; Tyurina, Daria A.; Ivanova, Olga N.; Kochetkov, Sergey N.; Bartosch, Birke; Isaguliants, Maria G.

    2017-01-01

    Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review. PMID:27965466

  10. The Dance of the Foci

    ERIC Educational Resources Information Center

    Seppala-Holtzman, David

    2010-01-01

    It's well known that slicing a cone with a plane and then allowing the plane to rotate through all possible angles of inclination yields the conic sections. What paths then do the foci of these conics trace out as this cutting plane passes through the different angles? In this article, we derive formulae for these trajectories and generate the…

  11. Human aberrant crypt foci with carcinoma in situ from a patient with sporadic colon cancer.

    PubMed

    Konstantakos, A K; Siu, I M; Pretlow, T G; Stellato, T A; Pretlow, T P

    1996-09-01

    Aberrant crypt foci are putative preneoplastic lesions found in the colons of carcinogen-treated rodents and at an increased frequency in humans at increased risk for colon cancer. There is a strong association between aberrant crypt foci and colon cancer, including many shared phenotypic and genetic alterations. The aim of this study is to present further evidence of a relationship between aberrant crypt foci and colon cancer in humans. Multiple aberrant crypt foci from a single patient were identified in unembedded colonic mucosa. Histological sections of the aberrant crypt foci and adjacent mucosa were evaluated for dysplasia, proliferative activity, and pigment-laden macrophages that were characterized with histochemical techniques. The first patient with sporadic colon cancer identified with aberrant crypt foci with carcinoma in situ is described. It is interesting that this 99-year-old patient had multiple carcinomas in situ, pseudomelanosis coli, and two metachronous colon cancers. These data lend support to the hypothesis that aberrant crypt foci are precursors of some colon cancers.

  12. Identification of Chinese plague foci from long-term epidemiological data

    PubMed Central

    Ben-Ari, Tamara; Neerinckx, Simon; Agier, Lydiane; Cazelles, Bernard; Xu, Lei; Zhang, Zhibin; Fang, Xiye; Wang, Shuchun; Liu, Qiyong; Stenseth, Nils C.

    2012-01-01

    Carrying out statistical analysis over an extensive dataset of human plague reports in Chinese villages from 1772 to 1964, we identified plague endemic territories in China (i.e., plague foci). Analyses rely on (i) a clustering method that groups time series based on their time-frequency resemblances and (ii) an ecological niche model that helps identify plague suitable territories characterized by value ranges for a set of predefined environmental variables. Results from both statistical tools indicate the existence of two disconnected plague territories corresponding to Northern and Southern China. Altogether, at least four well defined independent foci are identified. Their contours compare favorably with field observations. Potential and limitations of inferring plague foci and dynamics using epidemiological data is discussed. PMID:22570501

  13. miR-217 regulates ethanol-induced hepatic inflammation by disrupting sirtuin 1-lipin-1 signaling.

    PubMed

    Yin, Huquan; Liang, Xiaomei; Jogasuria, Alvin; Davidson, Nicholas O; You, Min

    2015-05-01

    Ethanol-mediated injury, combined with gut-derived lipopolysaccharide (LPS), provokes generation of proinflammatory cytokines in Kupffer cells, causing hepatic inflammation. Among the mediators of these effects, miR-217 aggravates ethanol-induced steatosis in hepatocytes. However, the role of miR-217 in ethanol-induced liver inflammation process is unknown. Here, we examined the role of miR-217 in the responses to ethanol, LPS, or a combination of ethanol and LPS in RAW 264.7 macrophages and in primary Kupffer cells. In macrophages, ethanol substantially exacerbated LPS-mediated induction of miR-217 and production of proinflammatory cytokines compared with LPS or ethanol alone. Consistently, ethanol administration to mice led to increases in miR-217 abundance and increased production of inflammatory cytokines in isolated primary Kupffer cells exposed to the combination of ethanol and LPS. miR-217 promoted combined ethanol and LPS-mediated inhibition of sirtuin 1 expression and activity in macrophages. Moreover, miR-217-mediated sirtuin 1 inhibition was accompanied by increased activities of two vital inflammatory regulators, NF-κB and the nuclear factor of activated T cells c4. Finally, adenovirus-mediated overexpression of miR-217 led to steatosis and inflammation in mice. These findings suggest that miR-217 is a pivotal regulator involved in ethanol-induced hepatic inflammation. Strategies to inhibit hepatic miR-217 could be a viable approach in attenuating alcoholic hepatitis. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  14. White Pitaya (Hylocereus undatus) Juice Attenuates Insulin Resistance and Hepatic Steatosis in Diet-Induced Obese Mice

    PubMed Central

    Song, Haizhao; Zheng, Zihuan; Wu, Jianan; Lai, Jia; Chu, Qiang; Zheng, Xiaodong

    2016-01-01

    Insulin resistance and hepatic steatosis are the most common complications of obesity. Pitaya is an important source of phytochemicals such as polyphenols, flavonoid and vitamin C which are related to its antioxidant activity. The present study was conducted to evaluate the influence of white pitaya juice (WPJ) on obesity-related metabolic disorders (e.g. insulin resistance and hepatic steatosis) in high-fat diet-fed mice. Forty-eight male C57BL/6J mice were assigned into four groups and fed low-fat diet with free access to water or WPJ, or fed high-fat diet with free access to water or WPJ for 14 weeks. Our results showed that administration of WPJ improved high-fat diet-induced insulin resistance, hepatic steatosis and adipose hypertrophy, but it exerted no influence on body weight gain in mice. Hepatic gene expression analysis indicated that WPJ supplement not only changed the expression profile of genes involved in lipid and cholesterol metabolism (Srebp1, HMGCoR, Cpt1b, HL, Insig1 and Insig2) but also significantly increased the expression levels of FGF21-related genes (Klb, FGFR2, Egr1 and cFos). In conclusion, WPJ protected from diet-induced hepatic steatosis and insulin resistance, which was associated with the improved FGF21 resistance and lipid metabolism. PMID:26914024

  15. [Inhibitory effects of silymarin on hepatic fibrosis induced by dimethylnitrosamine: experiment with rats].

    PubMed

    Zhao, Xin-yan; Wang, Bao-en; Wang, Tai-ling; Li, Xin-min

    2006-09-26

    To investigate the antifibrotic effects of silymarin on hepatic fibrosis. Sixty-one male Wistar rats were randomly divided into three groups: control group (15 rats); DMN model group (23 rats), injected intraperitoneally with dimethylnitrosamine (DMN) 10 mg/kg twice per week for 8 weeks to induce hepatic fibrosis; and silymarin group (23 rats), injected intraperitoneally with DMN and given silymarin 50 mg/kg by gastric gavage daily for 8 weeks. Eight weeks late all rats were sacrificed. Blood samples were collected to measure the alanine transaminase (ALT), aspirate aminotransferase (AST), albumin, and total bilirubin (TBIL). The hydroxyproline (Hyp) content in the liver tissue was measured. The histopathological changes as well as the fibrosis stages and score were examined by microscopy. The levels of ALT, AST, and TBIL of the silymarin groups were 59 U/L +/- 19 U/L, 159 U/L +/- 39 U/L, and mean rank 24 respectively, all significantly lower than those of the DMN model group (128 U/L +/- 25 U/L, 246 U/L +/- 61 U/L, and mean rank 37 respectively, P < 0.01, P = 0.001, and P = 0.003). Compared with DMN rats, the level of Hyp of the silymarin was lower by 42.6%, the hepatic score of the silymarin was 6.2 +/- 2.4, significantly than that of the DMN model group (12.8 +/- 4.4, P = 0.001), and more cases in the silymarin group were at the lower stages. Silymarin markedly inhibits and reverse the progression of hepatic fibrosis induced by dimethylnitrosamine.

  16. Protective Role of Taurine against Arsenic-Induced Mitochondria-Dependent Hepatic Apoptosis via the Inhibition of PKCδ-JNK Pathway

    PubMed Central

    Das, Joydeep; Ghosh, Jyotirmoy; Manna, Prasenjit; Sil, Parames C.

    2010-01-01

    Background Oxidative stress-mediated hepatotoxic effect of arsenic (As) is mainly due to the depletion of glutathione (GSH) in liver. Taurine, on the other hand, enhances intracellular production of GSH. Little is known about the mechanism of the beneficial role of taurine in As-induced hepatic pathophysiology. Therefore, in the present study we investigated its beneficial role in As-induced hepatic cell death via mitochondria-mediated pathway. Methodology/Principal Findings Rats were exposed to NaAsO2 (2 mg/kg body weight for 6 months) and the hepatic tissue was used for oxidative stress measurements. In addition, the pathophysiologic effect of NaAsO2 (10 µM) on hepatocytes was evaluated by determining cell viability, mitochondrial membrane potential and ROS generation. As caused mitochondrial injury by increased oxidative stress and reciprocal regulation of Bcl-2, Bcl-xL/Bad, Bax, Bim in association with increased level of Apaf-1, activation of caspase 9/3, cleavage of PARP protein and ultimately led to apoptotic cell death. In addition, As markedly increased JNK and p38 phosphorylation with minimal disturbance of ERK. Pre-exposure of hepatocytes to a JNK inhibitor SP600125 prevented As-induced caspase-3 activation, ROS production and loss in cell viability. Pre-exposure of hepatocytes to a p38 inhibitor SB2035, on the other hand, had practically no effect on these events. Besides, As activated PKCδ and pre-treatment of hepatocytes with its inhibitor, rottlerin, suppressed the activation of JNK indicating that PKCδ is involved in As-induced JNK activation and mitochondrial dependent apoptosis. Oral administration of taurine (50 mg/kg body weight for 2 weeks) both pre and post to NaAsO2 exposure or incubation of the hepatocytes with taurine (25 mM) were found to be effective in counteracting As-induced oxidative stress and apoptosis. Conclusions/Significance Results indicate that taurine treatment improved As-induced hepatic damages by inhibiting PKC

  17. Azithromycin induced hepatocellular toxicity and hepatic encephalopathy in asymptomatic dilated cardiomyopathy

    PubMed Central

    Das, Bidyut Kumar

    2011-01-01

    Azithromycin is a widely used macrolide derivative and has generally been considered to be a very safe medication. Though gastrointestinal symptoms and reversible hearing loss are common, potentially serious side effects including angioedema and cholestatic jaundice occurred in less than one percent of patients. We report a case of asymptomatic dilated cardiomyopathy with Azithromycin induced severe hepatocellular toxicity and hepatic encephalopathy. PMID:22144789

  18. Lactobacillus fermentum ZYL0401 Attenuates Lipopolysaccharide-Induced Hepatic TNF-α Expression and Liver Injury via an IL-10- and PGE2-EP4-Dependent Mechanism

    PubMed Central

    Lv, Longxian; Yang, Jianzhuan; Lu, Haifeng; Li, Lanjuan

    2015-01-01

    Lipopolysaccharide (LPS) has essential role in the pathogenesis of D-galactosamine-sensitized animal models and alcoholic liver diseases of humans, by stimulating release of pro-inflammatory mediators that cause hepatic damage and intestinal barrier impairment. Oral pretreatment of probiotics has been shown to attenuate LPS-induced hepatic injury, but it is unclear whether the effect is direct or due to improvement in the intestinal barrier. The present study tested the hypothesis that pretreatment with probiotics enables the liver to withstand directly LPS-induced hepatic injury and inflammation. In a mouse model of LPS-induced hepatic injury, the levels of hepatic tumor necrosis factor-alpha (TNF-α) and serum alanine aminotransferase (ALT) of mice with depleted intestinal commensal bacteria were not significantly different from that of the control models. Pre-feeding mice for 10 days with Lactobacillus fermentum ZYL0401 (LF41), significantly alleviated LPS-induced hepatic TNF-α expression and liver damage. After LF41 pretreatment, mice had dramatically more L.fermentum-specific DNA in the ileum, significantly higher levels of ileal cyclooxygenase (COX)-2 and interleukin 10 (IL-10) and hepatic prostaglandin E2 (PGE2). However, hepatic COX-1, COX-2, and IL-10 protein levels were not changed after the pretreatment. There were also higher hepatic IL-10 protein levels after LPS challenge in LF41-pretreaed mice than in the control mice. Attenuation of hepatic TNF-α was mediated via the PGE2/E prostanoid 4 (EP4) pathway, and serum ALT levels were attenuated in an IL-10-dependent manner. A COX-2 blockade abolished the increase in hepatic PGE2 and IL-10 associated with LF41. In LF41-pretreated mice, a blockade of IL-10 caused COX-2-dependent promotion of hepatic PGE2, without affecting hepatic COX-2levels. In LF41-pretreated mice, COX2 prevented enhancing TNF-α expression in both hepatic mononuclear cells and the ileum, and averted TNF-α-mediated increase in

  19. Immunizations with chimeric hepatitis B virus-like particles to induce potential anti-hepatitis C virus neutralizing antibodies.

    PubMed

    Vietheer, Patricia T K; Boo, Irene; Drummer, Heidi E; Netter, Hans-Jürgen

    2007-01-01

    Virus-like particles (VLPs) are highly immunogenic and proven to induce protective immunity. The small surface antigen (HBsAg-S) of hepatitis B virus (HBV) self-assembles into VLPs and its use as a vaccine results in protective antiviral immunity against HBV infections. Chimeric HBsAg-S proteins carrying foreign epitopes allow particle formation and have the ability to induce anti-foreign humoral and cellular immune responses. The insertion of the hypervariable region 1 (HVR1) sequence derived from the envelope protein 2 (E2) of hepatitis C virus (HCV) into the major antigenic site of HBsAg-S ('a'-determinant) resulted in the formation of highly immunogenic VLPs that retained the antigenicity of the inserted HVR1 sequence. BALB/c mice were immunized with chimeric VLPs, which resulted in antisera with anti-HCV activity. The antisera were able to immunoprecipitate native HCV envelope complexes (E1E2) containing homologous or heterologous HVR1 sequences. HCV E1E2 pseudotyped HIV-1 particles (HCVpp) were used to measure entry into HuH-7 target cells in the presence or absence of antisera that were raised against chimeric VLPs. Anti-HVR1 VLP sera interfered with entry of entry-competent HCVpps containing either homologous or heterologous HVR1 sequences. Also, immunizations with chimeric VLPs induced antisurface antigen (HBsAg) antibodies, indicating that HBV-specific antigenicity and immunogenicity of the 'a'-determinant region is retained. A multivalent vaccine against different pathogens based on the HBsAg delivery platform should be possible. We hypothesize that custom design of VLPs with an appropriate set of HCV-neutralizing epitopes will induce antibodies that would serve to decrease the viral load at the initial infecting inoculum.

  20. Activation of the Farnesoid X Receptor Induces Hepatic Expression and Secretion of Fibroblast Growth Factor 21*

    PubMed Central

    Cyphert, Holly A.; Ge, Xuemei; Kohan, Alison B.; Salati, Lisa M.; Zhang, Yanqiao; Hillgartner, F. Bradley

    2012-01-01

    Previous studies have shown that starvation or consumption of a high fat, low carbohydrate (HF-LC) ketogenic diet induces hepatic fibroblast growth factor 21 (FGF21) gene expression in part by activating the peroxisome proliferator-activated receptor-α (PPARα). Using primary hepatocyte cultures to screen for endogenous signals that mediate the nutritional regulation of FGF21 expression, we identified two sources of PPARα activators (i.e. nonesterified unsaturated fatty acids and chylomicron remnants) that induced FGF21 gene expression. In addition, we discovered that natural (i.e. bile acids) and synthetic (i.e. GW4064) activators of the farnesoid X receptor (FXR) increased FGF21 gene expression and secretion. The effects of bile acids were additive with the effects of nonesterified unsaturated fatty acids in regulating FGF21 expression. FXR activation of FGF21 gene transcription was mediated by an FXR/retinoid X receptor binding site in the 5′-flanking region of the FGF21 gene. FGF19, a gut hormone whose expression and secretion is induced by intestinal bile acids, also increased hepatic FGF21 secretion. Deletion of FXR in mice suppressed the ability of an HF-LC ketogenic diet to induce hepatic FGF21 gene expression. The results of this study identify FXR as a new signaling pathway activating FGF21 expression and provide evidence that FXR activators work in combination with PPARα activators to mediate the stimulatory effect of an HF-LC ketogenic diet on FGF21 expression. We propose that the enhanced enterohepatic flux of bile acids during HF-LC consumption leads to activation of hepatic FXR and FGF19 signaling activity and an increase in FGF21 gene expression and secretion. PMID:22661717

  1. Fructose impairs glucose-induced hepatic triglyceride synthesis

    PubMed Central

    2011-01-01

    Obesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality. Consumption of refined carbohydrate and particularly fructose has increased significantly in recent years and has paralled the increased incidence of obesity and diabetes. Human and animal studies have demonstrated that high dietary fructose intake positively correlates with increased dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation (hepatic steatosis). This results in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression. Here we demonstrate that fructose alters glucose-stimulated expression of activated acetyl CoA carboxylase (ACC), pSer hormone sensitive lipase (pSerHSL) and adipose triglyceride lipase (ATGL) in hepatic HepG2 or primary hepatic cell cultures in vitro. This was associated with increased de novo triglyceride synthesis in vitro and hepatic steatosis in vivo in fructose- versus glucose-fed and standard-diet fed mice. These studies provide novel insight into the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia and identify fructose-uptake as a new potential therapeutic target for lipid-associated diseases. PMID:21261970

  2. [Possibilities of ultrasonic investigations in differentiation of a small-foci impairment of thyroid gland].

    PubMed

    Reyti, A O; Vityuk, N V; Medvedev, V E; Starushok, I O

    2015-03-01

    The results of ultrasound investigation of microcarcinomas and nontumoral foci of thyroid gland up to 10 mm in diameter and malignant foci over 10 mm are presented. Ultrasound signs are depicted, in accordance to which a potentially malignant thyroid gland foci are delineated, what demands a morphological (cytological) verification conduction.

  3. Zingiber officinale Roscoe prevents acetaminophen-induced acute hepatotoxicity by enhancing hepatic antioxidant status.

    PubMed

    Ajith, T A; Hema, U; Aswathy, M S

    2007-11-01

    A large number of xenobiotics are reported to be potentially hepatotoxic. Free radicals generated from the xenobiotic metabolism can induce lesions of the liver and react with the basic cellular constituents - proteins, lipids, RNA and DNA. Hepatoprotective activity of aqueous ethanol extract of Zingiber officinale was evaluated against single dose of acetaminophen-induced (3g/kg, p.o.) acute hepatotoxicity in rat. Aqueous extract of Z. officinale significantly protected the hepatotoxicity as evident from the activities of serum transaminase and alkaline phosphatase (ALP). Serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT) and ALP activities were significantly (p<0.01) elevated in the acetaminophen alone treated animals. Antioxidant status in liver such as activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase and glutathione-S-transferase (GST), a phase II enzyme, and levels of reduced glutathione (GSH) were declined significantly (p<0.01) in the acetaminophen alone treated animals (control group). Hepatic lipid peroxidation was enhanced significantly (p<0.01) in the control group. Administration of single dose of aqueous extract of Z. officinale (200 and 400mg/kg, p.o.) prior to acetaminophen significantly declines the activities of serum transaminases and ALP. Further the hepatic antioxidant status was enhanced in the Z. officinale plus acetaminophen treated group than the control group. The results of the present study concluded that the hepatoprotective effect of aqueous ethanol extract of Z. officinale against acetaminophen-induced acute toxicity is mediated either by preventing the decline of hepatic antioxidant status or due to its direct radical scavenging capacity.

  4. A rare cause of drug-induced hepatitis in an immunocompromised patient and the role of glutathione.

    PubMed

    Senadhi, Viplove; Arora, Deepika; Arora, Manish; Marsh, Franklin

    2012-08-27

    The Food and Drug Administration (FDA) has issued a warning on numerous herbal drugs, including many popular products at General Nutrition Centers (GNC), regarding unstudied hepatotoxicity. There have been recent reports of GNC products such as hydroxycut and herbalife, causing drug-induced hepatitis. Herbal medications are over-the-counter products and are not investigated thoroughly by the FDA. Given that the most common outpatient laboratory abnormality is elevated liver transaminases, a sign of hepatocellular toxicity; it is not surprising that some of these products end up causing hepatic dysfunction, especially when taken in large volume. There are numerous herbal supplements that are hepatotoxic, however, these medications have a much more significant effect in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome patients, which is secondary to depleted glutathione. We present a rare case of drug induced hepatitis secondary to herbal medications used to treat HIV and elucidate the role of glutathione depletion in immunocompromised patients.

  5. A rare cause of drug-induced hepatitis in an immunocompromised patient and the role of glutathione

    PubMed Central

    Senadhi, Viplove; Arora, Deepika; Arora, Manish; Marsh, Franklin

    2012-01-01

    The Food and Drug Administration (FDA) has issued a warning on numerous herbal drugs, including many popular products at General Nutrition Centers (GNC), regarding unstudied hepatotoxicity. There have been recent reports of GNC products such as hydroxycut and herbalife, causing drug-induced hepatitis. Herbal medications are over-the-counter products and are not investigated thoroughly by the FDA. Given that the most common outpatient laboratory abnormality is elevated liver transaminases, a sign of hepatocellular toxicity; it is not surprising that some of these products end up causing hepatic dysfunction, especially when taken in large volume. There are numerous herbal supplements that are hepatotoxic, however, these medications have a much more significant effect in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome patients, which is secondary to depleted glutathione. We present a rare case of drug induced hepatitis secondary to herbal medications used to treat HIV and elucidate the role of glutathione depletion in immunocompromised patients. PMID:22993667

  6. LOSS OF L-FABP, SCP-2/SCP-X, OR BOTH INDUCES HEPATIC LIPID ACCUMULATION IN FEMALE MICE

    PubMed Central

    Martin, Gregory G.; Atshaves, Barbara P.; Landrock, Kerstin K.; Landrock, Danilo; Schroeder, Friedhelm; Kier, Ann B.

    2015-01-01

    Although roles for both sterol carrier protein-2/sterol carrier protein-x (SCP-2/SCP-x) and liver fatty acid binding protein (L-FABP) have been proposed in hepatic lipid accumulation, individually ablating these genes has been complicated by concomitant alterations in the other gene product(s). For example, ablating SCP2/SCP-x induces upregulation of L-FABP in female mice. Therefore, the impact of ablating SCP-2/SCP-x (DKO) or L-FABP (LKO) individually or both together (TKO) was examined in female mice. Loss of SCP-2/SCP-x (DKO, TKO) more so than loss of L-FABP alone (LKO) increased hepatic total lipid and total cholesterol content, especially cholesteryl ester. Hepatic accumulation of nonesterified long chain fatty acids (LCFA) and phospholipids occurred only in DKO and TKO mice. Loss of SCP-2/SCP-x (DKO, TKO) increased serum total lipid primarily by increasing triglycerides. Altered hepatic level of proteins involved in cholesterol uptake, efflux, and/or secretion was observed, but did not compensate for the loss of L-FABP, SCP-2/SCP-x or both. However, synergistic responses were not seen with the combinatorial knock out animals—suggesting that inhibiting SCP-2/SCP-x is more correlative with hepatic dysfunction than L-FABP. The DKO- and TKO-induced hepatic accumulation of cholesterol and long chain fatty acids shared significant phenotypic similarities with non-alcoholic fatty liver disease (NAFLD). PMID:26116377

  7. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism

    DOE PAGES

    Shin, Andrew C.; Fasshauer, Martin; Filatova, Nika; ...

    2014-10-09

    Circulating branched-chain amino acid (BCAA) levels are elevated in obesity and diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway in the liver. Selective induction of hypothalamic insulin signaling in rats as well as inducible and lifelong genetic modulation of brain insulin receptor expression in mice both demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Further, short-term overfeedingmore » impairs the ability of brain insulin to lower circulating BCAA levels in rats. Chronic high-fat feeding in primates and obesity and/or type 2 diabetes in humans is associated with reduced BCKDH protein expression in liver, further supporting the concept that decreased hepatic BCKDH is a primary cause of increased plasma BCAA levels in insulin-resistant states. These findings demonstrate that neuroendocrine pathways control BCAA homeostasis and that hypothalamic insulin resistance can be a cause of impaired BCAA metabolism in obesity and diabetes.« less

  8. Brain insulin lowers circulating BCAA levels by inducing hepatic BCAA catabolism

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Shin, Andrew C.; Fasshauer, Martin; Filatova, Nika

    Circulating branched-chain amino acid (BCAA) levels are elevated in obesity and diabetes and are a sensitive predictor for type 2 diabetes. Here we show in rats that insulin dose-dependently lowers plasma BCAA levels through induction of protein expression and activity of branched-chain α-keto acid dehydrogenase (BCKDH), the rate-limiting enzyme in the BCAA degradation pathway in the liver. Selective induction of hypothalamic insulin signaling in rats as well as inducible and lifelong genetic modulation of brain insulin receptor expression in mice both demonstrate that brain insulin signaling is a major regulator of BCAA metabolism by inducing hepatic BCKDH. Further, short-term overfeedingmore » impairs the ability of brain insulin to lower circulating BCAA levels in rats. Chronic high-fat feeding in primates and obesity and/or type 2 diabetes in humans is associated with reduced BCKDH protein expression in liver, further supporting the concept that decreased hepatic BCKDH is a primary cause of increased plasma BCAA levels in insulin-resistant states. These findings demonstrate that neuroendocrine pathways control BCAA homeostasis and that hypothalamic insulin resistance can be a cause of impaired BCAA metabolism in obesity and diabetes.« less

  9. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity

    USDA-ARS?s Scientific Manuscript database

    The etiology of type 2 diabetes often involves diet-induced obesity (DIO), which is associated with elevated plasma fatty acids and lipoprotein associated triglycerides. Since aberrant hepatic fatty acid uptake may contribute to this, we investigated whether increased expression of a fatty acid tran...

  10. Comparison of imatinib, nilotinib and silymarin in the treatment of carbon tetrachloride-induced hepatic oxidative stress, injury and fibrosis.

    PubMed

    Shaker, Mohamed E; Zalata, Khaled R; Mehal, Wajahat Z; Shiha, Gamal E; Ibrahim, Tarek M

    2011-04-15

    Effective and well-tolerated anti-fibrotic drugs are currently lacking. Therefore, this study was carried out to investigate the potential anti-fibrotic effects of imatinib, nilotinib and silymarin on established hepatic fibrosis in the carbon tetrachloride (CCl(4)) rat model. Male Wistar rats received intraperitoneal injections of CCl(4) twice weekly for 8weeks, as well as daily intraperitoneal treatments of imatinib (10 and 20mg/kg), nilotinib (10 and 20mg/kg) and silymarin (100mg/kg) during the last 4weeks of CCl(4)-intoxication. At the end of the study, hepatic damage was evaluated by analysis of liver function tests and hepatic oxidative stress parameters. Hepatic fibrosis was evaluated by histopathology and morphometry, as well as collagen and 4-hydroxyproline contents. Nilotinib (20mg/kg) was the most effective treatment to counteract CCl(4)-induced hepatic injury as indicated by liver function tests and histopathology. Nilotinib (10mg/kg), nilotinib (20mg/kg) and silymarin (100mg/kg) treatments reduced the mean score of hepatic fibrosis by 31%, 68% and 47%, respectively, and hepatic collagen content by 47%, 49% and 18%, respectively in CCl(4)-treated rats. Hepatic morphometric evaluation and 4-hydroxyproline content revealed that CCl(4)-induced fibrosis was ameliorated significantly by nilotinib (20mg/kg) and imatinib (20mg/kg). Unlike nilotinib, imatinib (20mg/kg) showed some sort of hepatic injury evidenced by elevation of serum aminotransferases and total bilirubin levels, and hepatic total nitrate/nitrite content, as well as characteristic anisonucleosis visualized with the hematoxylin-eosin staining. In conclusion, this study provides the evidence that nilotinib exerts anti-fibrotic activity and suggests that it may be valuable in the treatment of hepatic fibrosis in humans. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice.

    PubMed

    Yasuda, Makiko; Gan, Lin; Chen, Brenden; Kadirvel, Senkottuvelan; Yu, Chunli; Phillips, John D; New, Maria I; Liebow, Abigail; Fitzgerald, Kevin; Querbes, William; Desnick, Robert J

    2014-05-27

    The acute hepatic porphyrias are inherited disorders of heme biosynthesis characterized by life-threatening acute neurovisceral attacks. Factors that induce the expression of hepatic 5-aminolevulinic acid synthase 1 (ALAS1) result in the accumulation of the neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG), which recent studies indicate are primarily responsible for the acute attacks. Current treatment of these attacks involves i.v. administration of hemin, but a faster-acting, more effective, and safer therapy is needed. Here, we describe preclinical studies of liver-directed small interfering RNAs (siRNAs) targeting Alas1 (Alas1-siRNAs) in a mouse model of acute intermittent porphyria, the most common acute hepatic porphyria. A single i.v. dose of Alas1-siRNA prevented the phenobarbital-induced biochemical acute attacks for approximately 2 wk. Injection of Alas1-siRNA during an induced acute attack significantly decreased plasma ALA and PBG levels within 8 h, more rapidly and effectively than a single hemin infusion. Alas1-siRNA was well tolerated and a therapeutic dose did not cause hepatic heme deficiency. These studies provide proof-of-concept for the clinical development of RNA interference therapy for the prevention and treatment of the acute attacks of the acute hepatic porphyrias.

  12. Hepatic Scavenger Receptor BI Protects Against Polymicrobial-induced Sepsis through Promoting LPS Clearance in Mice*

    PubMed Central

    Guo, Ling; Zheng, Zhong; Ai, Junting; Huang, Bin; Li, Xiang-An

    2014-01-01

    Recent studies revealed that scavenger receptor BI (SR-BI or Scarb1) plays a critical protective role in sepsis. However, the mechanisms underlying this protection remain largely unknown. In this study, using Scarb1I179N mice, a mouse model specifically deficient in hepatic SR-BI, we report that hepatic SR-BI protects against cecal ligation and puncture (CLP)-induced sepsis as shown by 75% fatality in Scarb1I179N mice, but only 21% fatality in C57BL/6J control mice. The increase in fatality in Scarb1I179N mice was associated with an exacerbated inflammatory cytokine production. Further study demonstrated that hepatic SR-BI exerts its protection against sepsis through its role in promoting LPS clearance without affecting the inflammatory response in macrophages, the glucocorticoid production in adrenal glands, the leukocyte recruitment to peritoneum or the bacterial clearance in liver. Our findings reveal hepatic SR-BI as a critical protective factor in sepsis and point out that promoting hepatic SR-BI-mediated LPS clearance may provide a therapeutic approach for sepsis. PMID:24719333

  13. Ameliorative Effect of Gallic Acid on Cyclophosphamide-Induced Oxidative Injury and Hepatic Dysfunction in Rats

    PubMed Central

    Olayinka, Ebenezer Tunde; Ore, Ayokanmi; Ola, Olaniyi Solomon; Adeyemo, Oluwatobi Adewumi

    2015-01-01

    Cyclophosphamide (CP), a bifunctional alkylating agent used in chemotherapy has been reported to induce organ toxicity mediated by generation of reactive oxygen species and oxidative stress. Gallic acid (GA), a phenolic substance, is a natural antioxidant with proven free radical scavenging activity and offers protection against oxidative damage. This research study was designed to investigate the ameliorative effect of GA against CP-induced toxicity in rats. Twenty-five male Wistar rats (180–200 g) were randomized into five treatment groups: (A) control, (B) CP, 2 mg/kg body weight (b.w.), (C) pre-treatment with GA (20 mg/kg b.w.) for seven days followed by CP (2 mg/kg b.w.) for seven days, (D) co-treatment with GA (20 mg/kg b.w) and CP (2 mg/kg b.w.) for seven days, and (E) GA (20 mg/kg b.w.) for seven days. CP induced marked renal and hepatic damages as plasma levels of urea, creatinine, bilirubin and activities of AST, ALT, ALP and GGT were significantly elevated (p < 0.05) in the CP-treated group relative to control. In addition, hepatic levels of GSH, vitamin C and activities of SOD, catalase and GST significantly reduced in the CP-treated group when compared with control. This was accompanied with a significant increase in hepatic lipid peroxidation. The restoration of the markers of renal and hepatic damages as well as antioxidant indices and lipid peroxidation by pre- and co-treatment with GA clearly shows that GA offers ameliorative effect by scavenging the reactive oxygen species generated by CP. This protective effect may be attributed to the antioxidant property of gllic acid. PMID:29083393

  14. [Activity of liver mitochondrial NAD+-dependent dehydrogenases of the krebs cycle in rats with acetaminophen-induced hepatitis developed under conditions of alimentary protein deficiency].

    PubMed

    Voloshchuk, O N; Kopylchuk, G P

    2016-01-01

    Activity of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, malate dehydrogenase, and the NAD(+)/NADН ratio were studied in the liver mitochondrial fraction of rats with toxic hepatitis induced by acetaminophen under conditions of alimentary protein deprivation. Acetaminophen-induced hepatitis was characterized by a decrease of isocitrate dehydrogenase, α-ketoglutarate dehydrogenase and malate dehydrogenase activities, while the mitochondrial NAD(+)/NADН ratio remained at the control level. Modeling of acetaminophen-induced hepatitis in rats with alimentary protein caused a more pronounced decrease in the activity of NAD(+)-dependent dehydrogenases studied and a 2.2-fold increase of the mitochondrial NAD(+)/NADН ratio. This suggests that alimentary protein deprivation potentiated drug-induced liver damage.

  15. Nanostructure of DNA repair foci revealed by superresolution microscopy.

    PubMed

    Sisario, Dmitri; Memmel, Simon; Doose, Sören; Neubauer, Julia; Zimmermann, Heiko; Flentje, Michael; Djuzenova, Cholpon S; Sauer, Markus; Sukhorukov, Vladimir L

    2018-06-12

    Induction of DNA double-strand breaks (DSBs) by ionizing radiation leads to formation of micrometer-sized DNA-repair foci, whose organization on the nanometer-scale remains unknown because of the diffraction limit (∼200 nm) of conventional microscopy. Here, we applied diffraction-unlimited, direct stochastic optical-reconstruction microscopy ( dSTORM) with a lateral resolution of ∼20 nm to analyze the focal nanostructure of the DSB marker histone γH2AX and the DNA-repair protein kinase (DNA-PK) in irradiated glioblastoma multiforme cells. Although standard confocal microscopy revealed substantial colocalization of immunostained γH2AX and DNA-PK, in our dSTORM images, the 2 proteins showed very little (if any) colocalization despite their close spatial proximity. We also found that γH2AX foci consisted of distinct circular subunits ("nanofoci") with a diameter of ∼45 nm, whereas DNA-PK displayed a diffuse, intrafocal distribution. We conclude that γH2AX nanofoci represent the elementary, structural units of DSB repair foci, that is, individual γH2AX-containing nucleosomes. dSTORM-based γH2AX nanofoci counting and distance measurements between nanofoci provided quantitative information on the total amount of chromatin involved in DSB repair as well as on the number and longitudinal distribution of γH2AX-containing nucleosomes in a chromatin fiber. We thus estimate that a single focus involves between ∼0.6 and ∼1.1 Mbp of chromatin, depending on radiation treatment. Because of their ability to unravel the nanostructure of DSB-repair foci, dSTORM and related single-molecule localization nanoscopy methods will likely emerge as powerful tools in biology and medicine to elucidate the effects of DNA damaging agents in cells.-Sisario, D., Memmel, S., Doose, S., Neubauer, J., Zimmermann, H., Flentje, M., Djuzenova, C. S., Sauer, M., Sukhorukov, V. L. Nanostructure of DNA repair foci revealed by superresolution microscopy.

  16. High-fat diet-induced hepatic steatosis reduces glucagon receptor content in rat hepatocytes: potential interaction with acute exercise

    PubMed Central

    Charbonneau, Alexandre; Unson, Cecilia G; Lavoie, Jean-Marc

    2007-01-01

    Studies have revealed that high-fat (HF) diets promote hyperglycaemia, whole-body insulin resistance and non-alcoholic fatty liver disease (NAFLD). Recently, hepatic glucagon resistance has been shown to occur in rats fed a HF diet. More precisely, diet-induced obesity (DIO) reduces the number of hepatic plasma membrane glucagon receptors (GR), which results in a diminished response to glucagon during a hyperglucagonaemic clamp. The present study was undertaken to test the hypothesis that a HF-DIO is associated with a desensitization and destruction of the hepatic GR. We also hypothesized that a single bout of endurance exercise would modify the GR cellular distribution under our DIO model. Male rats were either fed a standard (sd) or a HF diet for two weeks. Each group was subdivided into a non-exercised (Rest) and an acute exercised (EX) group. The HF diet resulted in a reduction of total hepatic GR (55%) and hepatic plasma membrane GR protein content (20%). These changes were accompanied by a significant increase in endosomal and lysosomal GR content with the feeding of a HF diet. The reduction of GR plasma membrane as well as the increase in endosomal GR was strongly correlated with an increase of PKC-α, suggesting a role of PKC-α in GR desensitization. EX increased significantly PKC-α protein content in both diets, suggesting a role of PKC-α in EX-induced GR desensitization. The present results suggest that liver lipid infiltration plays a role in reducing glucagon action in the liver through a reduction in total cellular and plasma membrane GR content. Furthermore, the GR desensitization observed in our in vivo model of HF diet-induced hepatic steatosis and in EX individuals may be regulated by PKC-α. PMID:17053032

  17. Diabetes-induced hepatic pathogenic damage, inflammation, oxidative stress, and insulin resistance was exacerbated in zinc deficient mouse model.

    PubMed

    Zhang, Chi; Lu, Xuemian; Tan, Yi; Li, Bing; Miao, Xiao; Jin, Litai; Shi, Xue; Zhang, Xiang; Miao, Lining; Li, Xiaokun; Cai, Lu

    2012-01-01

    Zinc (Zn) deficiency often occurs in the patients with diabetes. Effects of Zn deficiency on diabetes-induced hepatic injury were investigated. Type 1 diabetes was induced in FVB mice with multiple low-dose streptozotocin. Hyperglycemic and age-matched control mice were treated with and without Zn chelator, N,N,N',N'-tetrakis (2-pyridylemethyl) ethylenediamine (TPEN), at 5 mg/kg body-weight daily for 4 months. Hepatic injury was examined by serum alanine aminotransferase (ALT) level and liver histopathological and biochemical changes. Hepatic Zn deficiency (lower than control level, p<0.05) was seen in the mice with either diabetes or TPEN treatment and more evident in the mice with both diabetes and TPEN. Zn deficiency exacerbated hepatic injuries, shown by further increased serum ALT, hepatic lipid accumulation, inflammation, oxidative damage, and endoplasmic reticulum stress-related cell death in Diabetes/TPEN group compared to Diabetes alone. Diabetes/TPEN group also showed a significant decrease in nuclear factor-erythroid 2-related factor 2 (Nrf2) expression and transcription action along with significant increases in Akt negative regulators, decrease in Akt and GSK-3β phosphorylation, and increase in nuclear accumulation of Fyn (a Nrf2 negative regulator). In vitro study with HepG2 cells showed that apoptotic effect of TPEN at 0.5-1.0 µM could be completely prevented by simultaneous Zn supplementation at the dose range of 30-50 µM. Zn is required for maintaining Akt activation by inhibiting the expression of Akt negative regulators; Akt activation can inhibit Fyn nuclear translocation to export nuclear Nrf2 to cytoplasm for degradation. Zn deficiency significantly enhanced diabetes-induced hepatic injury likely through down-regulation of Nrf2 function.

  18. Localized air foci in the lower thorax in the patients with pneumothorax: skip pneumothoraces.

    PubMed

    Higuchi, Takeshi; Takahashi, Naoya; Kiguchi, Takao; Shiotani, Motoi; Maeda, Haruo

    2013-08-01

    To investigate the characteristics and imaging features of localized air foci in the lower thorax in patients with pneumothorax using thin-section multidetector computed tomography. Of 10,547 consecutive CT examinations comprising the chest, the CT scans of 146 patients with ordinary pneumothoraces were identified and retrospectively evaluated. The study group included 110 male and 36 female patients (mean age, 50 years; range, 1-93 years). All examinations were performed at our institution between January 2009 and December 2009. Cause of pneumothorax was classified as traumatic or non-traumatic. Localized air foci in the lower thorax were defined as being localized air collections in the lower thorax that did not appear to be adjacent to the lung. If these criteria were met, the shape, size, location laterality, and number of foci were evaluated. Associations with trauma, sex, severity of the pneumothorax, and laterality were evaluated using the χ(2) test. All P values <0.05 were considered significant. Localized air foci in the lower thorax presented as slit-like or small ovoid air collections in the lowest part of the pleural space. These foci were observed in 79/146 (54.1%) patients. The traumatic pneumothoraces group showed a higher prevalence of these features than the non-traumatic group. Some foci that were situated in the anterior part mimicked the appearance of free intraperitoneal air. Patients with pneumothorax commonly had localized air foci in the lower thorax. Because such foci can mimic pneumoperitoneum, accurate recognition of them is required to avoid confusion with free intraperitoneal air, especially in traumatic cases. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Orlistat-induced fulminant hepatic failure.

    PubMed

    Sall, D; Wang, J; Rashkin, M; Welch, M; Droege, C; Schauer, D

    2014-12-01

    Orlistat was approved by the Food and Drug Administration in 1998 and has been shown to be superior to placebo in achieving weight loss. It is generally well tolerated. However, severe liver injury has been reported. We present a case of hepatic failure in a patient taking orlistat. A 54-year-old African-American woman with hypertension presented with hepatic failure. She had noticed increasing fatigue, jaundice and confusion. She used alcohol sparingly and denied tobacco or illicit drug use, but had been taking over-the-counter orlistat for the past two months. Physical examination revealed scleral icterus, jaundice, asterixis and slow speech. Laboratory testing showed markedly abnormal liver function tests with coagulopathy. Acute viral and autoimmune serologies were negative, as was toxicology screen. Liver biopsy showed necrotic hepatic parenchyma likely secondary to drug toxicity. Based upon her clinical presentation and time course, the pattern of liver injury seen on liver biopsy and lack of an alternative plausible explanation, her liver failure was most likely associated with orlistat use. She continued to deteriorate and ultimately underwent orthotopic liver transplantation. Fourteen cases of severe liver injury associated with orlistat use have been reported, four of which are detailed in the literature. This is the second published case of liver failure associated with over-the-counter orlistat usage. Clinicians should be aware of the growing number of cases associating liver injury and orlistat use and carefully monitor their patients on this medication for signs of hepatic dysfunction. © 2014 The Authors. Clinical Obesity © 2014 World Obesity.

  20. Immune responses to plague infection in wild Rattus rattus, in Madagascar: a role in foci persistence?

    PubMed

    Andrianaivoarimanana, Voahangy; Telfer, Sandra; Rajerison, Minoarisoa; Ranjalahy, Michel A; Andriamiarimanana, Fehivola; Rahaingosoamamitiana, Corinne; Rahalison, Lila; Jambou, Ronan

    2012-01-01

    Plague is endemic within the central highlands of Madagascar, where its main reservoir is the black rat, Rattus rattus. Typically this species is considered susceptible to plague, rapidly dying after infection inducing the spread of infected fleas and, therefore, dissemination of the disease to humans. However, persistence of transmission foci in the same area from year to year, supposes mechanisms of maintenance among which rat immune responses could play a major role. Immunity against plague and subsequent rat survival could play an important role in the stabilization of the foci. In this study, we aimed to investigate serological responses to plague in wild black rats from endemic areas of Madagascar. In addition, we evaluate the use of a recently developed rapid serological diagnostic test to investigate the immune response of potential reservoir hosts in plague foci. We experimentally infected wild rats with Yersinia pestis to investigate short and long-term antibody responses. Anti-F1 IgM and IgG were detected to evaluate this antibody response. High levels of anti-F1 IgM and IgG were found in rats one and three weeks respectively after challenge, with responses greatly differing between villages. Plateau in anti-F1 IgM and IgG responses were reached for as few as 500 and 1500 colony forming units (cfu) inoculated respectively. More than 10% of rats were able to maintain anti-F1 responses for more than one year. This anti-F1 response was conveniently followed using dipsticks. Inoculation of very few bacteria is sufficient to induce high immune response in wild rats, allowing their survival after infection. A great heterogeneity of rat immune responses was found within and between villages which could heavily impact on plague epidemiology. In addition, results indicate that, in the field, anti-F1 dipsticks are efficient to investigate plague outbreaks several months after transmission.

  1. Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production.

    PubMed

    Shishova, Ekaterina Y; Stoll, Janis M; Ersoy, Baran A; Shrestha, Sudeep; Scapa, Erez F; Li, Yingxia; Niepel, Michele W; Su, Ya; Jelicks, Linda A; Stahl, Gregory L; Glicksman, Marcie A; Gutierrez-Juarez, Roger; Cuny, Gregory D; Cohen, David E

    2011-08-01

    Phosphatidylcholine transfer protein (PC-TP, synonym StARD2) is a highly specific intracellular lipid binding protein that is enriched in liver. Coding region polymorphisms in both humans and mice appear to confer protection against measures of insulin resistance. The current study was designed to test the hypotheses that Pctp-/- mice are protected against diet-induced increases in hepatic glucose production and that small molecule inhibition of PC-TP recapitulates this phenotype. Pctp-/- and wildtype mice were subjected to high-fat feeding and rates of hepatic glucose production and glucose clearance were quantified by hyperinsulinemic euglycemic clamp studies and pyruvate tolerance tests. These studies revealed that high-fat diet-induced increases in hepatic glucose production were markedly attenuated in Pctp-/- mice. Small molecule inhibitors of PC-TP were synthesized and their potencies, as well as mechanism of inhibition, were characterized in vitro. An optimized inhibitor was administered to high-fat-fed mice and used to explore effects on insulin signaling in cell culture systems. Small molecule inhibitors bound PC-TP, displaced phosphatidylcholines from the lipid binding site, and increased the thermal stability of the protein. Administration of the optimized inhibitor to wildtype mice attenuated hepatic glucose production associated with high-fat feeding, but had no activity in Pctp-/- mice. Indicative of a mechanism for reducing glucose intolerance that is distinct from commonly utilized insulin-sensitizing agents, the inhibitor promoted insulin-independent phosphorylation of key insulin signaling molecules. These findings suggest PC-TP inhibition as a novel therapeutic strategy in the management of hepatic insulin resistance. Copyright © 2011 American Association for the Study of Liver Diseases.

  2. Sildenafil protects against bile duct ligation induced hepatic fibrosis in rats: Potential role for silent information regulator 1 (SIRT1).

    PubMed

    Abd El Motteleb, Dalia M; Ibrahim, Islam A A E-H; Elshazly, Shimaa M

    2017-11-15

    Hepatic fibrosis is a potential health problem that may end with life-threatening cirrhosis and primary liver cancer. Recent studies point out to the protective effects of silent information regulator1 (SIRT1), against different models of organs fibrosis. This work aimed to investigate the possible protective effect of sildenafil (SIRT1 activator) against hepatic fibrosis induced by bile duct ligation (BDL). Firstly, three different doses of sildenafil (5, 10, 20mg/kg/day) were investigated; to detect the most protective one against BDL induced liver dysfunction and hepatic fibrosis. The most protective dose is then used; to study its effect on BDL induced SIRT1 downregulation, imbalance of oxidant/antioxidant status, increased inflammatory cytokines and fibrosis. Sildenafil (20mg/kg/day) was the most protective one, it caused upregulation of SIRT1, reduction of hepatic malondialdehyde (MDA) content, increase in expression of nuclear factor erythroid 2-related factor 2 (Nrf2), hemeoxygenease (HO)-1, reduced glutathione (GSH) content and superoxide dismutase (SOD) activity. Hepatic content of tumor necrosis factor-α (TNF-α) and nuclear factor κB (NFκB) expression & content displayed significant reductions with sildenafil treatment, Furthermore, sildenafil caused marked reductions of transforming growth factor (TGF)-β content, expression of plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), α-smooth muscle actin (α-SMA), fibronectin, collagen I (α1) and hydroxyproline content. However, sildenafil protective effects were significantly reduced by co-administration of EX527 (SIRT1 inhibitor). Our work showed, for the first time that, sildenafil has promising protective effects against BDL induced liver dysfunction and hepatic fibrosis. These effects may be, in part, mediated by up regulation of SIRT1. Copyright © 2017. Published by Elsevier Inc.

  3. [EFFECT OF ACETYLCYSTEINE, CORVITIN AND THEIR COMBINATION ON THE FUNCTIONAL STATE OF LIVER IN RATS WITH PARACETAMOL INDUCED TOXIC HEPATITIS].

    PubMed

    Ghonghadze, M; Antelava, N; Liluashvili, K; Okujava, M; Pachkoria, K

    2017-02-01

    Nowadays drug-induced hepatotoxicity is urgent problem worldwide. Currently more than 1000 drugs are hepatotoxic and most often are the reason of acute fulminant hepatitis and hepatocellular failure, the states requiring liver transplantation. The paracetamol induced liver toxicity is related with accumulation of its toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is the free radical and enhances peroxidation of lipids, disturbs the energy status and causes death of hepatocytes. During our research we investigated and assessed the efficacy of acetylcysteine, corvitin and their combination in rat model of paracetamol induced acute toxic hepatitis. The study was performed on mature white male Wistar rates with body mass 150-180 g. 50 rats were randomly divided into 5 groups (10 rats in each group). To get the model of acute toxic hepatitis single intraperitoneal injection of paracetamol solution was used (750 mg/kg). Toxic hepatitis was treated with intrapertoneal administration of 40mg/kg acetylcysteine or 100mg/kg corvitin, as well as with combination of these drugs. Monotherapy with acetylcysteine and corvitin of paracetamol induced toxic hepatitis improved the liver function, decreased relative mass of the liver and animal mortality. The treatment of toxic hepatitis was most effective in the case of simultaneous administration of acetylcysteine and corvitin. The normal value of laboratory tests (ALT, ACT, alkaline phosphatase, total and unconjugated bilirubin) was reached and mortality was not more observed. On the bases of obtained data was concluded that acetylcysteine and corvitin have almost equal hepatoprotective activity. The combination of two drugs actually improves the liver function. The most pronounced hepatoprotective effect may be due to synergic action of acetylcysteine and corvitin and such regime can be recommended for correction of liver function.

  4. Aldehyde dedydrogenase-2 plays a beneficial role in ameliorating chronic alcohol-induced hepatic steatosis and inflammation through regulation of autophagy.

    PubMed

    Guo, Rui; Xu, Xihui; Babcock, Sara A; Zhang, Yingmei; Ren, Jun

    2015-03-01

    Mitochondrial aldehyde dehydrogenase (ALDH2) plays a critical role in the detoxification of the ethanol metabolite acetaldehyde. This study was designed to examine the impact of global ALDH2 overexpression on alcohol-induced hepatic steatosis. Wild type Friend virus B (FVB) and ALDH2 transgenic mice were placed on a 4% alcohol or control diet for 12 weeks. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin and cholesterol, hepatic triglyceride, steatosis, fat metabolism-related proteins, pro-inflammatory cytokines, glutathione (GSH), oxidized glutathione (GSSG), autophagy and autophagy signalling were examined. The role of autophagy was evaluated in alcohol dehydrogenase 1 (ADH1)-transfected human hepatocellular liver carcinoma cells (VA-13) treated with or without the autophagy inducer rapamycin and lysosomal inhibitors. Chronic alcohol intake led to elevated AST-, ALT-levels, bilirubin, AST/ALT ratio, cholesterol, hepatic triglycerides and hepatic fat deposition as evidenced by H&E and Oil Red O staining. Hepatic fat deposition was associated with disturbed levels of fat metabolism-related proteins (fatty acid synthase, SCD1), upregulated interleukin-6, TNF-α, cyclooxygenase, oxidative stress, and loss of autophagy, effects which were attenuated or ablated by the ALDH2 transgene. Moreover, ethanol (100 mM) and acetaldehyde (100 and 500 μM) increased levels of IL-6 and IFN-γ, and suppressed autophagy in VA-13 cells, effects which were markedly alleviated by rapamycin. In addition, lysosomal inhibitors mimicked ethanol-induced p62 accumulation with little additive effect with ethanol. Ethanol significantly suppressed LC3 conversion in the presence of lysosomal inhibitors. In summary, our results revealed that ALDH2 plays a beneficial role in ameliorating chronic alcohol intake-induced hepatic steatosis and inflammation through regulation of autophagy. Copyright © 2014 European Association for the Study of the Liver

  5. Reliability of a Fully Automated Interpretation of γ -H2AX Foci in Lymphocytes of Moderately Trained Subjects under Resting Conditions.

    PubMed

    Heydenreich, Juliane; Otto, Christoph; Mayer, Frank; Carlsohn, Anja

    2014-01-01

    Background. Analysis of γ-H2AX foci is a promising approach to evaluate exercise-induced DNA damage. However, baseline levels and day-to-day variability of γ-H2AX foci have not been investigated in healthy subjects at rest. Methods. Blood was taken from eight moderately trained healthy males (29 ± 3 yrs, 1.84 ± 0.03 m, and 85 ± 6 kg) at two separate days (M1/M2) after 24-hour exercise cessation. Number of γ-H2AX foci per 100 lymphocytes (N), number of foci per affected lymphocyte (NAL), percentage of affected lymphocytes (PAL), and diameter (D) of γ-H2AX foci were analyzed (mean ± SD). Differences between M1 and M2 were analyzed using paired t-tests (α = 0.05). Day-to-day variability was evaluated by calculating the coefficients of variation (CV%), bias, and limits of agreement (LoA). Results. There were no statistically significant differences between M1 (N: 7.6 ± 4.4, NAL: 1.2 ± 0.2, PAL: 5.9 ± 2.6%, and D: 0.63 ± 0.07) and M2 (N: 8.4 ± 4.6, NAL: 1.3 ± 0.1, PAL: 6.9 ± 4.2%, and D: 0.66 ± 0.06). CV was calculated to be 98.5% (N), 88.9% (PAL), 11.3% (NAL), and 8.0% (D). Bias (LoA) was 0.75 (-15.2/13.7), -0.02 (-0.36/0.33), -1.0 (-11.9/9.9), and -0.04 (-0.16/0.09), respectively. Conclusions. Background level in healthy subjects is approximately 0.07 to 0.09 γ-H2AX foci/cell. NAL and D are reliable measures.

  6. Protective effect of Curcuma longa L. extract on CCl4-induced acute hepatic stress.

    PubMed

    Lee, Geum-Hwa; Lee, Hwa-Young; Choi, Min-Kyung; Chung, Han-Wool; Kim, Seung-Wook; Chae, Han-Jung

    2017-02-01

    The Curcuma longa L. (CLL) rhizome has long been used to treat patients with hepatic dysfunction. CLL is a member of the ginger family of spices that are widely used in China, India, and Japan, and is a common spice, coloring, flavoring, and traditional medicine. This study was performed to evaluate the hepatoprotective activity of CLL extract and its active component curcumin in an acute carbon tetrachloride (CCl 4 )-induced liver stress model. Acute hepatic stress was induced by a single intraperitoneal injection of CCl 4 (0.1 ml/kg body weight) in rats. CLL extract was administered once a day for 3 days at three dose levels (100, 200, and 300 mg/kg/day) and curcumin was administered once a day at the 200 mg/kg/day. We performed alanine transaminase (ALT) and aspartate transaminase (AST). activity analysis and also measured total lipid, triglyceride, and cholesterol levels, and lipid peroxidation. At 100 g CLL, the curcuminoid components curcumin (901.63 ± 5.37 mg/100 g), bis-demethoxycurcumin (108.28 ± 2.89 mg/100 g), and demethoxycurcumin (234.85 ± 1.85 mg/100 g) were quantified through high liquid chromatography analysis. In CCl 4 -treated rats, serum AST and ALT levels increased 2.1- and 1.2-fold compared with the control. AST but not ALT elevation induced by CCl 4 was significantly alleviated in CLL- and curcumin-treated rats. Peroxidation of membrane lipids in the liver was significantly prevented by CLL (100, 200, and 300 mg/kg/day) on tissue lipid peroxidation assay and immunostaining with anti-4HNE antibody. We found that CLL extract and curcumin exhibited significant protection against liver injury by improving hepatic superoxide dismutase (p < 0.05) and glutathione peroxidase activity, and glutathione content in the CCl 4 -treated group (p < 0.05), leading to a reduced lipid peroxidase level. Our data suggested that CLL extract and curcumin protect the liver from acute CCl 4 -induced injury in a rodent model by suppressing

  7. Involvement of the TNF and FasL produced by CD11b Kupffer cells/macrophages in CCl4-induced acute hepatic injury.

    PubMed

    Sato, Atsushi; Nakashima, Hiroyuki; Nakashima, Masahiro; Ikarashi, Masami; Nishiyama, Kiyoshi; Kinoshita, Manabu; Seki, Shuhji

    2014-01-01

    We previously reported that F4/80(+) Kupffer cells are subclassified into CD68(+) Kupffer cells with phagocytic and ROS producing capacity, and CD11b(+) Kupffer cells with cytokine-producing capacity. Carbon tetrachloride (CCl4)-induced hepatic injury is a well-known chemical-induced hepatocyte injury. In the present study, we investigated the immunological role of Kupffer cells/macrophages in CCl4-induced hepatitis in mice. The immunohistochemical analysis of the liver and the flow cytometry of the liver mononuclear cells showed that clodronate liposome (c-lipo) treatment greatly decreased the spindle-shaped F4/80(+) or CD68(+) cells, while the oval-shaped F4/80+ CD11b(+) cells increased. Notably, severe hepatic injury induced by CCl4 was further aggravated by c-lipo-pretreatment. The population of CD11b(+) Kupffer cells/macrophages dramatically increased 24 hour (h) after CCl4 administration, especially in c-lipo-pretreated mice. The CD11b(+) Kupffer cells expressed intracellular TNF and surface Fas-ligand (FasL). Furthermore, anti-TNF Ab pretreatment (which decreased the FasL expression of CD11b(+) Kupffer cells), anti-FasL Ab pretreatment or gld/gld mice attenuated the liver injury induced by CCl4. CD1d-/- mouse and cell depletion experiments showed that NKT cells and NK cells were not involved in the hepatic injury. The adoptive transfer and cytotoxic assay against primary cultured hepatocytes confirmed the role of CD11b(+) Kupffer cells in CCl4-induced hepatitis. Interestingly, the serum MCP-1 level rapidly increased and peaked at six h after c-lipo pretreatment, suggesting that the MCP-1 produced by c-lipo-phagocytized CD68(+) Kupffer cells may recruit CD11b(+) macrophages from the periphery and bone marrow. The CD11b(+) Kupffer cells producing TNF and FasL thus play a pivotal role in CCl4-induced acute hepatic injury.

  8. Involvement of the TNF and FasL Produced by CD11b Kupffer Cells/Macrophages in CCl4-Induced Acute Hepatic Injury

    PubMed Central

    Sato, Atsushi; Nakashima, Hiroyuki; Nakashima, Masahiro; Ikarashi, Masami; Nishiyama, Kiyoshi; Kinoshita, Manabu; Seki, Shuhji

    2014-01-01

    We previously reported that F4/80+ Kupffer cells are subclassified into CD68+ Kupffer cells with phagocytic and ROS producing capacity, and CD11b+ Kupffer cells with cytokine-producing capacity. Carbon tetrachloride (CCl4)-induced hepatic injury is a well-known chemical-induced hepatocyte injury. In the present study, we investigated the immunological role of Kupffer cells/macrophages in CCl4-induced hepatitis in mice. The immunohistochemical analysis of the liver and the flow cytometry of the liver mononuclear cells showed that clodronate liposome (c-lipo) treatment greatly decreased the spindle-shaped F4/80+ or CD68+ cells, while the oval-shaped F4/80+ CD11b+ cells increased. Notably, severe hepatic injury induced by CCl4 was further aggravated by c-lipo-pretreatment. The population of CD11b+ Kupffer cells/macrophages dramatically increased 24 hour (h) after CCl4 administration, especially in c-lipo-pretreated mice. The CD11b+ Kupffer cells expressed intracellular TNF and surface Fas-ligand (FasL). Furthermore, anti-TNF Ab pretreatment (which decreased the FasL expression of CD11b+ Kupffer cells), anti-FasL Ab pretreatment or gld/gld mice attenuated the liver injury induced by CCl4. CD1d−/− mouse and cell depletion experiments showed that NKT cells and NK cells were not involved in the hepatic injury. The adoptive transfer and cytotoxic assay against primary cultured hepatocytes confirmed the role of CD11b+ Kupffer cells in CCl4-induced hepatitis. Interestingly, the serum MCP-1 level rapidly increased and peaked at six h after c-lipo pretreatment, suggesting that the MCP-1 produced by c-lipo-phagocytized CD68+ Kupffer cells may recruit CD11b+ macrophages from the periphery and bone marrow. The CD11b+ Kupffer cells producing TNF and FasL thus play a pivotal role in CCl4-induced acute hepatic injury. PMID:24667392

  9. Docosahexaenoic acid attenuates Western diet-induced hepatic fibrosis in Ldlr−/− mice by targeting the TGFβ-Smad3 pathway[S

    PubMed Central

    Lytle, Kelli A.; Depner, Christopher M.; Wong, Carmen P.; Jump, Donald B.

    2015-01-01

    DHA (22:6,ω3), but not EPA (20:5,ω3), attenuates Western diet (WD)-induced hepatic fibrosis in a Ldlr−/− mouse model of nonalcoholic steatohepatitis. We examined the molecular basis for the differential effect of dietary EPA and DHA on WD-induced hepatic fibrosis. DHA was more effective than EPA at preventing WD-induced effects on hepatic transcripts linked to fibrosis, including collagen 1A1 (Col1A1), transforming growth factor-β (TGFβ) signaling and proteins involved in remodeling the extracellular matrix, including metalloproteases, tissue inhibitors of metalloproteases, and lysyl oxidase subtypes. Examination of the TGFβ pathway showed that mice fed the WD supplemented with either olive oil or EPA had a significant (≥2.5-fold) increase in hepatic nuclear abundance of phospho-mothers against decapentaplegic homolog (Smad)3 when compared with mice fed the reference diet (RD); Smad3 is a key regulator of Col1A1 expression in stellate cells. In contrast, mice fed the WD supplemented with DHA had no increase in phospho-Smad3 when compared with mice fed the RD. Changes in hepatic phospho-Smad3 nuclear content correlated with proCol1A1 mRNA and protein abundance. Pretreatment of human LX2 stellate cells with DHA, but not other unsaturated fatty acids, blocked TGFβ1-mediated induction of Col1A1. In conclusion, DHA attenuates WD-induced fibrosis by targeting the TGFβ-Smad3-Col1A1 pathway in stellate cells. PMID:26315048

  10. CRACC-CRACC Interaction between Kupffer and NK Cells Contributes to Poly I:C/D-GalN Induced Hepatitis

    PubMed Central

    Li, Yangxi; Cao, Guoshuai; Zheng, Xiaodong; Wang, Jun; Wei, Haiming; Tian, Zhigang; Sun, Rui

    2013-01-01

    CD2-like receptor activating cytotoxic cells (CRACC) is known as a critical activating receptor of natural killer (NK) cells. We have previously reported that NK cells contribute to Poly I:C/D-galactosamine (D-GalN)-induced fulminant hepatitis. Since natural killer group 2, member D (NKG2D) is considered critical but not the only activating receptor for NK cells, we investigated the role of CRACC in this model. We found that CRACC was abundant on hepatic NK cells but with low expression levels on Kupffer cells under normal conditions. Expression of CRACC on NK cells and Kupffer cells was remarkably upregulated after poly I:C injection. Hepatic CRACC mRNA levels were also upregulated in Poly I:C/D-GalN-treated mice, and correlated positively with the serum alanine aminotransferase (ALT) levels. CRACC expression on Kupffer cells was specifically silenced by nano-particle encapsulated siRNA in vivo, which significantly reduced Poly I:C/D-GalN-induced liver injury. In co-culture experiments, it was further verified that silencing CRACC expression or blockade of CRACC activation by mAb reduced the production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Collectively, our findings suggest that CRACC-CRACC interaction between NK cells and resident Kupffer cells contributes to Poly I:C/D-GalN-induced fulminant hepatitis. PMID:24098802

  11. Hepatocyte-specific deletion of LASS2 protects against diet-induced hepatic steatosis and insulin resistance.

    PubMed

    Fan, Shaohua; Wang, Yanyan; Wang, Cun; Jin, Haojie; Wu, Zheng; Lu, Jun; Zhang, Zifeng; Sun, Chunhui; Shan, Qun; Wu, Dongmei; Zhuang, Juan; Sheng, Ning; Xie, Ying; Li, Mengqiu; Hu, Bin; Fang, Jingyuan; Zheng, Yuanlin; Qin, Wenxin

    2018-05-20

    Homo sapienslongevity assurance homolog 2 of yeast LAG1 (LASS2) is expressed mostly in human liver. Here, we explored roles of LASS2 in pathogenesis of hepatic steatosis. Hepatocyte-specific LASS2 knockout (LASS2 -/- ) mice were generated using Cre-LoxP system. LASS2 -/- and wild-type (WT) mice were fed with chow or high-fat diet (HFD). We found LASS2 -/- mice were resistant to HFD-induced hepatic steatosis and insulin resistance. In HFD-fed mice, LASS2 deficiency significantly inhibited p38 MAPK and ERK1/ERK2 signaling in mouse liver. This effect was mediated by a significant increase of V-ATPase activity and a decrease of ROS level. We also observed that elevated expression of LASS2 in mouse hepatocyte cell line AML12 obviously decreased V-ATPase activity and increased ROS level by activation of p38 MAPK and ERK1/ERK2 signaling. Our findings indicate that LASS2 plays an important role in the pathogenesis of diet-induced hepatic steatosis and is a potential novel target for prevention and intervention of liver diseases. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Hepatitis Virus Infections in Poultry.

    PubMed

    Yugo, Danielle M; Hauck, Ruediger; Shivaprasad, H L; Meng, Xiang-Jin

    2016-09-01

    acute, fatal infections in ducklings with a rapid decline within 1-2 hr and clinical and pathologic signs virtually indistinguishable from DHAV. DAstV-1 has only been recognized in the United Kingdom and recently in China, while DAstV-2 has been reported in ducks in the United States. FAdV, the causative agent of inclusion body hepatitis, is a Group I avian adenovirus in the genus Aviadenovirus. The affected birds have a swollen, friable, and discolored liver, sometimes with necrotic or hemorrhagic foci. Histologic lesions include multifocal necrosis of hepatocytes and acute hepatitis with intranuclear inclusion bodies in the nuclei of the hepatocytes. THV is a picornavirus that is likely the causative agent of turkey viral hepatitis. Currently there are more questions than answers about THV, and the pathogenesis and clinical impacts remain largely unknown. Future research in viral hepatic diseases of poultry is warranted to develop specific diagnostic assays, identify suitable cell culture systems for virus propagation, and develop effective vaccines.

  13. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver.

    PubMed

    Savransky, Vladimir; Bevans, Shannon; Nanayakkara, Ashika; Li, Jianguo; Smith, Philip L; Torbenson, Michael S; Polotsky, Vsevolod Y

    2007-10-01

    Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia (CIH) during sleep. OSA is associated with nonalcoholic steatohepatitis (NASH) in obese individuals and may contribute to progression of nonalcoholic fatty liver disease from steatosis to NASH. The purpose of this study was to examine whether CIH induces inflammatory changes in the liver in mice with diet-induced hepatic steatosis. C57BL/6J mice (n = 8) on a high-fat, high-cholesterol diet were exposed to CIH for 6 mo and were compared with mice on the same diet exposed to intermittent air (control; n = 8). CIH caused liver injury with an increase in serum ALT (461 +/- 58 U/l vs. 103 +/- 16 U/l in the control group; P < 0.01) and AST (637 +/- 37 U/l vs. 175 +/- 13 U/l in the control group; P < 0.001), whereas alkaline phosphatase and total bilirubin levels were unchanged. Histology revealed hepatic steatosis in both groups, with mild accentuation of fat staining in the zone 3 hepatocytes in mice exposed to CIH. Animals exposed to CIH exhibited lobular inflammation and fibrosis in the liver, which were not evident in control mice. CIH caused significant increases in lipid peroxidation in serum and liver tissue; significant increases in hepatic levels of myeloperoxidase and proinflammatory cytokines IL-1beta, IL-6, and CXC chemokine MIP-2; a trend toward an increase in TNF-alpha; and an increase in alpha1(I)-collagen mRNA. We conclude that CIH induces lipid peroxidation and inflammation in the livers of mice on a high-fat, high-cholesterol diet.

  14. Hepatoprotective effect of Matrine salvianolic acid B salt on Carbon Tetrachloride-Induced Hepatic Fibrosis

    PubMed Central

    2012-01-01

    The aim of this study was to investigate the hepatoprotective effect of Matrine salvianolic acid B salt on carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats. Salvianolic acid B and Matrine has long been used to treat liver fibrosis. Matrine salvianolic acid B salt is a new compound containing Salvianolic acid B and Matrine. Hepatic fibrosis induced by CCl4 was studied in animal models using Wistar rats. Organ coefficient, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), hexadecenoic acid (HA), laminin (LN), hydroxyproline (Hyp), and glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) in liver tissues were measured, respectively. Histopathological changes in the livers were studied by hematoxylin-eosin (H&E) staining and Masson Trichrome (MT) examination. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) was observed by immunohistochemical analysis. A significant reduction in serum levels of AST, ALT, HA, LN and Hyp was observed in the Matrine salvianolic acid B salt treated groups, suggesting that the salt had hepatoprotective effects. The depletion of GSH and SOD, as well as MDA accumulation in liver tissues was suppressed by Matrine salvianolic acid B salt too. The expression of TGF-β1 and α-SMA measured by immunohistology was significantly reduced by Matrine salvianolic acid B salt in a dose-dependent manner. Matrine salvianolic acid B salt treatment attenuated the necro-inflammation and fibrogenesis induced by CCl4 injection, and thus it is promising as a therapeutic anti-fibrotic agent against hepatic fibrosis. PMID:22559721

  15. Hepatoprotective effect of Matrine salvianolic acid B salt on Carbon Tetrachloride-Induced Hepatic Fibrosis.

    PubMed

    Gao, Hong-Ying; Li, Guo-Yu; Lou, Meng-Meng; Li, Xiao-Yu; Wei, Xiu-Yan; Wang, Jin-Hui

    2012-05-04

    The aim of this study was to investigate the hepatoprotective effect of Matrine salvianolic acid B salt on carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats. Salvianolic acid B and Matrine has long been used to treat liver fibrosis. Matrine salvianolic acid B salt is a new compound containing Salvianolic acid B and Matrine. Hepatic fibrosis induced by CCl4 was studied in animal models using Wistar rats. Organ coefficient, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), hexadecenoic acid (HA), laminin (LN), hydroxyproline (Hyp), and glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD) in liver tissues were measured, respectively. Histopathological changes in the livers were studied by hematoxylin-eosin (H&E) staining and Masson Trichrome (MT) examination. The expression of transforming growth factor-β1 (TGF-β1) and α-smooth muscle actin (α-SMA) was observed by immunohistochemical analysis. A significant reduction in serum levels of AST, ALT, HA, LN and Hyp was observed in the Matrine salvianolic acid B salt treated groups, suggesting that the salt had hepatoprotective effects. The depletion of GSH and SOD, as well as MDA accumulation in liver tissues was suppressed by Matrine salvianolic acid B salt too. The expression of TGF-β1 and α-SMA measured by immunohistology was significantly reduced by Matrine salvianolic acid B salt in a dose-dependent manner. Matrine salvianolic acid B salt treatment attenuated the necro-inflammation and fibrogenesis induced by CCl4 injection, and thus it is promising as a therapeutic anti-fibrotic agent against hepatic fibrosis.

  16. Mapping transmission foci to eliminate malaria in the People's Republic of China, 2010-2015: a retrospective analysis.

    PubMed

    Feng, Jun; Tu, Hong; Zhang, Li; Zhang, Shaosen; Jiang, Shan; Xia, Zhigui; Zhou, Shuisen

    2018-03-07

    China has initiated the National Malaria Elimination Action Plan, which aims to eliminate malaria by 2020. However, the transmission of malaria occurs sporadically or in distinct foci, which greatly hampers progress toward elimination in China and other countries. The object of this study was to foci categorization and evaluates whether the response met the requirements issued by the nation or WHO. Residual transmissions were investigated and located with fine spatial resolution mapping from parasitological confirmed malaria cases by use of routine national surveillance data. The "1-3-7" timeframes were monitored for each focus between 2012 and 2015. Each focus was identified, and the application of appropriate measures was evaluated. A total of 5996 indigenous cases were recorded between 2010 and 2015; during this period, the number of cases declined by 99.1% (2010, n = 4262; 2015, n = 39). Most indigenous cases (92.5%) were reported in Anhui (n = 2326), Yunnan (n = 1373), Henan (n = 930), Hubei (n = 459), and Guizhou (n = 458). The temporal distribution showed that the indigenous malaria cases were clustered during the period of May to August. A total of 320 foci were carefully investigated and analyzed: 24 were active foci; 72, residual non-active foci; and 224 cleared-up foci. For the foci response evaluation, all the active foci were investigated within 7 days, while 80.2% of the residual non-active foci were responded within 7 days. In addition, reactive case detection (RACD) was carried out with 92.9% of the active foci and vector investigation carried out with 75%. For residual non-active foci, RACD was carried out with 83.2% and vector investigation with 78.2% of the foci. This study used nationwide data to categorize foci in China and evaluate the response of these areas during the control and elimination phases. Our approach stratifies future control responses by identifying those locations where the elimination of endemic

  17. Lindane-induced oxidative stress. II. Time course of changes in hepatic glutathione status.

    PubMed

    Barros, S B; Videla, L A; Simizu, K; Van Halsema, L; Junqueira, V B

    1988-11-01

    1. Four hours after treatment of rats with lindane (60 mg/kg), hepatic GSH content was decreased (22%) and GSSG was increased (20%), while biliary concentration and excretion of both GSH and GSSG and bile flow were diminished. These changes coincide with the onset of hepatic lipid peroxidation. 2. The changes induced by lindane at 4 h disappeared at 6 h after treatment, but liver GSSG content (91%), biliary GSSG excretion (133%) and bile flow (42%) were enhanced at 24 h. 3. The data indicate that lindane treatment elicits marked changes in hepatocyte glutathione status, with a decrease in the GSH/GSSG ratio at early (2-4 h) and late (24 h) periods of poisoning.

  18. Bee's honey attenuates non-alcoholic steatohepatitis-induced hepatic injury through the regulation of thioredoxin-interacting protein-NLRP3 inflammasome pathway.

    PubMed

    Xiao, Jia; Liu, Yingxia; Xing, Feiyue; Leung, Tung Ming; Liong, Emily C; Tipoe, George L

    2016-06-01

    We aim to examine whether honey ameliorates hepatic injury in non-alcoholic steatohepatitis (NASH) animal and cell line steatosis models. NASH was induced in female Sprague-Dawley rat by 8-week feeding with a high-fat diet. During the experiment, 5 g/kg honey was intragastrically fed daily. Rat normal hepatocyte BRL-3A cell was treated with sodium palmitate (SP) to induce steatosis in the absence or presence of honey pre-treatment or specific siRNA/overexpress plasmid of thioredoxin-interacting protein (TXNIP) or antagonist/agonist of Nod-like receptor protein 3 (NLRP3). Honey significantly improved the high-fat-diet-induced hepatic injury, steatosis, fibrosis, oxidative stress, and inflammation in rats. Honey also inhibited the overexpression of TXNIP and the activation of NLRP3 inflammasome. These effects were replicated in BRL-3A cell line which showed that the down-regulation of TXNIP or inhibition of NLRP3 contributed to the suppression of NLRP3 inflammasome activation, inflammation, and re-balanced lipid metabolism. In contrast, overexpression of TXNIP or agonism of NLRP3 exacerbated the cellular damage induced by SP. Suppression of the TXNIP-NLRP3 inflammasome pathway may partly contribute to the amelioration of hepatic injury during the progression of NASH by honey. Targeting hepatic TXNIP-NLRP3 inflammasome pathway is a potential therapeutic way for the prevention and treatment of NASH.

  19. Potential mechanisms of hepatitis B virus induced liver injury

    PubMed Central

    Suhail, Mohd; Abdel-Hafiz, Hany; Ali, Ashraf; Fatima, Kaneez; Damanhouri, Ghazi A; Azhar, Esam; Chaudhary, Adeel GA; Qadri, Ishtiaq

    2014-01-01

    Chronic active hepatitis (CAH) is acknowledged as an imperative risk factor for the development of liver injury and hepatocellular carcinoma. The histological end points of CAH are chronic inflammation, fibrosis and cirrhosis which are coupled with increased DNA synthesis in cirrhotic vs healthy normal livers. The potential mechanism involved in CAH includes a combination of processes leading to liver cell necrosis, inflammation and cytokine production and liver scaring (fibrosis). The severity of liver damage is regulated by Hepatitis B virus genotypes and viral components. The viral and cellular factors that contribute to liver injury are discussed in this article. Liver injury caused by the viral infection affects many cellular processes such as cell signaling, apoptosis, transcription, DNA repair which in turn induce radical effects on cell survival, growth, transformation and maintenance. The consequence of such perturbations is resulted in the alteration of bile secretion, gluconeogenesis, glycolysis, detoxification and metabolism of carbohydrates, proteins, fat and balance of nutrients. The identification and elucidation of the molecular pathways perturbed by the viral proteins are important in order to design effective strategy to minimize and/or restore the hepatocytes injury. PMID:25253946

  20. CRISPR/Cas9 Technology Targeting Fas Gene Protects Mice From Concanavalin-A Induced Fulminant Hepatic Failure.

    PubMed

    Liang, Wei-Cheng; Liang, Pu-Ping; Wong, Cheuk-Wa; Ng, Tzi-Bun; Huang, Jun-Jiu; Zhang, Jin-Fang; Waye, Mary Miu-Yee; Fu, Wei-Ming

    2017-03-01

    Fulminant hepatic failure is a life-threatening disease which occurs in patients without preexisting liver disease. Nowadays, there is no ideal therapeutic tool in the treatment of fulminant hepatic failure. Recent studies suggested that a novel technology termed CRISPR/Cas9 may be a promising approach for the treatment of fulminant hepatic failure. In this project, we have designed single chimeric guide RNAs specifically targeting the genomic regions of mouse Fas gene. The in vitro and in vivo effects of sgRNAs on the production of Fas protein were examined in cultured mouse cells and in a hydrodynamic injection-based mouse model, respectively. The in vivo delivery of CRISPR/Cas9 could maintain liver homeostasis and protect hepatocytes from Fas-mediated cell apoptosis in the fulminant hepatic failure model. Our study indicates the clinical potential of developing the CRISPR/Cas9 system as a novel therapeutic strategy to rescue Concanavalin-A-induced fulminant hepatic failure in the mouse model. J. Cell. Biochem. 118: 530-536, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. A Paracrine Mechanism Accelerating Expansion of Human Induced Pluripotent Stem Cell-Derived Hepatic Progenitor-Like Cells

    PubMed Central

    Tsuruya, Kota; Chikada, Hiromi; Ida, Kinuyo; Anzai, Kazuya; Kagawa, Tatehiro; Inagaki, Yutaka; Mine, Tetsuya

    2015-01-01

    Hepatic stem/progenitor cells in liver development have a high proliferative potential and the ability to differentiate into both hepatocytes and cholangiocytes. In this study, we focused on the cell surface molecules of human induced pluripotent stem (iPS) cell-derived hepatic progenitor-like cells (HPCs) and analyzed how these molecules modulate expansion of these cells. Human iPS cells were differentiated into immature hepatic lineage cells by cytokines. In addition to hepatic progenitor markers (CD13 and CD133), the cells were coimmunostained for various cell surface markers (116 types). The cells were analyzed by flow cytometry and in vitro colony formation culture with feeder cells. Twenty types of cell surface molecules were highly expressed in CD13+CD133+ cells derived from human iPS cells. Of these molecules, CD221 (insulin-like growth factor receptor), which was expressed in CD13+CD133+ cells, was quickly downregulated after in vitro expansion. The proliferative ability was suppressed by a neutralizing antibody and specific inhibitor of CD221. Overexpression of CD221 increased colony-forming ability. We also found that inhibition of CD340 (erbB2) and CD266 (fibroblast growth factor-inducible 14) signals suppressed proliferation. In addition, both insulin-like growth factor (a ligand of CD221) and tumor necrosis factor-like weak inducer of apoptosis (a ligand of CD266) were provided by feeder cells in our culture system. This study revealed the expression profiles of cell surface molecules in human iPS cell-derived HPCs and that the paracrine interactions between HPCs and other cells through specific receptors are important for proliferation. PMID:25808356

  2. A Paracrine Mechanism Accelerating Expansion of Human Induced Pluripotent Stem Cell-Derived Hepatic Progenitor-Like Cells.

    PubMed

    Tsuruya, Kota; Chikada, Hiromi; Ida, Kinuyo; Anzai, Kazuya; Kagawa, Tatehiro; Inagaki, Yutaka; Mine, Tetsuya; Kamiya, Akihide

    2015-07-15

    Hepatic stem/progenitor cells in liver development have a high proliferative potential and the ability to differentiate into both hepatocytes and cholangiocytes. In this study, we focused on the cell surface molecules of human induced pluripotent stem (iPS) cell-derived hepatic progenitor-like cells (HPCs) and analyzed how these molecules modulate expansion of these cells. Human iPS cells were differentiated into immature hepatic lineage cells by cytokines. In addition to hepatic progenitor markers (CD13 and CD133), the cells were coimmunostained for various cell surface markers (116 types). The cells were analyzed by flow cytometry and in vitro colony formation culture with feeder cells. Twenty types of cell surface molecules were highly expressed in CD13(+)CD133(+) cells derived from human iPS cells. Of these molecules, CD221 (insulin-like growth factor receptor), which was expressed in CD13(+)CD133(+) cells, was quickly downregulated after in vitro expansion. The proliferative ability was suppressed by a neutralizing antibody and specific inhibitor of CD221. Overexpression of CD221 increased colony-forming ability. We also found that inhibition of CD340 (erbB2) and CD266 (fibroblast growth factor-inducible 14) signals suppressed proliferation. In addition, both insulin-like growth factor (a ligand of CD221) and tumor necrosis factor-like weak inducer of apoptosis (a ligand of CD266) were provided by feeder cells in our culture system. This study revealed the expression profiles of cell surface molecules in human iPS cell-derived HPCs and that the paracrine interactions between HPCs and other cells through specific receptors are important for proliferation.

  3. Tranilast reduces serum IL-6 and IL-13 and protects against thioacetamide-induced acute liver injury and hepatic encephalopathy.

    PubMed

    Abdelaziz, Rania R; Elkashef, Wagdi F; Said, Eman

    2015-07-01

    Hepatic encephalopathy is a serious neuropsychiatric disorder usually affecting either acute or chronic hepatic failure patients. Hepatic encephalopathy was replicated in a validated rat model to assess the potential protective efficacy of tranilast against experimentally induced hepatic encephalopathy. Thioacetamide injection significantly impaired hepatic synthetic, metabolic and excretory functions with significant increase in serum NO, IL-6 and IL-13 levels and negative shift in the oxidant/antioxidant balance. Most importantly, there was a significant increase in serum ammonia levels with significant astrocytes' swelling and vacuolization; hallmarks of hepatic encephalopathy. Tranilast administration (300 mg/kg, orally) for 15 days significantly improved hepatic functions, restored oxidant/antioxidant balance, reduced serum NO, IL-6 and IL-13 levels. Meanwhile, serum ammonia significantly declined with significant reduction in astrocytes' swelling and vacuolization. Several mechanisms can be implicated in the observed hepato- and neuroprotective potentials of tranilast, such as its anti-inflammatory potential, its antioxidant potential as well as its immunomodulatory properties. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Ethanol extracts collected from the Styela clava tunic alleviate hepatic injury induced by carbon tetrachloride (CCl4) through inhibition of hepatic apoptosis, inflammation, and fibrosis.

    PubMed

    Koh, Eun Kyoung; Kim, Ji Eun; Song, Sung Hwa; Sung, Ji Eun; Lee, Hyun Ah; Kim, Kil Soo; Hong, Jin Tae; Hwang, Dae Youn

    2017-10-01

    The Styela clava tunic (SCT) is known as a good raw material for preparing anti-inflammatory compounds, wound healing films, guided bone regeneration, and food additives. To investigate whether ethanol extracts of the SCT (EtSCT) could protect against hepatic injury induced by carbon tetrachloride (CCl 4 ) in ICR mice, alterations in serum biochemical indicators, histopathology, hepatic apoptosis, inflammation, and fibrosis were observed in ICR mice pretreated with EtSCT for 5 days before CCl 4 injection. EtSCT contained 15.6 mg/g of flavonoid and 37.5 mg/g phenolic contents with high 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (93.3%) and metal chelation activity (46.5%). The EtSCT+CCl 4 -treated groups showed decreased levels of ALT, LDH, and AST, indicating toxicity and a necrotic area in the liver, while the level of ALP remained constant. The formation of active caspase-3 and enhancement of Bax/Bcl-2 expression was effectively inhibited in the EtSCT+CCl 4 -treated groups. Furthermore, the levels of pro- and anti-inflammatory cytokines and the phosphorylation of p38 in the TNF-α downstream signaling pathway rapidly recovered in the EtSCT+CCl 4 -treated groups. The EtSCT+CCl 4 -treated groups showed a significant decrease in hepatic fibrosis markers including collagen accumulation, MMP-2 expression, TGF-β1 concentration, and phosphorylation of Smad2/3. Moreover, a significant decline in malondialdehyde (MDA) concentration and enhancement of superoxide dismutase (SOD) expression were observed in the EtSCT+CCl 4 -treated groups. Taken together, these results indicate that EtSCT can protect against hepatic injury induced by CCl 4 -derived reactive intermediates through the suppression of hepatic apoptosis, inflammation, and fibrosis.

  5. Ethanol extracts collected from the Styela clava tunic alleviate hepatic injury induced by carbon tetrachloride (CCl4) through inhibition of hepatic apoptosis, inflammation, and fibrosis

    PubMed Central

    Koh, Eun Kyoung; Kim, Ji Eun; Song, Sung Hwa; Sung, Ji Eun; Lee, Hyun Ah; Kim, Kil Soo; Hong, Jin Tae; Hwang, Dae Youn

    2017-01-01

    The Styela clava tunic (SCT) is known as a good raw material for preparing anti-inflammatory compounds, wound healing films, guided bone regeneration, and food additives. To investigate whether ethanol extracts of the SCT (EtSCT) could protect against hepatic injury induced by carbon tetrachloride (CCl4) in ICR mice, alterations in serum biochemical indicators, histopathology, hepatic apoptosis, inflammation, and fibrosis were observed in ICR mice pretreated with EtSCT for 5 days before CCl4 injection. EtSCT contained 15.6 mg/g of flavonoid and 37.5 mg/g phenolic contents with high 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity (93.3%) and metal chelation activity (46.5%). The EtSCT+CCl4-treated groups showed decreased levels of ALT, LDH, and AST, indicating toxicity and a necrotic area in the liver, while the level of ALP remained constant. The formation of active caspase-3 and enhancement of Bax/Bcl-2 expression was effectively inhibited in the EtSCT+CCl4-treated groups. Furthermore, the levels of pro- and anti-inflammatory cytokines and the phosphorylation of p38 in the TNF-α downstream signaling pathway rapidly recovered in the EtSCT+CCl4-treated groups. The EtSCT+CCl4-treated groups showed a significant decrease in hepatic fibrosis markers including collagen accumulation, MMP-2 expression, TGF-β1 concentration, and phosphorylation of Smad2/3. Moreover, a significant decline in malondialdehyde (MDA) concentration and enhancement of superoxide dismutase (SOD) expression were observed in the EtSCT+CCl4-treated groups. Taken together, these results indicate that EtSCT can protect against hepatic injury induced by CCl4-derived reactive intermediates through the suppression of hepatic apoptosis, inflammation, and fibrosis. PMID:29097839

  6. [Differential chronic hepatitis diagnosis].

    PubMed

    Hinterberger, W

    2000-01-01

    Chronic hepatitis comprises a group of disorders of the liver exhibiting a chronic necroinflammatory process that differs in etiology, clinical course and treatment strategies. A diagnosis of chronic hepatitis is usually made when inflammation and liver cell necrosis persist for longer than 6 months. Clinical manifestations range from asymptomatic patients to those with advanced hepatic failure. Both sexes and all age groups are affected. Chronic hepatitis may emerge as a sequelae of hepatitis C and less often after hepatitis B. Both diseases are treatable and require rapid and exact diagnosis. The differential diagnosis must exclude autoimmune hepatitis, chronic steatohepatitis, congenital metabolic hepatopathies and drug-induced hepatopathies. Laboratory tests, histologic investigations and clinical differential diagnosis must exclude other causes of chronic liver disease.

  7. Immune reactions in acute viral hepatitis.

    PubMed Central

    Newble, D I; Holmes, K T; Wangel, A G; Forbes, I J

    1975-01-01

    Serial studies of PHA-induced lymphocyte transformation, serum autoantibodies, immunoglobulins and complement were performed in seventeen patients with hepatitis A and nine patients with hepatitis B. In both types of hepatitis PHA-induced transformation was markedly impaired during the 1st week after the onset of jaundice and there was less marked but prolonged impairment for a further period of 6-10 weeks. A group of eleven subjects with a previous history of hepatitis had values which were similar to those of healthy persons. Serum from patients with hepatitis A and hepatitis B contains an inhibitor of lymphocyte response to PHA. The inhibitor depresses the function of both patients' and normal lymphocytes and is only detectable during the acute phase of the illness. Washing lymphocytes free from autologous serum did not restore the PHA response to normal but the markedly impaired response present during the first 2 weeks of the illness was improved. A serum factor or factors may therefore be responsible for at least part of the impaired response of lymphocytes to PHA during the acute phase of hepatitis but does not appear to account for the more prolonged impairment of the PHA response. The protracted lymphocyte defect is possibly induced by hepatitis virus. The incidence of autoantibodies and the changes in immunoglobulin levels were similar to those reported by other workers. PMID:1204253

  8. Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Strakovsky, Rita S.; Wang, Huan; Engeseth, Nicki J.

    Developmental bisphenol A (BPA) exposure increases adulthood hepatic steatosis with reduced mitochondrial function. To investigate the potential epigenetic mechanisms behind developmental BPA-induced hepatic steatosis, pregnant Sprague–Dawley rats were dosed with vehicle (oil) or BPA (100 μg/kg/day) from gestational day 6 until postnatal day (PND) 21. After weaning, offspring were either challenged with a high-fat (HF; 45% fat) or remained on a control (C) diet until PND110. From PND60 to 90, both BPA and HF diet increased the fat/lean ratio in males only, and the combination of BPA and HF diet appeared to cause the highest ratio. On PND110, Oil-HF, BPA-C,more » and BPA-HF males had higher hepatic lipid accumulation than Oil-C, with microvesicular steatosis being marked in the BPA-HF group. Furthermore, on PND1, BPA increased and modified hepatic triglyceride (TG) and free fatty acid (FFA) compositions in males only. In PND1 males, BPA increased hepatic expression of FFA uptake gene Fat/Cd36, and decreased the expression of TG synthesis- and β-oxidation-related genes (Dgat, Agpat6, Cebpα, Cebpβ, Pck1, Acox1, Cpt1a, Cybb). BPA altered DNA methylation and histone marks (H3Ac, H4Ac, H3Me2K4, H3Me3K36), and decreased the binding of several transcription factors (Pol II, C/EBPβ, SREBP1) within the male Cpt1a gene, the key β-oxidation enzyme. In PND1 females, BPA only increased the expression of genes involved in FFA uptake and TG synthesis (Lpl, Fasn, and Dgat). These data suggest that developmental BPA exposure alters and reprograms hepatic β-oxidation capacity in males, potentially through the epigenetic regulation of genes, and further alters the response to a HF diet. - Highlights: • Developmental BPA exposure exacerbates HF-diet induced steatosis in adult males. • Gestational BPA exposure increases hepatic lipid accumulation in neonatal males. • BPA decreases Cpt1a and other hepatic β-oxidation genes in neonatal males. • BPA alters neonatal male

  9. Therapeutic role of ursolic acid on ameliorating hepatic steatosis and improving metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats.

    PubMed

    Li, Songtao; Liao, Xilu; Meng, Fanyu; Wang, Yemei; Sun, Zongxiang; Guo, Fuchuan; Li, Xiaoxia; Meng, Man; Li, Ying; Sun, Changhao

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA), an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model. Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR)-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD.

  10. Therapeutic Role of Ursolic Acid on Ameliorating Hepatic Steatosis and Improving Metabolic Disorders in High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Rats

    PubMed Central

    Meng, Fanyu; Wang, Yemei; Sun, Zongxiang; Guo, Fuchuan; Li, Xiaoxia; Meng, Man; Li, Ying; Sun, Changhao

    2014-01-01

    Background Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA), an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model. Methodology/Principal Findings Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR)-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. Conclusions/Significance These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD. PMID:24489777

  11. Free fatty acid-induced hepatic insulin resistance is attenuated following lifestyle intervention in obese individuals with impaired glucose tolerance.

    PubMed

    Haus, Jacob M; Solomon, Thomas P J; Marchetti, Christine M; Edmison, John M; González, Frank; Kirwan, John P

    2010-01-01

    The objective of the study was to examine the effects of an exercise/diet lifestyle intervention on free fatty acid (FFA)-induced hepatic insulin resistance in obese humans. Obese men and women (n = 23) with impaired glucose tolerance were randomly assigned to either exercise training with a eucaloric (EU; approximately 1800 kcal; n = 11) or hypocaloric (HYPO; approximately 1300 kcal; n = 12) diet for 12 wk. Hepatic glucose production (HGP; milligrams per kilogram fat-free mass(-1) per minute(-1)) and hepatic insulin resistance were determined using a two-stage sequential hyperinsulinemic (40 mU/m(2) . min(-1)) euglycemic (5.0 mm) clamp with [3-(3)H]glucose. Measures were obtained at basal, during insulin infusion (INS; 120 min), and insulin plus intralipid/heparin infusion (INS/FFA; 300 min). At baseline, basal HGP was similar between groups; hyperinsulinemia alone did not completely suppress HGP, whereas INS/FFA exhibited less suppression than INS (EU, 4.6 +/- 0.8, 2.0 +/- 0.5, and 2.6 +/- 0.4; HYPO, 3.8 +/- 0.5, 1.2 +/- 0.3, and 2.3 +/- 0.4, respectively). After the intervention the HYPO group lost more body weight (P < 0.05) and fat mass (P < 0.05). However, both lifestyle interventions reduced hepatic insulin resistance during basal (P = 0.005) and INS (P = 0.001) conditions, and insulin-mediated suppression of HGP during INS was equally improved in both groups (EU: -42 +/- 22%; HYPO: -50 +/- 20%, before vs. after, P = 0.02). In contrast, the ability of insulin to overcome FFA-induced hepatic insulin resistance and HGP was improved only in the HYPO group (EU: -15 +/- 24% vs. HYPO: -58 +/- 19%, P = 0.02). Both lifestyle interventions are effective in reducing hepatic insulin resistance under basal and hyperinsulinemic conditions. However, the reversal of FFA-induced hepatic insulin resistance is best achieved with a combined exercise/caloric-restriction intervention.

  12. Free Fatty Acid-Induced Hepatic Insulin Resistance is Attenuated Following Lifestyle Intervention in Obese Individuals with Impaired Glucose Tolerance

    PubMed Central

    Haus, Jacob M.; Solomon, Thomas P. J.; Marchetti, Christine M.; Edmison, John M.; González, Frank; Kirwan, John P.

    2010-01-01

    Objective: The objective of the study was to examine the effects of an exercise/diet lifestyle intervention on free fatty acid (FFA)-induced hepatic insulin resistance in obese humans. Research Design and Methods: Obese men and women (n = 23) with impaired glucose tolerance were randomly assigned to either exercise training with a eucaloric (EU; ∼1800 kcal; n = 11) or hypocaloric (HYPO; ∼1300 kcal; n = 12) diet for 12 wk. Hepatic glucose production (HGP; milligrams per kilogram fat-free mass−1 per minute−1) and hepatic insulin resistance were determined using a two-stage sequential hyperinsulinemic (40 mU/m2 · min−1) euglycemic (5.0 mm) clamp with [3-3H]glucose. Measures were obtained at basal, during insulin infusion (INS; 120 min), and insulin plus intralipid/heparin infusion (INS/FFA; 300 min). Results: At baseline, basal HGP was similar between groups; hyperinsulinemia alone did not completely suppress HGP, whereas INS/FFA exhibited less suppression than INS (EU, 4.6 ± 0.8, 2.0 ± 0.5, and 2.6 ± 0.4; HYPO, 3.8 ± 0.5, 1.2 ± 0.3, and 2.3 ± 0.4, respectively). After the intervention the HYPO group lost more body weight (P < 0.05) and fat mass (P < 0.05). However, both lifestyle interventions reduced hepatic insulin resistance during basal (P = 0.005) and INS (P = 0.001) conditions, and insulin-mediated suppression of HGP during INS was equally improved in both groups (EU: −42 ± 22%; HYPO: −50 ± 20%, before vs. after, P = 0.02). In contrast, the ability of insulin to overcome FFA-induced hepatic insulin resistance and HGP was improved only in the HYPO group (EU: −15 ± 24% vs. HYPO: −58 ± 19%, P = 0.02). Conclusions: Both lifestyle interventions are effective in reducing hepatic insulin resistance under basal and hyperinsulinemic conditions. However, the reversal of FFA-induced hepatic insulin resistance is best achieved with a combined exercise/caloric-restriction intervention. PMID:19906790

  13. Impaired adipogenesis in adipose tissue associated with hepatic lipid deposition induced by chronic inflammation in mice with chew diet.

    PubMed

    Yang, Shumin; Zhang, Wenlong; Zhen, Qianna; Gao, Rufei; Du, Tingting; Xiao, Xiaoqiu; Wang, Zhihong; Ge, Qian; Hu, Jinbo; Ye, Peng; Zhu, Qibo; Li, Qifu

    2015-09-15

    Chronic inflammation might be associated with hepatic lipid deposition independent of overnutrition. However, the mechanism is not fully understood. In this study, we investigate if impaired adipogenesis in adipose tissue is associated with hepatic lipid deposition induced by chronic inflammation in mice with chew diet. Casein injection in C57BL/6J mice was given every other day to induce chronic inflammation. All mice were sacrificed after 18weeks of injections. The serum, liver and adipose tissue were collected for analysis. Real-time polymerase chain reaction and western blotting were used to examine the gene and protein expressions of molecules involved in hepatic lipid metabolism and adipose adipogenesis. Casein injection elevated serum levels of insulin, free fatty acid (FFA) and proinflammatory factors. The gene expression of proinflammatory factors of adipose tissue and the liver also increased in the casein group as compared with the control group. Chronic inflammation up-regulated the hepatic expression of fatty acid translocase (CD36) and down-regulated microsomal triacylglycerol transfer protein (MTP), carnitine palmitoyltransferase 1a (CPT1a) and acyl-coenzyme a oxidase 1 (ACOX1). Meanwhile, chronic inflammation not only diminished the size of adipocytes, but also down-regulated the expression of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding proteinα (C/EBPα), both indicating an impaired adipogenesis. Besides disturbed lipid metabolism in the liver per se, impaired adipogenesis in the adipose tissue might also be associated with hepatic lipid deposition induced by chronic inflammation in mice with chew diet. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Protective Effect of Quercetin on Melphalan-Induced Oxidative Stress and Impaired Renal and Hepatic Functions in Rat

    PubMed Central

    Ola, Olaniyi Solomon; Adeyemo, Oluwatobi Adewumi

    2014-01-01

    One major challenge with the use of anticancer agents is the phenomenon of drug-induced toxicity. Melphalan (MPLN) is an alkylating anticancer agent, while quercetin (QCT) is an antioxidant. We investigated the protective role of quercetin against MPLN-induced toxicity. Twenty-five male Wistar rats (160–170 g) were randomized into five treatment groups; (I) control, (II) MPLN (0.2 mg/kg b.w.), (III) pre-treated with QCT (20 mg/kg b.w.) for 7 days followed by MPLN (0.2 mg/kg b.w.) for 7 days, (IV) cotreated with QCT (20 mg/kg b.w.) and MPLN (0.2 mg/kg b.w.) for 7 days, and (V) QCT (20 mg/kg b.w.) alone. MPLN caused a significant increase in plasma bilirubin, urea, and creatinine by 122.2%, 102.3%, and 188%, respectively (P < 0.05). Similarly, plasma ALP, ALT, AST, and γ-GT activities increased significantly by 57.9%, 144.3%, 71.3%, and 307.2%, respectively, relative to control. However, pre or cotreatment with QCT ameliorated the levels of renal and hepatic function indices. Hepatic ascorbic acid and GSH and activities of glutathione-S-transferase, SOD, and catalase decreased significantly by 36.2%, 188%, 46.5%, 34.4%, and 55.2%, respectively, followed by increase in MDA content by 46.5% relative to control. Pre- and cotreatment with QCT reestablished the hepatic antioxidant status and lipid peroxidation. Overall, quercetin protected against MPLN-induced renal and hepatic toxicity in rats. PMID:25574394

  15. Does senna extract promote growth of aberrant crypt foci and malignant tumors in rat colon?

    PubMed

    Mascolo, N; Mereto, E; Borrelli, F; Orsi, P; Sini, D; Izzo, A A; Massa, B; Boggio, M; Capasso, F

    1999-11-01

    Current evidence suggests that aberrant crypt foci (ACF) can be used to evaluate agents for their potential colon carcinogenic activity. The aim of the present study was to determine whether senna pod extract (SE) itself induces ACF and tumors in the rat colon or increases the development of ACF and tumors induced by azoxymethane (AOM). A daily administration of SE 10 mg/kg by mouth for 13-28 weeks produced a weak laxative effect but did not itself cause the appearance of ACF or tumors. The numbers of ACF and tumors induced by AOM were, however, increased by a dose of SE (100 mg/kg) able to induce chronic diarrhea over three months. These results suggest that SE does not cause the appearance of ACF or tumors in the rat colon nor does it have a promoting effect when given to rats at a dose that produces laxation (10 mg/kg), whereas a diarrhogenic dose (100 mg/kg) increases the appearance of tumors induced by AOM.

  16. Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Wahlang, Banrida; Song, Ming; Beier, Juliane I.

    Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity (DIO). Male C57Bl/6J mice were fed control diet or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20 mg/kg or 200 mg/kg in corn oil) for 12 weeks. A glucose tolerance test was performed; plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression. Aroclor 1260 exposuremore » was associated with decreased body fat in HFD-fed mice but had no effect on blood glucose/lipid levels. Paradoxically, Aroclor 1260 + HFD co-exposed mice demonstrated increased hepatic inflammatory foci at both doses while the degree of steatosis did not change. Serum cytokines, ALT levels and hepatic expression of IL-6 and TNFα were increased only at 20 mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200 mg/kg exposure. Aroclor 1260 induced hepatic expression of cytochrome P450s including Cyp3a11 (Pregnane-Xenobiotic Receptor target) and Cyp2b10 (constitutive androstane receptor target) but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (aryl hydrocarbon Receptor target) was induced only at 200 mg/kg. In summary, Aroclor 1260 worsened hepatic and systemic inflammation in DIO. The results indicated a bimodal response of PCB-diet interactions in the context of inflammation which could potentially be explained by xenobiotic receptor activation. Thus, PCB exposure may be a relevant “second hit” in the transformation of steatosis to steatohepatitis. - Highlights: • Aroclor 1260 exposure decreased adiposity in mice fed with high fat diet • Aroclor 1260 exposure induced steatohepatitis in diet-induced obese mice • Aroclor 1260 (20 and 200 mg

  17. Effects of eicosapentaenoic acid on hepatic dyslipidemia and oxidative stress in high fat diet-induced steatosis.

    PubMed

    Hirotani, Yoshihiko; Ozaki, Nozomi; Tsuji, Yoshihiro; Urashima, Yoko; Myotoku, Michiaki

    2015-01-01

    We investigated the ability of eicosapentaenoic acid (EPA) to prevent high-fat diet (HFD)-induced obesity and non-alcoholic fatty liver disease (NAFLD). Male C57BL/6J mice were fed standard chow (5.3% fat content), an HFD (32.0% fat content) or an HFD + EPA (1 g/kg/day EPA for the last 6 weeks) for 12 weeks. Serum total cholesterol, hepatic triglyceride and total cholesterol levels were significantly increased in the HFD group, in comparison with those of normal mice (p < 0.01). In contrast, hepatic triglyceride and total cholesterol levels were significantly decreased in the HFD + EPA group, in comparison with those of the HFD group (p < 0.05). In addition, EPA decreased the body weight of obese mice and improved hepatic function. Hepatic superoxide dismutase activity and glutathione levels were significantly decreased in obese mice, but increased with EPA administration. Our data suggest that EPA supplementation has a beneficial effect on NAFLD progression.

  18. Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients.

    PubMed

    Teixeira, Raquel Lima de Figueiredo; Morato, Renata Gomes; Cabello, Pedro Hernan; Muniz, Ligia Mayumi Kitada; Moreira, Adriana da Silva Rezende; Kritski, Afrânio Lineu; Mello, Fernanda Carvalho Queiroz; Suffys, Philip Noel; Miranda, Antonio Basilio de; Santos, Adalberto Rezende

    2011-09-01

    Isoniazid (INH), one of the most important drugs used in antituberculosis (anti-TB) treatment, is also the major drug involved in hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, such as NAT2, CYP2E1, GSTM1 and GSTT1, that code for drug-metabolising enzymes. Our goal was to examine the polymorphisms in these enzymes as susceptibility factors to anti-TB drug-induced hepatitis in Brazilian individuals. In a case-control design, 167 unrelated active tuberculosis patients from the University Hospital of the Federal University of Rio de Janeiro, Brazil, were enrolled in this study. Patients with a history of anti-TB drug-induced acute hepatitis (cases with an increase to 3 times the upper limit of normal serum transaminases and symptoms of hepatitis) and patients with no evidence of anti-TB hepatic side effects (controls) were genotyped for NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms. Slow acetylators had a higher incidence of hepatitis than intermediate/rapid acetylators [22% (18/82) vs. 9.8% (6/61), odds ratio (OR), 2.86, 95% confidence interval (CI), 1.06-7.68, p = 0.04). Logistic regression showed that slow acetylation status was the only independent risk factor (OR 3.59, 95% CI, 2.53-4.64, p = 0.02) for the occurrence of anti-TB drug-induced hepatitis during anti-TB treatment with INH-containing schemes in Brazilian individuals.

  19. Protective effects of Fraxinus xanthoxyloides (Wall.) leaves against CCl4 induced hepatic toxicity in rat.

    PubMed

    Younis, Tahira; Khan, Muhammad Rashid; Sajid, Moniba

    2016-10-24

    Leaves and root bark of Fraxinus xanthoxyloides Wall. (Oleaceae) are used locally for the treatment of jaundice, malaria and pneumonia. Decoction of stem, twigs and bark is used in pain, internal injuries, rheumatism and in bone fracture. In this investigation we have evaluated the methanol extract of leaves for its hepatoprotective potential against CCl 4 induced hepatic injuries in rat. Powder of F. xanthoxyloides leaves was extracted with methanol (FXM) and subjected for the determination of polyphenolics through HPLC-DAD analysis. Sprague-Dawley (Rattus novergicus) male rats were divided into eight groups (six rats in each). Group I: non-treated control; Group II: vehicle treated (DMSO plus olive oil) while Group III- VI treated with 1 ml/kg body weight (bw) of CCl 4 (30 % in olive oil) for 30 days (15 dosages) to induce the hepatic injuries. Group IV: treated with silymarin (100 mg/kg bw); Group V and VI with FXM (200, 400 mg/kg bw) on alternate days with CCl 4 treatment. Group VII and VIII was administered with FXM (200, 400 mg/kg bw) alone (15 dosages). After 30 days the serum was evaluated for liver function enzymes and biochemical markers, liver samples for antioxidant enzymes, biochemical markers, comet assay and for histopathology. HPLC-DAD analysis of FXM revealed the existence of rutin and caffeic acid. In CCl 4 treated rats the level of alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin was significantly increased while the albumin concentration in serum was decreased as compared to control group. The level of hepatic antioxidant enzymes, catalase (CAT), peroxidase (POD), superoxide dismutase (SOD), glutathione-S-transferase (GST) and glutathione reductase (GSR) was significantly decreased against the control group. Further, significant decrease in GSH while increase in lipid peroxides (TBARS), H 2 O 2 , DNA damages and comet length was induced with CCl 4 in hepatic tissues of rat. In contrast, co-administration of FXM

  20. Transcriptomic Profiling of High-Density Giardia Foci Encysting in the Murine Proximal Intestine

    PubMed Central

    Pham, Jonathan K.; Nosala, Christopher; Scott, Erica Y.; Nguyen, Kristofer F.; Hagen, Kari D.; Starcevich, Hannah N.; Dawson, Scott C.

    2017-01-01

    Giardia is a highly prevalent, understudied protistan parasite causing significant diarrheal disease worldwide. Its life cycle consists of two stages: infectious cysts ingested from contaminated food or water sources, and motile trophozoites that colonize and attach to the gut epithelium, later encysting to form new cysts that are excreted into the environment. Current understanding of parasite physiology in the host is largely inferred from transcriptomic studies using Giardia grown axenically or in co-culture with mammalian cell lines. The dearth of information about the diversity of host-parasite interactions occurring within distinct regions of the gastrointestinal tract has been exacerbated by a lack of methods to directly and non-invasively interrogate disease progression and parasite physiology in live animal hosts. By visualizing Giardia infections in the mouse gastrointestinal tract using bioluminescent imaging (BLI) of tagged parasites, we recently showed that parasites colonize the gut in high-density foci. Encystation is initiated in these foci throughout the entire course of infection, yet how the physiology of parasites within high-density foci in the host gut differs from that of cells in laboratory culture is unclear. Here we use BLI to precisely select parasite samples from high-density foci in the proximal intestine to interrogate in vivo Giardia gene expression in the host. Relative to axenic culture, we noted significantly higher expression (>10-fold) of oxidative stress, membrane transporter, and metabolic and structural genes associated with encystation in the high-density foci. These differences in gene expression within parasite foci in the host may reflect physiological changes associated with high-density growth in localized regions of the gut. We also identified and verified six novel cyst-specific proteins, including new components of the cyst wall that were highly expressed in these foci. Our in vivo transcriptome data support an

  1. Transcriptomic Profiling of High-Density Giardia Foci Encysting in the Murine Proximal Intestine.

    PubMed

    Pham, Jonathan K; Nosala, Christopher; Scott, Erica Y; Nguyen, Kristofer F; Hagen, Kari D; Starcevich, Hannah N; Dawson, Scott C

    2017-01-01

    Giardia is a highly prevalent, understudied protistan parasite causing significant diarrheal disease worldwide. Its life cycle consists of two stages: infectious cysts ingested from contaminated food or water sources, and motile trophozoites that colonize and attach to the gut epithelium, later encysting to form new cysts that are excreted into the environment. Current understanding of parasite physiology in the host is largely inferred from transcriptomic studies using Giardia grown axenically or in co-culture with mammalian cell lines. The dearth of information about the diversity of host-parasite interactions occurring within distinct regions of the gastrointestinal tract has been exacerbated by a lack of methods to directly and non-invasively interrogate disease progression and parasite physiology in live animal hosts. By visualizing Giardia infections in the mouse gastrointestinal tract using bioluminescent imaging (BLI) of tagged parasites, we recently showed that parasites colonize the gut in high-density foci. Encystation is initiated in these foci throughout the entire course of infection, yet how the physiology of parasites within high-density foci in the host gut differs from that of cells in laboratory culture is unclear. Here we use BLI to precisely select parasite samples from high-density foci in the proximal intestine to interrogate in vivo Giardia gene expression in the host. Relative to axenic culture, we noted significantly higher expression (>10-fold) of oxidative stress, membrane transporter, and metabolic and structural genes associated with encystation in the high-density foci. These differences in gene expression within parasite foci in the host may reflect physiological changes associated with high-density growth in localized regions of the gut. We also identified and verified six novel cyst-specific proteins, including new components of the cyst wall that were highly expressed in these foci. Our in vivo transcriptome data support an

  2. Preventive activity of banana peel polyphenols on CCl4-induced experimental hepatic injury in Kunming mice.

    PubMed

    Wang, Rui; Feng, Xia; Zhu, Kai; Zhao, Xin; Suo, Huayi

    2016-05-01

    The aim of the present study was to evaluate the preventive effects of banana peel polyphenols (BPPs) against hepatic injury. Mice were divide into normal, control, 100 mg/kg and 200 mg/kg banana peel polyphenol and silymarin groups. All the mice except normal mice were induced with hepatic damage using CCl 4 . The serum and tissue levels of mice were determined by a kit and the tissues were further examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. BPPs reduced the serum levels of aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase in a CCl 4 -induced mouse model of hepatic injury. Furthermore, BPPs reduced the levels of malondialdehyde and triglyceride, while increasing glutathione levels in the serum and liver tissues of mice. In addition, the effects of 200 mg/kg treatment were more evident, and these effects were comparable to those of the drug silymarin. Serum levels of the cytokines, interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α and interferon-γ, were reduced in the mice treated with BPPs compared with injury control group mice, and these levels were comparable to those of the normal and silymarin-treated groups. Histopathological examination indicated that BPPs were able to reduce the extent of CCl 4 -induced liver tissue injury and protect the liver cells. Furthermore, the mRNA and protein expression levels of the inflammation-associated factors cyclooxygenase-2, nitric oxide synthase, TNF-α and IL-1β were reduced in mice treated with BPPs compared with the control group mice. Mice that received 200 mg/kg BPP exhibited reduced expression levels of these factors compared with mice that received 100 mg/kg BPP. In conclusion, the results of the present study suggested that BPPs exert a good preventive effect against hepatic injury.

  3. Protective effect of chitosan from Sepia kobiensis (Hoyle 1885) cuttlebone against CCl4 induced hepatic injury.

    PubMed

    Ramasamy, Pasiyappazham; Subhapradha, Namasivayam; Shanmugam, Vairamani; Shanmugam, Annaian

    2014-04-01

    Carbon tetrachloride (CCl4) is a potent hepatotoxic agent causing hepatic necrosis and it is widely used in animal models for induction of acute and chronic liver damage. The antioxidative and hepatoprotective effects of chitosan from Sepia kobiensis against CCl4 induced liver toxicity in Wistar rats was studied by measuring the activity of lipid peroxidation (TBARS, lipid hydroperoxides), non enzymatic antioxidant (GSH), antioxidant enzyme activities (SOD, CAT and GPx), liver marker enzymes (ALT and AST), lipid profile (FFA, TG, cholesterol and HDL cholesterol) and histopathological changes. Rats treated with chitosan against CCl4 toxicity showed significantly decreased levels of ALT and AST activities, total cholesterol, triglyceride and free fatty acid in plasma and tissue. Whereas the treatment with chitosan along with CCl4 showed markedly increased level of hepatic and circulatory in SOD, CAT, GPx and reduced glutathione and decreased the malondialdehyde level. Histopathological observations proved the marked hepatoprotective effect of chitosan. The CCl4 induced alterations in circulatory and hepatic antioxidant defense system were normalized by chitosan and it could be concluded that the hepatoprotective effect of chitosan may be due to its antioxidant and antilipidemic properties. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Oligonucleotides targeting TCF4 triplet repeat expansion inhibit RNA foci and mis-splicing in Fuchs' dystrophy.

    PubMed

    Hu, Jiaxin; Rong, Ziye; Gong, Xin; Zhou, Zhengyang; Sharma, Vivek K; Xing, Chao; Watts, Jonathan K; Corey, David R; Mootha, V Vinod

    2018-03-15

    Fuchs' endothelial corneal dystrophy (FECD) is the most common repeat expansion disorder. FECD impacts 4% of U.S. population and is the leading indication for corneal transplantation. Most cases are caused by an expanded intronic CUG tract in the TCF4 gene that forms nuclear foci, sequesters splicing factors and impairs splicing. We investigated the sense and antisense RNA landscape at the FECD gene and find that the sense-expanded repeat transcript is the predominant species in patient corneas. In patient tissue, sense foci number were negatively correlated with age and showed no correlation with sex. Each endothelial cell has ∼2 sense foci and each foci is single RNA molecule. We designed antisense oligonucleotides (ASOs) to target the mutant-repetitive RNA and demonstrated potent inhibition of foci in patient-derived cells. Ex vivo treatment of FECD human corneas effectively inhibits foci and reverses pathological changes in splicing. FECD has the potential to be a model for treating many trinucleotide repeat diseases and targeting the TCF4 expansion with ASOs represents a promising therapeutic strategy to prevent and treat FECD.

  5. Retinoic acid receptor-related orphan receptor α-induced activation of adenosine monophosphate-activated protein kinase results in attenuation of hepatic steatosis.

    PubMed

    Kim, Eun-Jin; Yoon, Young-Sil; Hong, Suckchang; Son, Ho-Young; Na, Tae-Young; Lee, Min-Ho; Kang, Hyun-Jin; Park, Jinyoung; Cho, Won-Jea; Kim, Sang-Gun; Koo, Seung-Hoi; Park, Hyeung-geun; Lee, Mi-Ock

    2012-05-01

    There is increasing evidence that the retinoic acid receptor-related orphan receptor α (RORα) plays an important role in the regulation of metabolic pathways, particularly of fatty acid and cholesterol metabolism; however, the role of RORα in the regulation of hepatic lipogenesis has not been studied. Here, we report that RORα attenuates hepatic steatosis, probably via activation of the adenosine monophosphate (AMP)-activated protein kinase (AMPK) and repression of the liver X receptor α (LXRα). First, RORα and its activator, cholesterol sulfate (CS), induced phosphorylation of AMPK, which was accompanied by the activation of serine-threonine kinase liver kinase B1 (LKB1). Second, the activation of RORα, either by transient transfection or CS treatment, decreased the TO901317-induced transcriptional expression of LXRα and its downstream target genes, such as the sterol regulatory element binding protein-1 (SREBP-1) and fatty acid synthase. RORα interacted physically with LXRα and inhibited the LXRα response element in the promoter of LXRα, indicating that RORα interrupts the autoregulatory activation loop of LXRα. Third, infection with adenovirus encoding RORα suppressed the lipid accumulation that had been induced by a free-fatty-acid mixture in cultured cells. Furthermore, we observed that the level of expression of the RORα protein was decreased in the liver of mice that were fed a high-fat diet. Restoration of RORα via tail-vein injection of adenovirus (Ad)-RORα decreased the high-fat-diet-induced hepatic steatosis. Finally, we synthesized thiourea derivatives that activated RORα, thereby inducing activation of AMPK and repression of LXRα. These compounds decreased hepatic triglyceride levels and lipid droplets in the high-fat-diet-fed mice. We found that RORα induced activation of AMPK and inhibition of the lipogenic function of LXRα, which may be key phenomena that provide the beneficial effects of RORα against hepatic steatosis

  6. Vitis vinifera Extract Ameliorate Hepatic and Renal Dysfunction Induced by Dexamethasone in Albino Rats

    PubMed Central

    Hasona, Nabil A.; Alrashidi, Ahmed A.; Aldugieman, Thamer Z.; Alshdokhi, Ali M.; Ahmed, Mohammed Q.

    2017-01-01

    This study was conducted to evaluate the biochemical effects of grape seed extract against dexamethasone-induced hepatic and renal dysfunction in a female albino rat. Twenty-eight adult female rats were divided randomly into four equal groups: Group 1: animals were injected subcutaneously with saline and consider as normal control one. Group 2: animals were injected subcutaneously with dexamethasone in a dose of 0.1 mg/kg body weight. Group 3: animals were injected subcutaneously with 0.1 mg/kg body weight of dexamethasone, and then treated with a grape seed extract in a dose of 200 mg/kg body weight by oral gavage. Group 4: animals were injected subcutaneously with 0.1 mg/kg body weight of dexamethasone, and then treated with a grape seed extract in a dose of 400 mg/kg body weight by oral gavage. After 4 weeks, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) activities, albumin, uric acid, creatinine, and glucose levels were assayed. Hepatic reduced glutathione (GSH), total protein content, and catalase and glucose-6-phosphate dehydrogenase activities were also assayed. Dexamethasone administration caused elevation of serum levels of glucose, uric acid, creatinine, ALT, AST activities, and a decrease in other parameters such as hepatic glutathione, total protein levels, and catalase enzyme activity. Treatment with Vitis vinifera L. seed extract showed a significant increase in the body weight of rats in the group treated with Vitis vinifera L. seed extract orally compared with the dexamethasone control group. An increase in GSH and catalase activity in response to oral treatment with Vitis vinifera L. seed extract was observed after treatment. Grape seed extract positively affects glucocorticoid-induced hepatic and renal alteration in albino rats. PMID:29051443

  7. Omega-3 polyunsaturated fatty acids alleviate hepatic steatosis-induced inflammation through Sirt1-mediated nuclear translocation of NF-κB p65 subunit in hepatocytes of large yellow croaker (Larmichthys crocea).

    PubMed

    Wang, Tianjiao; Yang, Bo; Ji, Renlei; Xu, Wei; Mai, Kangsen; Ai, Qinghui

    2017-12-01

    Hepatic steatosis induced inflammation is becoming increasingly prevalent in farmed fish. This study was conducted to investigate the protective effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) against hepatic steatosis-induced inflammation and its potential molecular mechanisms in hepatocyte of large yellow croaker (Larmichthys crocea). We found that the hepatic steatosis-induced inflammation was relieved by ω-3 PUFAs, meanwhile, the Sirt1 activity and transcript expression was increased by ω-3 PUFAs. The increased Sirt1 activity can decrease the hepatic steatosis-induced inflammation. The protective effects of ω-3 PUFAs against hepatic steatosis-induced inflammation was reversed by the treatment with Sirt1 inhibitor EX-527. The nuclear translocation of nuclear transcription factor kappa-B (NF-κB) p65 was significantly decreased after ω-3 PUFAs treatments compared to the palmitic acid stimulation group. The ω-3 PUFAs induced cytoplasm translocation of NF-κB p65 was reversed by EX-527. Together, ω-3 PUFAs alleviate hepatic steatosis-induced inflammation through Sirt1-mediated nuclear translocation of NF-κB p65 subunit in hepatocytes of large yellow croaker. The present study provides important insight into the mechanisms of the protective effects of ω-3 PUFAs, providing theory bases for alleviating the hepatic steatosis induced inflammation of farmed fish, thereby offering great benefits to the aquaculture industry and fish consumers. Copyright © 2017. Published by Elsevier Ltd.

  8. DNA Double-strand Breaks Induced byFractionated Neutron Beam Irradiation for Boron Neutron Capture Therapy.

    PubMed

    Kinashi, Yuko; Yokomizo, Natsuya; Takahashi, Sentaro

    2017-04-01

    To use the 53BP1 foci assay to detect DNA double-strand breaks induced by fractionated neutron beam irradiation of normal cells. The Kyoto University Research Reactor heavy-water facility and gamma-ray irradiation system were used as experimental radiation sources. After fixation of Chinese Hamster Ovary cells with 3.6% formalin, immunofluorescence staining was performed. Number and size of foci were analyzed using ImageJ software. Fractionated neutron irradiation induced 25% fewer 53BP1 foci than single irradiation at the same dose. By contrast, gamma irradiation induced 30% fewer 53BP1 foci than single irradiation at the same dose. Fractionated neutron irradiation induced larger foci than gamma irradiation, raising the possibility that persistent unrepaired DNA damage was amplified due to the high linear energy transfer component in the neutron beam. Unrepaired cluster DNA damage was more prevalent after fractionated neutron irradiation than after gamma irradiation. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  9. Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease.

    PubMed

    Jegatheesan, Prasanthi; Beutheu, Stéphanie; Ventura, Gabrielle; Sarfati, Gilles; Nubret, Esther; Kapel, Nathalie; Waligora-Dupriet, Anne-Judith; Bergheim, Ina; Cynober, Luc; De-Bandt, Jean-Pascal

    2016-02-01

    Fructose diets have been shown to induce insulin resistance and to alter liver metabolism and gut barrier function, ultimately leading to non-alcoholic fatty liver disease. Citrulline, Glutamine and Arginine may improve insulin sensitivity and have beneficial effects on gut trophicity. Our aim was to evaluate their effects on liver and gut functions in a rat model of fructose-induced non-alcoholic fatty liver disease. Male Sprague-Dawley rats (n = 58) received a 4-week fructose (60%) diet or standard chow with or without Citrulline (0.15 g/d) or an isomolar amount of Arginine or Glutamine. All diets were made isonitrogenous by addition of non-essential amino acids. At week 4, nutritional and metabolic status (plasma glucose, insulin, cholesterol, triglycerides and amino acids, net intestinal absorption) was determined; steatosis (hepatic triglycerides content, histological examination) and hepatic function (plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin) were assessed; and gut barrier integrity (myeloperoxidase activity, portal endotoxemia, tight junction protein expression and localization) and intestinal and hepatic inflammation were evaluated. We also assessed diets effects on caecal microbiota. In these experimental isonitrogenous fructose diet conditions, fructose led to steatosis with dyslipidemia but without altering glucose homeostasis, liver function or gut permeability. Fructose significantly decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia. Arginine and Glutamine supplements were ineffective but Citrulline supplementation prevented hypertriglyceridemia and attenuated liver fat accumulation. While nitrogen supply alone can attenuate fructose-induced non-alcoholic fatty liver disease, Citrulline appears to act directly on hepatic lipid metabolism by partially preventing hypertriglyceridemia and steatosis. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition

  10. Effect of dietary monosodium glutamate on HFCS-induced hepatic steatosis: expression profiles in the liver and visceral fat.

    PubMed

    Collison, Kate S; Maqbool, Zakia M; Inglis, Angela L; Makhoul, Nadine J; Saleh, Soad M; Bakheet, Razan H; Al-Johi, Mohammed A; Al-Rabiah, Rana K; Zaidi, Marya Z; Al-Mohanna, Futwan A

    2010-06-01

    It has previously been shown that patients with nonalcoholic fatty liver disease (NAFLD) exhibit alterations in both hepatic and adipose tissue metabolism, and the dietary factors that contribute to the pathogenesis of NAFLD are likely to be multifactorial. Using C57BL/6J mice, we examined whether chronic exposure to low-dose dietary monosodium glutamate (MSG), high-fructose corn syrup (HFCS), or a combination of the two, vs. control would affect metabolism and hepatic and visceral fat gene expression in adult male progeny. A maternal diet containing 20% HFCS and/or dietary MSG (97.2 +/- 6.3 mg/kg body weight (bw), provided in the drinking water) was offered ad libitum from 3 weeks before mating, and continued throughout gestation and weaning until the progeny reached 32 weeks of age. Liver and abdominal fat gene expression was compared with control animals fed isocaloric standard chow under identical conditions. HFCS induced hepatic steatosis and increased the expression of genes involved in carbohydrate and lipid metabolism. Conversely, dietary MSG elevated serum free fatty acids (FFAs), triglycerides (TGs), high-density lipoprotein-cholesterol (HDL-C), and insulin, together with the expression of hepatic genes involved in lipid metabolism and bile synthesis. The HFCS+MSG combination elevated hepatic TGs, serum FFAs, and TG levels. In visceral white adipose tissue, both MSG and HFCS diets increased the expression of transcription factor Srebf2 and decreased expression of Ppargc1a, while downregulating the expression of mitochondrial respiratory chain components. MSG increased the expression of several genes implicated in adipocytes differentiation. We hypothesize that HFCS may promote hepatic steatosis, whereas dietary MSG induces dyslipidemia and markers of insulin resistance.

  11. Sensitive immunodetection of radiotoxicity after iodine-131 therapy for thyroid cancer using γ-H2AX foci of DNA damage in lymphocytes.

    PubMed

    Doai, Mariko; Watanabe, Naoto; Takahashi, Tomoko; Taniguchi, Mitsuru; Tonami, Hisao; Iwabuchi, Kuniyoshi; Kayano, Daiki; Fukuoka, Makoto; Kinuya, Seigo

    2013-04-01

    The purpose of our study was to evaluate the degree of radiotoxicity to lymphocytes in thyroid cancer after iodine-131(I-131) therapy using γ-H2AX foci immunodetection. This study focused on 15 patients who underwent I-131 therapy for differentiated thyroid cancer after surgery. All patients received 3.7 GBq of I-131. Venous blood samples were collected from each patient before therapy and 4 days thereafter. Lymphocytes were isolated from the blood samples and subjected to γ-H2AX immunofluorescence staining. The number (mean ± SD) of foci per lymphocyte nucleus was 0.41 ± 0.51 before and 6.19 ± 1.80 after radioiodine therapy, and this difference was statistically significant (P = 0.001 < 0.05). Absorbed doses estimated for the 15 patients were 0.77 ± 0.31 Gy applying standard line in vitro external radiation doses. γ-H2AX foci immunodetection in lymphocytes may detect radiation-induced DNA damage associated with I-131 therapy for thyroid cancer, and may facilitate estimation of the radiation doses absorbed with this therapy.

  12. Ketoconazole-induced fulminant hepatitis.

    PubMed Central

    Bercoff, E; Bernuau, J; Degott, C; Kalis, B; Lemaire, A; Tilly, H; Rueff, B; Benhamou, J P

    1985-01-01

    We report the cases of two adult patients in whom fulminant hepatitis developed after 17 and 103 days of ketoconazole administration. Histologic administration showed massive, predominantly centrilobular necrosis. Clinical manifestations of hypersensitivity and eosinophilia were absent in both patients, which suggests that ketoconazole hepatotoxicity is not mediated through an immunoallergic mechanism. Images Fig. 2 PMID:4007605

  13. Babao Dan attenuates hepatic fibrosis by inhibiting hepatic stellate cells activation and proliferation via TLR4 signaling pathway.

    PubMed

    Liang, Lei; Yang, Xue; Yu, Yang; Li, Xiaoyong; Wu, Yechen; Shi, Rongyu; Jiang, Jinghua; Gao, Lu; Ye, Fei; Zhao, Qiudong; Li, Rong; Wei, Lixin; Han, Zhipeng

    2016-12-13

    Babao Dan (BBD), a traditional Chinese medicine, has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the protective effect of BBD on rat hepatic fibrosis induced by diethylnitrosamine (DEN) and explore it possible mechanism. BBD was administrated while DEN was given. After eight weeks, values of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) indicated that BBD significantly protected liver from damaging by DEN and had no obvious side effect on normal rat livers. Meanwhile, BBD attenuated hepatic inflammation and fibrosis in DEN-induced rat livers through histopathological examination and hepatic hydroxyproline content. Furthermore, we found that BBD inhibited hepatic stellate cells activation and proliferation without altering the concentration of lipopolysaccharide (LPS) in portal vein. In vitro study, serum from BBD treated rats (BBD-serum) could also significantly suppress LPS-induced HSCs activation through TLR4/NF-κB pathway. In addition, BBD-serum also inhibited the proliferation of HSCs by regulating TLR4/ERK pathway. Our study demonstrated that BBD may provide a new therapy strategy of hepatic injury and hepatic fibrosis.

  14. Sedum mexicanum Britt. Induces Apoptosis of Primary Rat Activated Hepatic Stellate Cells.

    PubMed

    Lee, Shou-Lun; Chin, Ting-Yu; Lai, Ching-Long; Wang, Wen-Han

    2015-01-01

    Background. Liver fibrosis is a significant liver disease in Asian countries. Sedum mexicanum Britt. (SM) has been claimed to have antihepatitis efficacy. In traditional folk medicine, a solution of boiling water-extracted SM (SME) is consumed to prevent and treat hepatitis. However, its efficacy has not yet been verified. The purpose of this study was to investigate the in vitro effect of SME on hepatoprotection. Methods. Hepatic stellate cells (HSCs) and hepatocytes (HCs) were isolated from the livers of the rats by enzymatic digestion and density gradient centrifugation. Results. Treating the HCs and aHSCs with SME caused a dose-dependent decrease in the viability of aHSCs but not that of HCs. In addition, treatment with SME resulted in apoptosis of aHSCs, as determined by DAPI analysis and flow cytometry. SME also increased the amount of cleaved caspase-3, cleaved caspase-9, and cleaved poly ADP-ribose polymerase (PARP) in aHSCs. Furthermore, SME treatment induced a dose-dependent reduction in Bcl-2 expression and increased the expression of Bax in aHSCs. Conclusions. SME did not cause cytotoxicity in HCs, but it induced apoptosis in aHSCs through the mitochondria-dependent caspase-3 pathway. Therefore, SME may possess therapeutic potential for liver fibrosis.

  15. Sedum mexicanum Britt. Induces Apoptosis of Primary Rat Activated Hepatic Stellate Cells

    PubMed Central

    Lee, Shou-Lun; Chin, Ting-Yu; Lai, Ching-Long; Wang, Wen-Han

    2015-01-01

    Background. Liver fibrosis is a significant liver disease in Asian countries. Sedum mexicanum Britt. (SM) has been claimed to have antihepatitis efficacy. In traditional folk medicine, a solution of boiling water-extracted SM (SME) is consumed to prevent and treat hepatitis. However, its efficacy has not yet been verified. The purpose of this study was to investigate the in vitro effect of SME on hepatoprotection. Methods. Hepatic stellate cells (HSCs) and hepatocytes (HCs) were isolated from the livers of the rats by enzymatic digestion and density gradient centrifugation. Results. Treating the HCs and aHSCs with SME caused a dose-dependent decrease in the viability of aHSCs but not that of HCs. In addition, treatment with SME resulted in apoptosis of aHSCs, as determined by DAPI analysis and flow cytometry. SME also increased the amount of cleaved caspase-3, cleaved caspase-9, and cleaved poly ADP-ribose polymerase (PARP) in aHSCs. Furthermore, SME treatment induced a dose-dependent reduction in Bcl-2 expression and increased the expression of Bax in aHSCs. Conclusions. SME did not cause cytotoxicity in HCs, but it induced apoptosis in aHSCs through the mitochondria-dependent caspase-3 pathway. Therefore, SME may possess therapeutic potential for liver fibrosis. PMID:26078767

  16. [A case of fulminant hepatic failure secondary to hepatic metastasis of small cell lung carcinoma].

    PubMed

    Hwang, Young Tae; Shin, Jung Woo; Lee, Jun Ho; Hwang, Dae Sung; Eum, Jun Bum; Choi, Hye Jeong; Park, Neung Hwa

    2007-12-01

    Although liver metastasis is commonly found in cancer patients, fulminant hepatic failure secondary to diffuse cancer infiltration into the liver is rare. Liver metastasis-induced fulminant hepatic failure has been reported in patients with primary cancer of the gastrointestinal tract, breast and uroepithelium, and in patients with melanoma and hematologic malignancy. Small cell lung cancer is so highly invasive that hepatic metastasis is common, but rapid progression to fulminant hepatic failure is extremely rare. We report here on a case of a patient who died because of rapid progression to fulminant hepatic failure as a result of hepatic metastasis of small cell lung carcinoma.

  17. Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective.

    PubMed

    Karamchandani, Dipti M; Chetty, Runjan

    2018-04-27

    Immune checkpoint inhibitors (CPIs) are a relatively new class of 'miracle' dugs that have revolutionised the treatment and prognosis of some advanced-stage malignancies, and have increased the survival rates significantly. This class of drugs includes cytotoxic T lymphocyte antigen-4 inhibitors such as ipilimumab; programmed cell death protein-1 inhibitors such as nivolumab, pembrolizumab and avelumab; and programmed cell death protein ligand-1 inhibitors such as atezolizumab. These drugs stimulate the immune system by blocking the coinhibitory receptors on the T cells and lead to antitumoural response. However, a flip side of these novel drugs is immune-related adverse events (irAEs), secondary to immune-mediated process due to disrupted self-tolerance. The irAEs in the gastrointestinal (GI) tract/liver may result in diarrhoea, colitis or hepatitis. An accurate diagnosis of CPI-induced colitis and/or hepatitis is essential for optimal patient management. As we anticipate greater use of these drugs in the future given the significant clinical response, pathologists need to be aware of the spectrum of histological findings that may be encountered in GI and/or liver biopsies received from these patients, as well as differentiate them from its histopathological mimics. This present review discusses the clinical features, detailed histopathological features, management and the differential diagnosis of the luminal GI and hepatic irAEs that may be encountered secondary to CPI therapy. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  18. Effects of dark chocolate on azoxymethane-induced colonic aberrant crypt foci.

    PubMed

    Hong, Mee Young; Nulton, Emily; Shelechi, Mahshid; Hernández, Lisa M; Nemoseck, Tricia

    2013-01-01

    Epidemiologic evidence supports that diets rich in polyphenols promote health and may delay the onset of colon cancer. Cocoa and chocolate products have some of the highest polyphenolic concentrations compared to other polyphenolic food sources. This study tested the hypothesis that a diet including dark chocolate can protect against colon cancer by inhibiting aberrant crypt foci (ACF) formation, downregulating gene expression of inflammatory mediators, and favorably altering cell kinetics. We also investigated whether bloomed dark chocolate retains the antioxidant capacity and protects against colon cancer. Forty-eight rats received either a diet containing control (no chocolate), regular dark chocolate, or bloomed dark chocolate and were injected subcutaneously with saline or azoxymethane. Relative to control, both regular and bloomed dark chocolate diets lowered the total number of ACF (P = 0.022). Chocolate diet-fed animals downregulated transcription levels of COX-2 (P = 0.035) and RelA (P = 0.045). Both chocolate diets lowered the proliferation index (P = 0.001). These results suggest that a diet including dark chocolate can reduce cell proliferation and some gene expression involving inflammation, which may explain the lower number of early preneoplastic lesions. These results provide new insight on polyphenol-rich chocolate foods and colon cancer prevention.

  19. Foci of cyclin A2 interact with actin and RhoA in mitosis.

    PubMed

    Loukil, Abdelhalim; Izard, Fanny; Georgieva, Mariya; Mashayekhan, Shaereh; Blanchard, Jean-Marie; Parmeggiani, Andrea; Peter, Marion

    2016-06-09

    Cyclin A2 is a key player in the regulation of the cell cycle. Its degradation in mid-mitosis depends primarily on the ubiquitin-proteasome system (UPS), while autophagy also contributes. However, a fraction of cyclin A2 persists beyond metaphase. In this work, we focus on cyclin A2-rich foci detected in mitosis by high resolution imaging and analyse their movements. We demonstrate that cyclin A2 interacts with actin and RhoA during mitosis, and that cyclin A2 depletion induces a dramatic decrease in active RhoA in mitosis. Our data suggest cyclin A2 participation in RhoA activation in late mitosis.

  20. Gentiana manshurica Kitagawa prevents acetaminophen-induced acute hepatic injury in mice via inhibiting JNK/ERK MAPK pathway

    PubMed Central

    Wang, Ai-Yan; Lian, Li-Hua; Jiang, Ying-Zi; Wu, Yan-Ling; Nan, Ji-Xing

    2010-01-01

    AIM: To investigate the in vivo hepatoprotective effects and mechanisms of Gentiana manshurica Kitagawa (GM) in acetaminophen (APAP)-induced liver injury in mice. METHODS: GM (200, 150 or 50 mg/kg body weight) or N-acetyl-L-cysteine (NAC; 300 mg/kg body weight) was administrated orally with a single dose 2 h prior to APAP (300 mg/kg body weight) injection in mice. RESULTS: APAP treatment significantly depleted hepatic glutathione (GSH), increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and malonyldialdehyde (MDA) and 4-hydroxynonenal levels, and decreased hepatic activity of glutathione peroxidase (GSH-px) and superoxide dismutase (SOD). However, the pretreatment of GM significantly alleviated APAP-induced oxidative stress by increasing GSH content, decreasing serum ALT, AST and MDA, and retaining the activity of GSH-px and SOD in the liver. Furthermore, GM pretreatment can inhibit caspase-3 activation and phosphorylation of c-Jun-NH2-terminal protein kinase 2 (JNK1/2) and extracellular signal-regulated kinase (ERK). GM also remarkably attenuated hepatocyte apoptosis confirmed by the terminal deoxynucleotidyl transferase mediated dUTP nick end-labeling method. CONCLUSION: Hepatoprotective effects of GM against APAP-induced acute toxicity are mediated either by preventing the decline of hepatic antioxidant status or its direct anti-apoptosis capacity. These results support that GM is a potent hepatoprotective agent. PMID:20082487

  1. Saccharomyces boulardii prevention of the hepatic injury induced by Salmonella Enteritidis infection.

    PubMed

    Wu, Daichao; Teng, Da; Wang, Xiumin; Dai, Changsong; Wang, Jianhua

    2014-10-01

    Salmonella enterica subsp. enterica serovar Enteritidis (Salmonella Enteritidis) is the predominant cause of serovar-associated food-borne outbreaks in many countries and causes significant clinical symptoms of liver injury, enteritis, and diarrheal diseases. Saccharomyces boulardii is used in clinical application for prophylaxis and the treatment of a variety of diseases caused by bacterial infection. We used a mouse model of Salmonella Enteritidis infection, which included pretreatment with S. boulardii, to reveal the protection mechanisms of S. boulardii against Salmonella Enteritidis infection, including the translocation of Salmonella Enteritidis to the liver 10 days after Salmonella Enteritidis challenge, and the colonisation of Salmonella Enteritidis and the formation of hepatic tissue lesions in mice after Salmonella Enteritidis challenge on the 10th day. Compared with Salmonella Enteritidis infection in mice, S. boulardii decreased Salmonella Enteritidis translocation to the liver by 96%, and 99% of Salmonella Enteritidis colonised the cecum on the 10th day. Saccharomyces boulardii also abated hepatic tissue injury caused by the infiltration of neutrophilic granulocytes, lymphocytes, and plasmocytes by decreasing the translocation of Salmonella to the liver. These findings demonstrated that S. boulardii is an effective agent in the prevention of the hepatic injury induced by Salmonella Enteritidis infection in a mouse model.

  2. Chlorogenic Acid Improves High Fat Diet-Induced Hepatic Steatosis and Insulin Resistance in Mice

    PubMed Central

    Ma, Yongjie; Gao, Mingming

    2015-01-01

    Purpose Chlorogenic acid (CGA), the most abundant component in coffee, has exhibited many biological activities. The objective of this study is to assess preventive and therapeutic effects of CGA on obesity and obesity-related liver steatosis and insulin resistance. Methods Two sets of experiments were conducted. In set 1, 6-week old C57BL/6 mice were fed a regular chow or high-fat diet (HFD) for 15 weeks with twice intra-peritoneal (IP) injection of CGA (100 mg/kg) or DMSO (carrier solution) per week. In set 2, obese mice (average 50 g) were treated by CGA (100 mg/kg, IP, twice weekly) or DMSO for 6 weeks. Body weight, body composition and food intake were monitored. Blood glucose, insulin and lipid levels were measured at end of the study. Hepatic lipid accumulation and glucose homeostasis were evaluated. Additionally, genes involved in lipid metabolism and inflammation were analyzed by real time PCR. Results CGA significantly blocked the development of diet-induced obesity but did not affect body weight in obese mice. CGA treatment curbed HFD-induced hepatic steatosis and insulin resistance. Quantitative PCR analysis shows that CGA treatment suppressed hepatic expression Pparγ, Cd36, Fabp4, and Mgat1 gene. CGA treatment also attenuated inflammation in the liver and white adipose tissue accompanied by a decrease in mRNA levels of macrophage marker genes including F4/80, Cd68, Cd11b, Cd11c, and Tnfa, Mcp-1 and Ccr2 encoding inflammatory proteins. Conclusion Our study provides direct evidence in support of CGA as a potent compound in preventing diet-induced obesity and obesity-related metabolic syndrome. Our results suggest that drinking coffee is beneficial in maintaining metabolic homeostasis when on a high fat diet. PMID:25248334

  3. Chlorogenic acid improves high fat diet-induced hepatic steatosis and insulin resistance in mice.

    PubMed

    Ma, Yongjie; Gao, Mingming; Liu, Dexi

    2015-04-01

    Chlorogenic acid (CGA), the most abundant component in coffee, has exhibited many biological activities. The objective of this study is to assess preventive and therapeutic effects of CGA on obesity and obesity-related liver steatosis and insulin resistance. Two sets of experiments were conducted. In set 1, 6-week old C57BL/6 mice were fed a regular chow or high-fat diet (HFD) for 15 weeks with twice intra-peritoneal (IP) injection of CGA (100 mg/kg) or DMSO (carrier solution) per week. In set 2, obese mice (average 50 g) were treated by CGA (100 mg/kg, IP, twice weekly) or DMSO for 6 weeks. Body weight, body composition and food intake were monitored. Blood glucose, insulin and lipid levels were measured at end of the study. Hepatic lipid accumulation and glucose homeostasis were evaluated. Additionally, genes involved in lipid metabolism and inflammation were analyzed by real time PCR. CGA significantly blocked the development of diet-induced obesity but did not affect body weight in obese mice. CGA treatment curbed HFD-induced hepatic steatosis and insulin resistance. Quantitative PCR analysis shows that CGA treatment suppressed hepatic expression of Pparγ, Cd36, Fabp4, and Mgat1 gene. CGA treatment also attenuated inflammation in the liver and white adipose tissue accompanied by a decrease in mRNA levels of macrophage marker genes including F4/80, Cd68, Cd11b, Cd11c, and Tnfα, Mcp-1 and Ccr2 encoding inflammatory proteins. Our study provides direct evidence in support of CGA as a potent compound in preventing diet-induced obesity and obesity-related metabolic syndrome. Our results suggest that drinking coffee is beneficial in maintaining metabolic homeostasis when on a high fat diet.

  4. The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury

    PubMed Central

    Selvaraj, Saravanakumar; Oh, Jung-Hwa; Spanel, Reinhard; Länger, Florian; Han, Hyoung-Yun; Lee, Eun-Hee; Yoon, Seokjoo; Borlak, Jürgen

    2017-01-01

    Hypersensitivity to non-steroidal anti-inflammatory drugs is a common adverse drug reaction and may result in serious inflammatory reactions of the liver. To investigate mechanism of immunoallergic hepatitis beagle dogs were given 1 or 3 mg/kg/day (HD) oral diclofenac for 28 days. HD diclofenac treatment caused liver function test abnormalities, reduced haematocrit and haemoglobin but induced reticulocyte, WBC, platelet, neutrophil and eosinophil counts. Histopathology evidenced hepatic steatosis and glycogen depletion, apoptosis, acute lobular hepatitis, granulomas and mastocytosis. Whole genome scans revealed 663 significantly regulated genes of which 82, 47 and 25 code for stress, immune response and inflammation. Immunopathology confirmed strong induction of IgM, the complement factors C3&B, SAA, SERPING1 and others of the classical and alternate pathway. Alike, marked expression of CD205 and CD74 in Kupffer cells and lymphocytes facilitate antigen presentation and B-cell differentiation. The highly induced HIF1A and KLF6 protein expression in mast cells and macrophages sustain inflammation. Furthermore, immunogenomics discovered 24, 17, 6 and 11 significantly regulated marker genes to hallmark M1/M2 polarized macrophages, lymphocytic and granulocytic infiltrates; note, the latter was confirmed by CAE staining. Other highly regulated genes included alpha-2-macroglobulin, CRP, hepcidin, IL1R1, S100A8 and CCL20. Diclofenac treatment caused unprecedented induction of myeloperoxidase in macrophages and oxidative stress as shown by SOD1/SOD2 immunohistochemistry. Lastly, bioinformatics defined molecular circuits of inflammation and consisted of 161 regulated genes. Altogether, the mechanism of diclofenac induced liver hypersensitivity reactions involved oxidative stress, macrophage polarization, mastocytosis, complement activation and an erroneous programming of the innate and adaptive immune system. PMID:29296203

  5. The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice.

    PubMed

    Pinto, Livia de Fraia; Compri, Cecília Melleti; Fornari, João Victor; Bartchewsky, Waldemar; Cintra, Dennys Eduardo; Trevisan, Miriam; Carvalho, Patrícia de Oliveira; Ribeiro, Marcelo Lima; Velloso, Licio A; Saad, Mario J; Pedrazzoli, José; Gambero, Alessandra

    2010-04-01

    Pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-alpha, are known to be involved in the establishment of insulin resistance. Insulin resistance plays a key role in the development of obesity-related pathologies, such as type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The state of chronic inflammation associated with obesity led us to hypothesize that TNF-alpha blockade may have an effect on experimentally obese animals. We studied the effects of thalidomide, an immunosuppressant and anti-TNF-alpha drug, on hepatic alterations that were induced by a high-fat diet (HFD) in mice. Obesity was induced in Swiss mice using a HFD for 12 weeks. Thalidomide-treated animals received thalidomide i.p. (100 mg/kg/day, 10 days). Glucose, aspartate aminotransferases and alanine aminotransferases levels were assessed in the blood. Insulin and glucose tolerance tests were performed. The liver was excised for histological, triglyceride, gene and protein expression analyses. We found improvements in both the basal glucose blood levels and the response to insulin administration in the treated animals. The molecular analysis of insulin signalling revealed a restoration of the hepatic insulin receptor substrate (IRS)-1 and AKT phosphorylation. The hepatic expression of TNF-alpha was inhibited and the levels correlated with a significant reduction in the steatosis area. Other hepatic inflammatory markers, such as iNOS and suppressor of cytokine signalling (SOCS-3), were also reduced. We suggest that immunosuppressant drugs that target TNF-alpha and that may also contribute to reductions in the inflammatory markers that are associated with obesity could be a therapeutic option in NAFLD and type 2 diabetes.

  6. The chemopreventive potential of Curcuma purpurascens rhizome in reducing azoxymethane-induced aberrant crypt foci in rats

    PubMed Central

    Rouhollahi, Elham; Moghadamtousi, Soheil Zorofchian; Al-Henhena, Nawal; Kunasegaran, Thubasni; Hasanpourghadi, Mohadeseh; Looi, Chung Yeng; Abd Malek, Sri Nurestri; Awang, Khalijah; Abdulla, Mahmood Ameen; Mohamed, Zahurin

    2015-01-01

    Curcuma purpurascens BI. rhizome, a member of the Zingiberaceae family, is a popular spice in Indonesia that is traditionally used in assorted remedies. Dichloromethane extract of C. purpurascens BI. rhizome (DECPR) has previously been shown to have an apoptosis-inducing effect on colon cancer cells. In the present study, we examined the potential of DECPR to prevent colon cancer development in rats treated with azoxymethane (AOM) (15 mg/kg) by determining the percentage inhibition in incidence of aberrant crypt foci (ACF). Starting from the day immediately after AOM treatment, three groups of rats were orally administered once a day for 2 months either 10% Tween 20 (5 mL/kg, cancer control), DECPR (250 mg/kg, low dose), or DECPR (500 mg/kg, high dose). Meanwhile, the control group was intraperitoneally injected with 5-fluorouracil (35 mg/kg) for 5 consecutive days. After euthanizing the rats, the number of ACF was enumerated in colon tissues. Bax, Bcl-2, and proliferating cell nuclear antigen (PCNA) protein expressions were examined using immunohistochemical and Western blot analyses. Antioxidant enzymatic activity was measured in colon tissue homogenates and associated with malondialdehyde level. The percentage inhibition of ACF was 56.04% and 68.68% in the low- and high-dose DECPR-treated groups, respectively. The ACF inhibition in the treatment control group was 74.17%. Results revealed that DECPR exposure at both doses significantly decreased AOM-induced ACF formation, which was accompanied by reduced expression of PCNA. Upregulation of Bax and downregulation of Bcl-2 suggested the involvement of apoptosis in the chemopreventive effect of DECPR. In addition, the oxidative stress resulting from AOM treatment was significantly attenuated after administration of DECPR, which was shown by the elevated antioxidant enzymatic activity and reduced malondialdehyde level. Taken together, the present data clearly indicate that DECPR significantly inhibits ACF formation

  7. Automated analysis of time-lapse fluorescence microscopy images: from live cell images to intracellular foci.

    PubMed

    Dzyubachyk, Oleh; Essers, Jeroen; van Cappellen, Wiggert A; Baldeyron, Céline; Inagaki, Akiko; Niessen, Wiro J; Meijering, Erik

    2010-10-01

    Complete, accurate and reproducible analysis of intracellular foci from fluorescence microscopy image sequences of live cells requires full automation of all processing steps involved: cell segmentation and tracking followed by foci segmentation and pattern analysis. Integrated systems for this purpose are lacking. Extending our previous work in cell segmentation and tracking, we developed a new system for performing fully automated analysis of fluorescent foci in single cells. The system was validated by applying it to two common tasks: intracellular foci counting (in DNA damage repair experiments) and cell-phase identification based on foci pattern analysis (in DNA replication experiments). Experimental results show that the system performs comparably to expert human observers. Thus, it may replace tedious manual analyses for the considered tasks, and enables high-content screening. The described system was implemented in MATLAB (The MathWorks, Inc., USA) and compiled to run within the MATLAB environment. The routines together with four sample datasets are available at http://celmia.bigr.nl/. The software is planned for public release, free of charge for non-commercial use, after publication of this article.

  8. Induced expression of hepatic N-methyl-D-aspartate receptor 2C subunit gene during liver enlargement induced by lead nitrate, a hepatocellular mitogen.

    PubMed

    Nemoto, Kiyomitsu; Ikeda, Ayaka; Hikida, Tokihiro; Kojima, Misaki; Degawa, Masakuni

    2013-02-01

    We previously demonstrated the super-induced expression of the Grin2c gene encoding the N-methyl-D-aspartate receptor 2C subunit during the development of liver enlargement with hepatocellular hypertrophy induced by phenobarbital, clofibrate, or piperonyl butoxide. In the present study, we assessed whether or not Grin2c gene expression was induced during the development of chemically induced liver enlargement with hyperplasia. Male Sprague-Dawley (SD) rats, stroke-prone spontaneously hypertensive rats (SHRSPs), and SHRSP's normotensive control, Wistar-Kyoto (WKY) rats, were administered lead nitrate (LN) (0.1 mmol/kg, single i.v.), a direct inducer of liver hyperplasia, and changes in the level of Grin2c mRNA in the liver were assessed by real-time RT-PCR. The level of hepatic Grin2c mRNA was significantly higher 6-48 hr after the injection in SD rats (about 30~40- and 70-fold over the control at 6~24 hr and 48 hr, respectively) and in WKY rats (about 20-fold over the control only at 12 hr), but was not significantly higher in SHRSPs. Such differences in LN-induced levels of Grin2c mRNA among SD rats, WKY rats, and SHRSPs were closely correlated with those in the previously reported increase in liver weight 48 hr after LN administration. The present findings suggest that the increase in the level of hepatic Grin2c mRNA relates to development of chemically induced liver enlargement with hyperplasia.

  9. Hepatic Complications of Anorexia Nervosa.

    PubMed

    Rosen, Elissa; Bakshi, Neeru; Watters, Ashlie; Rosen, Hugo R; Mehler, Philip S

    2017-11-01

    Anorexia nervosa (AN) has the highest mortality rate of all psychiatric illnesses due to the widespread organ dysfunction caused by the underlying severe malnutrition. Starvation causes hepatocyte injury and death leading to a rise in aminotransferases. Malnutrition-induced hepatitis is common among individuals with AN especially as body mass index decreases. Acute liver failure associated with coagulopathy and encephalopathy can rarely occur. Liver enzymes may also less commonly increase as part of the refeeding process due to hepatic steatosis and can be distinguished from starvation hepatitis by the finding of a fatty liver on ultrasonography. Individuals with AN and starvation-induced hepatitis are at increased risk of hypoglycemia due to depleted glycogen stores and impaired gluconeogenesis. Gastroenterology and hepatology consultations are often requested when patients with AN and signs of hepatitis are hospitalized. It should be noted that additional laboratory testing, imaging, or liver biopsy all have low diagnostic yield, are costly, and potentially invasive, therefore, not generally recommended for diagnostic purposes. While the hepatitis of AN can reach severe levels, a supervised increase in caloric intake and a return to a healthy body weight often quickly lead to normalization of elevated aminotransferases caused by starvation.

  10. A Case Report of Supplement-Induced Hepatitis in an Active Duty Service Member.

    PubMed

    Brazeau, Michael J; Castaneda, Joni L; Huitron, Sonny S; Wang, James

    2015-07-01

    The incidence of drug-induced hepatic injury has been increasing as a result of more widespread use of workout supplements containing anabolic steroids to increase muscle mass. Synthetic androgenic steroids are shown to cause cholestatic liver injury, but the exact mechanism of injury is not completely understood. We present a case of a healthy, young, active duty Army male soldier who developed pruritis and jaundice shortly after starting to take a body-building supplement containing anabolic steroids, and was subsequently found to have significant biopsy proven drug-induced liver injury. Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.

  11. Naringin ameliorates sodium arsenite-induced renal and hepatic toxicity in rats: decisive role of KIM-1, Caspase-3, TGF-β, and TNF-α.

    PubMed

    Adil, Mohammad; Kandhare, Amit D; Visnagri, Asjad; Bodhankar, Subhash L

    2015-01-01

    Chronic exposure of a naturally occurring metal arsenic leads to renal and hepatic diseases. Naringin, a flavanone glycoside, possesses anti-inflammatory and anti-oxidant potential. The aim of this investigation was to evaluate the protective effect of naringin against arsenic-induced renal and hepatic toxicity in rats. Renal and hepatic toxicity was induced in rats by sodium arsenite (5 mg/kg, p.o.). Rats were treated orally with either vehicle or naringin (20, 40, and 80 mg/kg) or Coenzyme Q10 (10 mg/kg) for 28 days. Various biochemical, histological, and molecular biomarkers were assessed in kidney and liver. Treatment with naringin (40 and 80 mg/kg) significantly and dose-dependently restored (p < 0.01 and p < 0.001) altered levels of kidney (serum creatinine, urine creatinine, BUN, uric acid, and creatinine clearance) and liver function test (AST and ALT) induced by sodium arsenite. Elevated levels of oxido-nitrosative stress in renal and hepatic tissue was significantly and dose-dependently decreased (p < 0.01 and p < 0.001) by naringin (40 and 80 mg/kg) treatment. It significantly and dose-dependently down-regulated (p < 0.01 and p < 0.001) renal KIM-1, Caspase-3, TGF-β, and TNF-α mRNA expression. Histopathological alteration induced in kidney and liver by sodium arsenite was reduced by naringin (40 and 80 mg/kg) treatment. In conclusion, naringin treatment ameliorates arsenic-induced renal and hepatic damage in rats due its antioxidant and anti-inflammatory properties via down-regulation of elevated oxido-nitrosative stress, KIM-1, Caspase-3, TGF-β, and TNF-α levels.

  12. A comprehensive statistical classifier of foci in the cell transformation assay for carcinogenicity testing.

    PubMed

    Callegaro, Giulia; Malkoc, Kasja; Corvi, Raffaella; Urani, Chiara; Stefanini, Federico M

    2017-12-01

    The identification of the carcinogenic risk of chemicals is currently mainly based on animal studies. The in vitro Cell Transformation Assays (CTAs) are a promising alternative to be considered in an integrated approach. CTAs measure the induction of foci of transformed cells. CTAs model key stages of the in vivo neoplastic process and are able to detect both genotoxic and some non-genotoxic compounds, being the only in vitro method able to deal with the latter. Despite their favorable features, CTAs can be further improved, especially reducing the possible subjectivity arising from the last phase of the protocol, namely visual scoring of foci using coded morphological features. By taking advantage of digital image analysis, the aim of our work is to translate morphological features into statistical descriptors of foci images, and to use them to mimic the classification performances of the visual scorer to discriminate between transformed and non-transformed foci. Here we present a classifier based on five descriptors trained on a dataset of 1364 foci, obtained with different compounds and concentrations. Our classifier showed accuracy, sensitivity and specificity equal to 0.77 and an area under the curve (AUC) of 0.84. The presented classifier outperforms a previously published model. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. 21-Aminosteroids prevent the down-regulation of hepatic cytochrome P450 induced by hypoxia and inflammation in conscious rabbits

    PubMed Central

    Galal, Ahmed; du Souich, Patrick

    1999-01-01

    This study was conducted to assess whether a 21-aminosteroid, U74389G, could prevent the down-regulation of hepatic cytochrome P450 (P450) induced by acute moderate hypoxia or an inflammatory reaction.The rabbits of two groups (n=6 per group) were subjected to acute moderate hypoxia (PaO2≈35 mmHg), one pre-treated with U74389G (3 mg kg−1 i.v. every 6 h, for 48 h). The rabbits of two other groups received 5 ml of turpentine s.c., one of them being pre-treated with U74389G (3 mg kg−1 i.v. every 6 h, for 72 h). The kinetics of theophylline (2.5 mg kg−1) were assessed to evaluate the activity of the P450. Once the rabbits were sacrificed, the P450 content and the amount of thiobarbituric acid reactive substances (TBARS), a marker of lipid peroxidation, were estimated in the liver.Compared with control rabbits, hypoxia and inflammation increased theophylline plasma concentrations, as a result of a decrease in theophylline systemic clearance (P<0.05). Both experimental conditions reduced hepatic content of P450 by 40–50% (P<0.05) and increased the amount of hepatic TBARS by around 50% (P<0.05). Pre-treatment with U74389G prevented the hypoxia- and inflammation-induced decrease in theophylline systemic clearance, the down-regulation of hepatic P450, and the increase in liver TBARS.It is concluded that in the rabbit, U74389G prevents hepatic P450 depression produced by acute moderate hypoxia and a turpentine-induced inflammatory reaction, possibly by eliciting a radical quenching antioxidant activity. PMID:10510447

  14. Dietary intake of ain-93 standard diet induces Fatty liver with altered hepatic fatty acid profile in Wistar rats.

    PubMed

    Farias Santos, Juliana; Suruagy Amaral, Monique; Lima Oliveira, Suzana; Porto Barbosa, Júnia; Rego Cabral, Cyro; Sofia Melo, Ingrid; Bezerra Bueno, Nassib; Duarte Freitas, Johnatan; Goulart Sant'ana, Antônio; Rocha Ataíde, Terezinha

    2015-05-01

    There are several standard diets for animals used in scientific research, usually conceived by scientific institutions. The AIN-93 diet is widely used, but there are some reports of fatty liver in Wistar rats fed this diet. We aimed to evaluate the hepatic repercussions of the AIN-93 diet intake in Wistar rats. Forty newly-weaned 21-day-old male Wistar rats were fed either the AIN-93 diet or a commercial diet for either 1 month or 4 months. Weight gain, serum biochemistry, hepatic histology, and hepatic fatty acid profile were analyzed. Hepatic steatosis was observed, especially in the group fed the AIN-93 diet. Serum blood glucose, absolute and relative liver weight and hepatic levels of oleic, palmitoleic, stearic, and palmitic fatty acids were related to the observed steatosis, while lipidogram and serum markers of liver function and injury were not. AIN-93 diet induced acute hepatic steatosis in Wistar rats, which may compromise its use as a standard diet for experimental studies with rodents. The hepatic fatty acid profile was associated with steatosis, with possible implications for disease prognosis. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  15. Identifying aggressive prostate cancer foci using a DNA methylation classifier.

    PubMed

    Mundbjerg, Kamilla; Chopra, Sameer; Alemozaffar, Mehrdad; Duymich, Christopher; Lakshminarasimhan, Ranjani; Nichols, Peter W; Aron, Manju; Siegmund, Kimberly D; Ukimura, Osamu; Aron, Monish; Stern, Mariana; Gill, Parkash; Carpten, John D; Ørntoft, Torben F; Sørensen, Karina D; Weisenberger, Daniel J; Jones, Peter A; Duddalwar, Vinay; Gill, Inderbir; Liang, Gangning

    2017-01-12

    Slow-growing prostate cancer (PC) can be aggressive in a subset of cases. Therefore, prognostic tools to guide clinical decision-making and avoid overtreatment of indolent PC and undertreatment of aggressive disease are urgently needed. PC has a propensity to be multifocal with several different cancerous foci per gland. Here, we have taken advantage of the multifocal propensity of PC and categorized aggressiveness of individual PC foci based on DNA methylation patterns in primary PC foci and matched lymph node metastases. In a set of 14 patients, we demonstrate that over half of the cases have multiple epigenetically distinct subclones and determine the primary subclone from which the metastatic lesion(s) originated. Furthermore, we develop an aggressiveness classifier consisting of 25 DNA methylation probes to determine aggressive and non-aggressive subclones. Upon validation of the classifier in an independent cohort, the predicted aggressive tumors are significantly associated with the presence of lymph node metastases and invasive tumor stages. Overall, this study provides molecular-based support for determining PC aggressiveness with the potential to impact clinical decision-making, such as targeted biopsy approaches for early diagnosis and active surveillance, in addition to focal therapy.

  16. CD40 dependent exacerbation of immune mediated hepatitis by hepatic CD11b+ Gr-1+ myeloid derived suppressor cells in tumor bearing mice

    PubMed Central

    Kapanadze, Tamar; Medina-Echeverz, José; Gamrekelashvili, Jaba; Weiss, Jonathan M.; Wiltrout, Robert H.; Kapoor, Veena; Hawk, Nga; Terabe, Masaki; Berzofsky, Jay A.; Manns, Michael P.; Wang, Ena; Marincola, Francesco M.; Korangy, Firouzeh; Greten, Tim F.

    2015-01-01

    Immunosuppressive CD11b+Gr-1+ myeloid-derived suppressor cells (MDSC) accumulate in the livers of tumor-bearing mice. We studied hepatic MDSC in two murine models of immune mediated hepatitis. Unexpectedly, treatment of tumor bearing mice with Concanavalin A or α-Galactosylceramide resulted in increased ALT and AST serum levels in comparison to tumor free mice. Adoptive transfer of hepatic MDSC into naïve mice exacerbated Concanavalin A induced liver damage. Hepatic CD11b+Gr-1+ cells revealed a polarized pro-inflammatory gene signature after Concanavalin A treatment. An interferon gamma- dependent up-regulation of CD40 on hepatic CD11b+Gr-1+ cells along with an up-regulation of CD80, CD86, and CD1d after Concanavalin A treatment was observed. Concanavalin A treatment resulted in a loss of suppressor function by tumor-induced CD11b+Gr-1+ MDSC as well as enhanced reactive oxygen species-mediated hepatotoxicity. CD40 knockdown in hepatic MDSC led to increased arginase activity upon Concanavalin A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40−/− tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased reactive oxygen species production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSC act as pro-inflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner. PMID:25616156

  17. Ameliorative effect of naringin in acetaminophen-induced hepatic and renal toxicity in laboratory rats: role of FXR and KIM-1.

    PubMed

    Adil, Mohammad; Kandhare, Amit D; Ghosh, Pinaki; Venkata, Shivakumar; Raygude, Kiran S; Bodhankar, Subhash L

    2016-07-01

    Acetaminophen (APAP) is an analgesic and antipyretic agent commonly known agent to cause hepatic and renal toxicity at a higher dose. Naringin, a bioflavonoid possesses multiple pharmacological properties such as antioxidant, anti-inflammatory, analgesic and anti-hyperlipidemic activity. To evaluate the effect of naringin against the APAP-induced hepatic and renal toxicity. Male Wistar albino rats (180-220 g) were divided into various groups, and toxicity was induced by APAP (700 mg/kg, p.o., 14 days). Naringin (20, 40 and 80 mg/kg, p.o.) or Silymarin (25 mg/kg) was administered to rats 2 h before APAP oral administration. Various biochemical, molecular and histopathological parameter were accessed in hepatic and renal tissue. Naringin pretreatment significantly decreased (p < 0.05) serum creatinine, blood urea nitrogen, bilirubin, aspartate transaminase, alanine transaminase, lactate dehydrogenase, low-density lipoprotein, very low-density lipoprotein, cholesterol and triglycerides as compared with APAP control rats. Decreased level of serum albumin, uric acid, and high-density lipoprotein were also significantly restored (p < 0.05) by naringin pretreatment. It also significantly restores (p < 0.05) the altered level of superoxide dismutase, reduced glutathione, malondialdehyde and nitric oxide in hepatic and renal tissue. Moreover, altered mRNA expression of hepatic farnesoid X receptor and renal injury molecule-1 (KIM-1) were significantly restored (p < 0.05) by naringin treatment. Naringin treatment also reduced histological alteration induced by APAP in the liver and kidney. Naringin exerts its hepato- and nephroprotective effect via modulation of oxido-nitrosative stress, FXR and KIM-1 mRNA expression.

  18. Human induced pluripotent stem cell-derived hepatic cell lines as a new model for host interaction with hepatitis B virus

    PubMed Central

    Kaneko, Shun; Kakinuma, Sei; Asahina, Yasuhiro; Kamiya, Akihide; Miyoshi, Masato; Tsunoda, Tomoyuki; Nitta, Sayuri; Asano, Yu; Nagata, Hiroko; Otani, Satoshi; Kawai-Kitahata, Fukiko; Murakawa, Miyako; Itsui, Yasuhiro; Nakagawa, Mina; Azuma, Seishin; Nakauchi, Hiromitsu; Nishitsuji, Hironori; Ujino, Saneyuki; Shimotohno, Kunitada; Iwamoto, Masashi; Watashi, Koichi; Wakita, Takaji; Watanabe, Mamoru

    2016-01-01

    Hepatitis B virus (HBV) is not eradicated by current antiviral therapies due to persistence of HBV covalently closed circular DNA (cccDNA) in host cells, and thus development of novel culture models for productive HBV infection is urgently needed, which will allow the study of HBV cccDNA eradication. To meet this need, we developed culture models of HBV infection using human induced pluripotent stem cell-derived hepatocyte lineages, including immature proliferating hepatic progenitor-like cell lines (iPS-HPCs) and differentiated hepatocyte-like cells (iPS-Heps). These cells were susceptible to HBV infection, produced HBV particles, and maintained innate immune responses. The infection efficiency of HBV in iPS-HPCs predominantly depended on the expression levels of sodium taurocholate cotransporting polypeptide (NTCP), and was low relative to iPS-Heps: however, long-term culture of iPS-Heps was difficult. To provide a model for HBV persistence, iPS-HPCs overexpressing NTCP were established. The long-term persistence of HBV cccDNA was detected in iPS-HPCs overexpressing NTCP, and depended on the inhibition of the Janus-kinase signaling pathway. In conclusion, this study provides evidence that iPS-derived hepatic cell lines can be utilized for novel HBV culture models with genetic variation to investigate the interactions between HBV and host cells and the development of anti-HBV strategies. PMID:27386799

  19. Menhaden Oil Decreases High-Fat Diet–Induced Markers of Hepatic Damage, Steatosis, Inflammation, and Fibrosis in Obese Ldlr−/− Mice123

    PubMed Central

    Depner, Christopher M.; Torres-Gonzalez, Moises; Tripathy, Sasmita; Milne, Ginger; Jump, Donald B.

    2012-01-01

    The frequency of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with obesity in the United States. NASH is progressive and characterized by hepatic damage, inflammation, fibrosis, and oxidative stress. Because C20–22 (n-3) PUFA are established regulators of lipid metabolism and inflammation, we tested the hypothesis that C20–22 (n-3) PUFA in menhaden oil (MO) prevent high-fat (HF) diet–induced fatty liver disease in mice. Wild-type (WT) and Ldlr−/− C57BL/6J mice were fed the following diets for 12 wk: nonpurified (NP), HF with lard (60% of energy from fat), HF–high-cholesterol with olive oil (HFHC-OO; 54.4% of energy from fat, 0.5% cholesterol), or HFHC-OO supplemented with MO (HFHC-MO). When compared with the NP diet, the HF and HFHC-OO diets induced hepatosteatosis and hepatic damage [elevated plasma alanine aminotransferase (ALT) and aspartate aminotransferases] and elevated hepatic expression of markers of inflammation (monocyte chemoattractant protein-1), fibrosis (procollagen 1α1), and oxidative stress (heme oxygenase-1) (P ≤ 0.05). Hepatic damage (i.e., ALT) correlated (r = 0.74, P < 0.05) with quantitatively higher (>140%, P < 0.05) hepatic cholesterol in Ldlr−/− mice fed the HFHC-OO diet than WT mice fed the HF or HFHC-OO diets. Plasma and hepatic markers of liver damage, steatosis, inflammation, and fibrosis, but not oxidative stress, were lower in WT and Ldlr−/− mice fed the HFHC-MO diet compared with the HFHC-OO diet (P < 0.05). In conclusion, MO [C20–22 (n-3) PUFA at 2% of energy] decreases many, but not all, HF diet–induced markers of fatty liver disease in mice. PMID:22739374

  20. Effects of Curcumin on Tobacco Smoke-induced Hepatic MAPK Pathway Activation and Epithelial-Mesenchymal Transition In Vivo.

    PubMed

    Liang, Zhaofeng; Wu, Rui; Xie, Wei; Xie, Chunfeng; Wu, Jieshu; Geng, Shanshan; Li, Xiaoting; Zhu, Mingming; Zhu, Weiwei; Zhu, Jianyun; Huang, Cong; Ma, Xiao; Xu, Wenrong; Zhong, Caiyun; Han, Hongyu

    2017-08-01

    Tobacco smoke is a major risk factor for hepatic cancer. Epithelial-mesenchymal transition (EMT) induced by tobacco smoke is crucially involved in the initiation and development of cancer. Mitogen-activated protein kinase (MAPK) pathways play important roles in tobacco smoke-associated carcinogenesis including EMT process. The chemopreventive effect of curcumin supplementation against cancers has been reported. In this study, we investigated the effects of tobacco smoke on MAPK pathway activation and EMT alterations, and then the preventive effect of curcumin was examined in the liver of BALB/c mice. Our results indicated that exposure of mice to tobacco smoke for 12 weeks led to activation of ERK1/2, JNK, p38 and ERK5 pathways as well as activator protein-1 (AP-1) proteins in liver tissue. Exposure of mice to tobacco smoke reduced the hepatic mRNA and protein expression of the epithelial markers, while the hepatic mRNA and protein levels of the mesenchymal markers were increased. Treatment of curcumin effectively attenuated tobacco smoke-induced activation of ERK1/2 and JNK MAPK pathways, AP-1 proteins and EMT alterations in the mice liver. Our data suggested the protective effect of curcumin in tobacco smoke-triggered MAPK pathway activation and EMT in the liver of BALB/c mice, thus providing new insights into the chemoprevention of tobacco smoke-associated hepatic cancer. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  1. Hepatoprotective effects of polysaccharide isolated from Agaricus bisporus industrial wastewater against CCl₄-induced hepatic injury in mice.

    PubMed

    Huang, Jiafu; Ou, Yixin; Yew, Tai Wai David; Liu, Jingna; Leng, Bo; Lin, Zhichao; Su, Yi; Zhuang, Yuanhong; Lin, Jiaofen; Li, Xiumin; Xue, Yu; Pan, Yutian

    2016-01-01

    During the industrial production of canned mushroom (Agaricus bisporus), a large quantity of wastewater is produced. In this study, the wastewater generated during the canning of mushroom was analyzed. From this wastewater, four polysaccharide components (Abnp1001, Abnp1002, Abap1001, and Abap1002) with hepatic-protective activity were isolated by ultrafiltration, DEAE cellulose-52 chromatography and Sephadex G-200 size-exclusion chromatography. Results of ultraviolet spectra analysis and molecular weight determination showed that Abnp1001, Abnp1002, Abap1001 and Abap1002 were uniform with average molecular weights of 336, 12.8, 330 and 15.8kDa, respectively. The monosaccharide composition analysis using gas chromatography (GC) showed that the four fractions were heteropolysaccharides and mainly composed of glucose. Fourier transform-infrared (FT-IR) analysis showed that the isolated fractions were all composed of β-glycoside linkages. Additionally, the potential hepatoprotective activities of these polysaccharides against CCl4-induced hepatic injury in mice were studied. Notably, Abnp1002 and Abap1002 could lower the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations in serum in a dose dependent manner and reduce the hepatocellular degeneration and necrosis, as well as inflammatory infiltration. These results indicate that these two polysaccharides had protective effects on acute hepatic injury induced by CCl4 in mice and suggest that the polysaccharides extracted from A. bisporus industrial wastewater might have potential in therapeutics of acute hepatic injury. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice

    PubMed Central

    Willecke, Florian; Scerbo, Diego; Nagareddy, Prabhakara; Obunike, Joseph C; Barrett, Tessa J; Abdillahi, Mariane L.; Trent, Chad M.; Huggins, Lesley Ann; Fisher, Edward A; Drosatos, Konstantinos; Goldberg, Ira J.

    2014-01-01

    Objective Diabetic hypertriglyceridemia is thought to be primarily driven by increased hepatic de novo lipogenesis. However, experiments in animal models indicated that insulin deficiency should decrease hepatic de novo lipogenesis and reduce plasma triglyceride levels. Approach and Results To address the discrepancy between human data and genetically altered mouse models, we investigated whether insulin deficient diabetic mice had triglyceride changes that resemble those in diabetic humans. Streptozotocin (STZ)–induced insulin deficiency increased plasma triglyceride levels in mice. Contrary to the mouse models with impaired hepatic insulin receptor signalling, insulin deficiency did not reduce hepatic triglyceride secretion and de novo lipogenesis-related gene expression. Diabetic mice had a marked decrease in postprandial TG clearance, which was associated with decreased lipoprotein lipase (LpL) and PPARα mRNA levels in peripheral tissues and decreased LpL activity in skeletal muscle, heart and brown adipose tissue. Diabetic heterozygous LpL knockout mice had markedly elevated fasting plasma triglyceride levels and prolonged postprandial TG clearance. Conclusion Insulin deficiency causes hypertriglyceridemia by decreasing peripheral lipolysis and not by an increase in hepatic TG production and secretion. PMID:25395613

  3. γ-H2AX/53BP1/pKAP-1 foci and their linear tracks induced by in vitro exposure to radon and its progeny in human peripheral blood lymphocytes

    PubMed Central

    Ding, Defang; Zhang, Yaping; Wang, Jing; Wang, Xufei; Fan, Dunhuang; He, Linfeng; Zhang, Xuxia; Gao, Yun; Li, Qiang; Chen, Honghong

    2016-01-01

    The biodosimetric information is critical for evaluating the human health hazards caused by radon and its progeny. Here, we demonstrated that the formation of phosphorylated histone variant H2AX (γ-H2AX), p53-binding protein 1 (53BP1) and phosphorylated KRAB-associated protein 1 (pKAP-1) foci and their linear tracks in human peripheral blood lymphocytes (HPBLs) in vitro exposed to radon and its progeny were dependent on the cumulative absorbed dose of radon exposure but was unrelated to the concentration of radon. Among them, γ-H2AX foci and its linear tracks were the most sensitive indicators with the lowest estimable cumulative absorbed dose of 1.74 mGy from their linear dose-response curves and sustained for 12 h after termination of radon exposure. In addition, three types of foci showed an overdispersed non-Poisson distribution in HPBLs. The ratios of pKAP-1/γ-H2AX foci co-localization, 53BP1/γ-H2AX foci co-localization and 53BP1/pKAP-1 foci co-localization were significantly increased in HPBLs exposed to radon while they were unrelated to the cumulative dose of radon exposure, suggesting that γ-H2AX, pKAP-1 and 53BP1 play an important role in the repair of heterochromatic double-strand breaks. Altogether, our findings provide an experimental basis for estimating the biological dose of internal α-particle irradiation from radon and its progeny exposure in humans. PMID:27922110

  4. Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling.

    PubMed

    Kido, Masahiro; Watanabe, Norihiko; Okazaki, Taku; Akamatsu, Takuji; Tanaka, Junya; Saga, Kazuyuki; Nishio, Akiyoshi; Honjo, Tasuku; Chiba, Tsutomu

    2008-10-01

    Because of the lack of animal models developing spontaneous autoimmune hepatitis (AIH), the molecular mechanisms involved in the development of AIH are still unclear. This study aims to examine the regulatory roles of naturally arising CD4(+)CD25(+) regulatory T (Treg) cells and programmed cell death 1 (PD-1)-mediated signaling in the development of AIH. To induce a concurrent loss of Treg cells and PD-1-mediated signaling, neonatal thymectomy (NTx), which severely reduces the number of Treg cells, was performed on PD-1(-/-) mice. After the NTx, we performed histologic examination, assessed autoantibody production and infiltrating cells in the liver, and conducted adoptive transfer experiments. In contrast to NTx mice and PD-1(-/-) mice, NTx-PD-1(-/-) mice produced antinuclear antibodies and developed fatal hepatitis characterized by a CD4(+) and CD8(+) T-cell infiltration invading the parenchyma with massive lobular necrosis. Induction of AIH in NTx-PD-1(-/-) mice was suppressed by transfer of Treg cells, even derived from PD-1(-/-) mice. Transfer of total but not CD4(+) T-cell-depleted splenocytes from NTx-PD-1(-/-) mice into RAG2(-/-) mice induced the development of severe hepatitis. In contrast, the transfer of CD8(+) T-cell-depleted splenocytes triggered only mononuclear infiltrates without massive necrosis of the parenchyma. NTx-PD-1(-/-) mice are the first mouse model of spontaneous fatal AIH. The concurrent loss of Treg cells and PD-1-mediated signaling can induce the development of fatal AIH. Autoreactive CD4(+) T cells are essential for induction of AIH, whereas CD8(+) T cells play an important role in progression to fatal hepatic damage.

  5. Abacavir-induced fulminant hepatic failure in a HIV/HCV co-infected patient

    PubMed Central

    Haas, Christopher; Ziccardi, Mary Rodriguez; Borgman, Jody

    2015-01-01

    Abacavir hypersensitivity is a rare, yet significant adverse reaction that results in a spectrum of physical and laboratory abnormalities, and has been postulated to stem from a variety of aetiological factors. The major histocompatibility complex haplotype human leucocyte antigen (HLA)-B5701 is a significant risk factor in development of hypersensitivity reactions, yet only 55% of HLA-B5701+ individuals develop such reactions, suggesting a multifactorial aetiology. Nevertheless, prospective screening and avoidance of abacavir in these patients has limited adverse events. Within this spectrum of adverse events, abacavir-induced liver toxicity is exceedingly rare and reported events have ranged from mild elevations of aminotransferases to fulminant hepatic failure. We report the case of a 50-year-old Caucasian woman with a history significant for HIV, hepatitis C virus and a HLA-B5701+ status, transferred to our emergency department in a hypotensive state and found to have acute liver failure, acute renal failure and significant rhabdomyolysis following a change of highly active antiretroviral therapy regimen. PMID:26670894

  6. Hepatic fibrosis: It is time to go with hepatic stellate cell-specific therapeutic targets.

    PubMed

    Ezhilarasan, Devaraj; Sokal, Etienne; Najimi, Mustapha

    2018-06-01

    Hepatic fibrosis is a pathological lesion, characterized by the progressive accumulation of extracellular matrix (ECM) in the perisinusoidal space and it is a major problem in chronic liver diseases. Phenotypic activation of hepatic stellate cells (HSC) plays a central role in the progression of hepatic fibrosis. Retardation of proliferation and clearance of activated HSCs from the injured liver is an appropriate therapeutic strategy for the resolution and treatment of hepatic fibrosis. Clearance of activated HSCs from the injured liver by autophagy inhibitors, proapoptotic agents and senescence inducers with the high affinity toward the activated HSCs may be the novel therapeutic strategy for the treatment of hepatic fibrosis in the near future. Copyright © 2018. Published by Elsevier B.V.

  7. GLP-1 analogue improves hepatic lipid accumulation by inducing autophagy via AMPK/mTOR pathway

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    He, Qin; Sha, Sha; Sun, Lei

    The incidence of nonalcoholic fatty liver disease (NAFLD) keeps rising year by year, and NAFLD is rapidly becoming the most common liver disease worldwide. Clinical studies have found that glucagon-like peptide-1 (GLP-1) analogue, liraglutide (LRG), cannot only reduce glucose levels, but also improve hepatic lipase, especially in patients also with type 2 diabetes mellitus (T2DM). In addition, enhancing autophagy decreases lipid accumulation in hepatocytes. The aim of the present study is to explore the effect of LRG on hepatocyte steatosis and the possible role of autophagy. We set up an obesity mouse model with a high-fat diet (HFD) and inducedmore » hepatocyte steatosis with free fatty acids (FFA) in human L-O2 cells. LRG and two inhibitors of autophagy, Chloroquine (CQ) and bafilomycin A1 (Baf), were added into each group, respectively. The lipid profiles and morphological modifications of each group were tested. Immunohistochemistry, immunofluorescence staining and transmission electron microscopy (TEM) were used to measure autophagy in this study. The autophagy protein expression of SQSTM1 (P62), and LC3B, along with the signaling pathway proteins of mTOR, phosphorylated mTOR (p-mTOR), AMPK, phosphorylated AMPK (p-AMPK) and Beclin1, were evaluated by western blot. Our results showed that LRG improved hepatocyte steatosis by inducing autophagy, and the AMPK/mTOR pathway is involved. These findings suggest an important mechanism for the positive effects of LRG on hepatic steatosis, and provide new evidence for clinical use of LRG in NAFLD. -- Highlights: •Liraglutide reduces lipid accumulation in hepatic steatosis both in vivo and in vitro. •Autophagy was involved in relieving effects of liraglutide on hepatic steatosis. •AMPK/mTOR pathway was involved in liraglutide-induced autophagy.« less

  8. MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes.

    PubMed

    Larter, Claire Z; Yeh, Matthew M; Williams, Jacqueline; Bell-Anderson, Kim S; Farrell, Geoffrey C

    2008-09-01

    In these studies, we tested the hypothesis that increased lipid intake would exacerbate the severity of nutritional steatohepatitis. C57Bl/6J mice were fed methionine-and-choline deficient (MCD) diets containing 20% (high) or 5% (low) fat by weight for 3 weeks and compared to lipid-matched controls. MCD feeding increased serum ALT levels and induced hepatic steatosis, lobular inflammation and ballooning degeneration of hepatocytes, irrespective of dietary fat content. Hepatic triglyceride accumulation was similar between high and low-fat MCD-fed mice, but lipoperoxide levels were approximately 3-fold higher in the high-fat MCD-fed animals. Serum adiponectin levels increased in MCD-fed mice, although to a lesser extent in high-fat fed animals. AMPK phosphorylation was correspondingly increased in muscle of MCD-fed mice, but hepatic AMPK phosphorylation decreased, and there was little evidence of PPAR alpha activation, suggesting impaired adiponectin action in the livers of MCD-fed animals. Hepatocyte PPAR gamma mRNA levels increased in MCD-fed mice, and were associated with increased aP2 expression, indicating adipogenic transformation of hepatocytes. Increased dietary lipid intake did not alter steatohepatitis severity in MCD-fed mice despite increased lipoperoxide accumulation. Instead, steatohepatitis was associated with impaired hepatic adiponectin action, and adipogenic transformation of hepatocytes in both low and high-fat MCD-fed mice.

  9. Interrogation of transcriptomic changes associated with drug-induced hepatic sinusoidal dilatation in colorectal cancer.

    PubMed

    Jarzabek, Monika A; Proctor, William R; Vogt, Jennifer; Desai, Rupal; Dicker, Patrick; Cain, Gary; Raja, Rajiv; Brodbeck, Jens; Stevens, Dale; van der Stok, Eric P; Martens, John W M; Verhoef, Cornelis; Hegde, Priti S; Byrne, Annette T; Tarrant, Jacqueline M

    2018-01-01

    Drug-related sinusoidal dilatation (SD) is a common form of hepatotoxicity associated with oxaliplatin-based chemotherapy used prior to resection of colorectal liver metastases (CRLM). Recently, hepatic SD has also been associated with anti-delta like 4 (DLL4) cancer therapies targeting the NOTCH pathway. To investigate the hypothesis that NOTCH signaling plays an important role in drug-induced SD, gene expression changes were examined in livers from anti-DLL4 and oxaliplatin-induced SD in non-human primate (NHP) and patients, respectively. Putative mechanistic biomarkers of bevacizumab (bev)-mediated protection against oxaliplatin-induced SD were also investigated. RNA was extracted from whole liver sections or centrilobular regions by laser-capture microdissection (LCM) obtained from NHP administered anti-DLL4 fragment antigen-binding (F(ab')2 or patients with CRLM receiving oxaliplatin-based chemotherapy with or without bev. mRNA expression was quantified using high-throughput real-time quantitative PCR. Significance analysis was used to identify genes with differential expression patterns (false discovery rate (FDR) < 0.05). Eleven (CCL2, CCND1, EFNB2, ERG, ICAM1, IL16, LFNG, NOTCH1, NOTCH4, PRDX1, and TGFB1) and six (CDH5, EFNB2, HES1, IL16, MIK67, HES1 and VWF) candidate genes were differentially expressed in the liver of anti-DLL4- and oxaliplatin-induced SD, respectively. Addition of bev to oxaliplatin-based chemotherapy resulted in differential changes in hepatic CDH5, HEY1, IL16, JAG1, MMP9, NOTCH4 and TIMP1 expression. This work implicates NOTCH and IL16 pathways in the pathogenesis of drug-induced SD and further explains the hepato-protective effect of bev in oxaliplatin-induced SD observed in CRLM patients.

  10. Fermented Moringa oleifera Decreases Hepatic Adiposity and Ameliorates Glucose Intolerance in High-Fat Diet-Induced Obese Mice.

    PubMed

    Joung, Hyunchae; Kim, Bobae; Park, Hyunjoon; Lee, Kyuyeon; Kim, Hee-Hoon; Sim, Ho-Cheol; Do, Hyun-Jin; Hyun, Chang-Kee; Do, Myoung-Sool

    2017-05-01

    Metabolic diseases, such as glucose intolerance and nonalcoholic fatty-liver disease (NAFLD), are primary risk factors for life-threatening conditions such as diabetes, heart attack, stroke, and hepatic cancer. Extracts from the tropical tree Moringa oleifera show antidiabetic, antioxidant, anti-inflammatory, and anticancer effects. Fermentation can further improve the safety and nutritional value of certain foods. We investigated the efficacy of fermented M. oleifera extract (FM) against high-fat diet (HFD)-induced glucose intolerance and hepatic lipid accumulation and investigated the underlying mechanisms by analyzing expression of proteins and genes involved in glucose and lipid regulation. C57BL/6 mice were fed with normal chow diet (ND) or HFD supplemented with distilled water (DW, control), nonfermented M. oleifera extract (NFM), or FM for 10 weeks. Although body weights were similar among HFD-fed treatment groups, liver weight was decreased, and glucose tolerance test (GTT) results improved in the FM group compared with DW and NFM groups. Hepatic lipid accumulation was also lower in the FM group, and expressions of genes involved in liver lipid metabolism were upregulated. In addition, HFD-induced endoplasmic reticulum (ER) stress, oxidative stress, and lipotoxicity in quadriceps muscles were decreased by FM. Finally, proinflammatory cytokine mRNA expression was decreased by FM in the liver, epididymal adipose tissue, and quadriceps of HFD-fed mice. FMs may decrease glucose intolerance and NAFLD under HFD-induced obesity by decreasing ER stress, oxidative stress, and inflammation.

  11. Mir-338-3p Mediates Tnf-A-Induced Hepatic Insulin Resistance by Targeting PP4r1 to Regulate PP4 Expression.

    PubMed

    Dou, Lin; Wang, Shuyue; Sun, Libo; Huang, Xiuqing; Zhang, Yang; Shen, Tao; Guo, Jun; Man, Yong; Tang, Weiqing; Li, Jian

    2017-01-01

    Insulin resistance is a critical factor contributing to the pathogenesis of type 2 diabetes and other metabolic diseases. Recent studies have indicated that miR-338-3p plays an important role in cancer. Here, we investigated whether miR-338-3p mediates tumour necrosis factor-α (TNF-α)-induced hepatic insulin resistance. The activation of the insulin signalling pathway and the level of glycogenesis were examined in the livers of the db/db and high fat diet (HFD)-fed mice and in HEP1-6 cells transfected with miR-338-3p mimic or inhibitor. Computational prediction of microRNA target, luciferase assay and Western blot were used to assess the miR-338-3p target. Chromatin immunoprecipitation (ChIP) assay was used to determine the transcriptional regulator of miR-338-3p. miR-338-3p was down-regulated in the livers of the db/db, HFD-fed and TNF-α-treated C57BL/6J mice, as well as in mouse HEP1-6 hepatocytes treated with TNF-α. Importantly the down-regulation of miR-338-3p induced insulin resistance, as indicated by impaired glucose tolerance and insulin tolerance. Further research showed that the down-regulated miR-338-3p resulted in the impaired AKT/ glycogen synthase kinase 3 beta (GSl·Gβ) signalling pathway and glycogen synthesis. In contrast, hepatic over-expression of miR-338-3p rescued the TNF-α-induced insulin resistance. Moreover, protein phosphatase 4 regulator subunit 1 (PP4R1) was identified as a direct target of miR-338-3p that mediated hepatic insulin signalling by regulating protein phosphatase 4 (PP4). Finally we identified hepatic nuclear factor 4 alpha (HNF-4α) as the transcriptional regulator of miRNA-338-3p. Our studies provide novel insight into the critical role and molecular mechanism by which miR-338-3p is involved in TNF-α-induced hepatic insulin resistance. miR-338-3p might mediate TNF-α-induced hepatic insulin resistance by targeting PP4R1 to regulate PP4 expression. © 2017 The Author(s). Published by S. Karger AG, Basel.

  12. Hepatic Histological Findings in Suspected Drug-Induced Liver Injury: Systematic Evaluation and Clinical Associations

    PubMed Central

    Kleiner, David E; Chalasani, Naga P; Lee, William M; Fontana, Robert J; Bonkovsky, Herbert L; Watkins, Paul B; Hayashi, Paul H; Davern, Timothy J; Navarro, Victor; Reddy, Rajender; Talwalkar, Jayant A; Stolz, Andrew; Gu, Jiezhun; Barnhart, Huiman; Hoofnagle, Jay H

    2014-01-01

    Drug-induced liver injury (DILI) is considered to be a diagnosis of exclusion. Liver biopsy may contribute to diagnostic accuracy, but the histological features of DILI and their relationship to biochemical parameters and outcomes are not well defined. We have classified the pathological pattern of liver injury and systematically evaluated histological changes in liver biopsies obtained from 249 patients with suspected DILI enrolled in the prospective, observational study conducted by the Drug Induced Liver Injury Network. Histological features were analyzed for their frequency within different clinical phenotypes of liver injury and to identify associations between clinical and laboratory findings and histological features. The most common histological patterns were acute (21%) and chronic hepatitis (14%), acute (9%) and chronic cholestasis (10%), and cholestatic hepatitis (29%). Liver histology from 128 patients presenting with hepatocellular injury had more severe inflammation, necrosis, and apoptosis and more frequently demonstrated lobular disarray, rosette formation, and hemorrhage than those with cholestasis. Conversely, histology of the 73 patients with cholestatic injury more often demonstrated bile plugs and duct paucity. Severe or fatal hepatic injury in 46 patients was associated with higher degrees of necrosis, fibrosis stage, microvesicular steatosis, and ductular reaction among other findings, whereas eosinophils and granulomas were found more often in those with milder injury. Conclusion: We describe an approach for evaluating liver histology in DILI and demonstrate numerous associations between pathological findings and clinical presentations that may serve as a foundation for future studies correlating DILI pathology with its causality and outcome. (Hepatology 2014;59:661–670) PMID:24037963

  13. Hepatitis C Virus Infection Induces Autophagy as a Prosurvival Mechanism to Alleviate Hepatic ER-Stress Response

    PubMed Central

    Dash, Srikanta; Chava, Srinivas; Aydin, Yucel; Chandra, Partha K.; Ferraris, Pauline; Chen, Weina; Balart, Luis A.; Wu, Tong; Garry, Robert F.

    2016-01-01

    Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, liver cirrhosis and hepatocellular carcinoma (HCC). The molecular mechanisms by which HCV infection leads to chronic liver disease and HCC are not well understood. The infection cycle of HCV is initiated by the attachment and entry of virus particles into a hepatocyte. Replication of the HCV genome inside hepatocytes leads to accumulation of large amounts of viral proteins and RNA replication intermediates in the endoplasmic reticulum (ER), resulting in production of thousands of new virus particles. HCV-infected hepatocytes mount a substantial stress response. How the infected hepatocyte integrates the viral-induced stress response with chronic infection is unknown. The unfolded protein response (UPR), an ER-associated cellular transcriptional response, is activated in HCV infected hepatocytes. Over the past several years, research performed by a number of laboratories, including ours, has shown that HCV induced UPR robustly activates autophagy to sustain viral replication in the infected hepatocyte. Induction of the cellular autophagy response is required to improve survival of infected cells by inhibition of cellular apoptosis. The autophagy response also inhibits the cellular innate antiviral program that usually inhibits HCV replication. In this review, we discuss the physiological implications of the HCV-induced chronic ER-stress response in the liver disease progression. PMID:27223299

  14. Expression of TNF-alpha and immunohistochemical distribution of hepatic macrophage surface markers in carbon tetrachloride-induced chronic liver injury in rats.

    PubMed

    Orfila, C; Lepert, J C; Alric, L; Carrera, G; Beraud, M; Vinel, J P; Pipy, B

    1999-10-01

    In liver injury induced by carbon tetrachloride, secondary hepatic injury occurs from inflammatory processes originating from products released by activated Kupffer cells, which play a central role in hepatic inflammation. The purpose of our study was to demonstrate, in rats, the relationships between a function of the hepatic macrophages, TNF-alpha production and the state of activation of these cells, characterized by their phenotype, in the different phases of the process and development of fibrosis in a carbon tetrachloride-induced cirrhosis model. The immunohistochemical localization of proinflammatory cytokine TNF-alpha and surface surface makers (ED1 and ED2) was studied in hepatitis and cirrhosis in response to 3 and 9 weeks ingestion of carbon tetrachloride. After carbon tetrachloride ingestion, accompanying the increased necrosis, immunohistochemical analysis of liver tissue sections demonstrated the significantly increased number of cells expressing ED1, ED2 and TNF-alpha, compared to normal. The number of cells expressing the surface phenotypic markers of liver macrophages increased and this change was concomitantly associated with an increased cellular expression of TNF-alpha. Local macrophage proliferation and influx of newly recruited blood monocytes resulted in an increase of the macrophage population. The populational changes involved difference in functional activity and enhanced TNF-alpha expression. This cytokine expressed in the carbon tetrachloride-induced inflammatory process is associated with the development of fibrosis and may contribute to disease severity.

  15. Partial hepatic resistance to IL-6-induced inflammation develops in type 2 diabetic mice, while the anti-inflammatory effect of AMPK is maintained.

    PubMed

    Cansby, Emmelie; Nerstedt, Annika; Amrutkar, Manoj; Durán, Esther Nuñez; Smith, Ulf; Mahlapuu, Margit

    2014-08-05

    Interleukin-6 (IL-6) induces hepatic inflammation and insulin resistance, and therapeutic strategies to counteract the IL-6 action in liver are of high interest. In this study, we demonstrate that acute treatment with AMP-activated protein kinase (AMPK) agonists AICAR and metformin efficiently repressed IL-6-induced hepatic proinflammatory gene expression and activation of STAT3 in a mouse model of diet-induced type 2 diabetes, bringing it back to basal nonstimulated level. Surprisingly, the inflammatory response in liver induced by IL-6 administration in vivo was markedly blunted in the mice fed a high-fat diet, compared to lean chow-fed controls, while this difference was not replicated in vitro in primary hepatocytes derived from these two groups of mice. In summary, our work reveals that partial hepatic IL-6 resistance develops in the mouse model of type 2 diabetes, while the anti-inflammatory action of AMPK is maintained. Systemic factors, rather than differences in intracellular IL-6 receptor signaling, are likely mediating the relative impairment in IL-6 effect. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  16. Motor correlates of models of secondary bilateral synchrony and multiple epileptic foci.

    PubMed

    Jiruska, Premysl; Proks, Jan; Otáhal, Jakub; Mares, Pavel

    2007-10-01

    Bilateral synchronous epileptiform discharges registered in patients with partial epilepsies may be generated by different pathophysiological mechanisms. Differentiation between underlying mechanisms is often crucial for correct diagnosis and adequate treatment in clinical epileptology. The aim of this study was to model in rats two possible mechanisms--secondary bilateral sychrony and interaction between multiple epilepic foci. Furthermore, to describe in detail semiology, laterality and differences in motor phenomena. Secondary bilateral synchrony was modeled by unilateral topical application of bicuculline methiodide (BMI) over the sensorimotor cortex. Bilateral symmetric application of BMI was used as a model of multiple epileptic foci. Electrographic and behavioural phenomena were recorded for 1h following the application of BMI. Electroencephalogram in both groups was characterized by presence of bilateral synchronous discharges. Myoclonic and clonic seizures involving forelimb and head muscles represented the most common motor seizure pattern in both groups. Significant differences were found in the laterality of motor phenomena. Motor seizures in unilateral foci always started in the contralateral limbs whereas symmetrical foci exhibited bilateral independent onset of convulsions. Similar lateralization was observed in interictal motor phenomena (myoclonic jerks). An important influence of posture on epileptic motor phenomena was demonstrated. Active or passive changes in animal posture (verticalization to bipedal posture) caused conversion from unilateral myoclonic jerks or clonic seizures to bilaterally synchronous (generalized) motor phenomena in both groups.

  17. Effects of beta-glucuronidase-deficient and lycopene-producing Escherichia coli strains on formation of azoxymethane-induced aberrant crypt foci in the rat colon.

    PubMed

    Arimochi, H; Kataoka, K; Kuwahara, T; Nakayama, H; Misawa, N; Ohnishi, Y

    1999-08-27

    We tried to inhibit the formation of azoxymethane-induced aberrant crypt foci (ACF) in the rat intestine by feeding a culture of a beta-glucuronidase-deficient Escherichia coli strain or a cell suspension of a lycopene-producing E. coli strain. Feeding of the former culture to F344 rats did not decrease fecal beta-glucuronidase activity or the number of ACF compared with the control beta-glucuronidase-proficient groups. However, a significant positive correlation between the fecal beta-glucuronidase activity and the ACF number was observed among groups treated with cultures of beta-glucuronidase-proficient and -deficient strains. In the group treated with lycopene-producing cells, the number of ACF was significantly lower than that in the control group. A vegetable juice containing a larger amount of lycopene than a cell suspension of the lycopene-producing E. coli also decreased the number of ACF to the same extent as a cell suspension of the lycopene-producing bacteria. These results suggest that feeding of the beta-glucuronidase-deficient E. coli is not very effective in preventing colon carcinogenesis, although activity of the fecal beta-glucuronidase is associated with AOM-induced ACF formation, and that lycopene-producing intestinal bacteria can effectively prevent colon carcinogenesis. Copyright 1999 Academic Press.

  18. Protective Effects of Astaxanthin on ConA-Induced Autoimmune Hepatitis by the JNK/p-JNK Pathway-Mediated Inhibition of Autophagy and Apoptosis

    PubMed Central

    Liu, Tong; Wang, Junshan; Dai, Weiqi; Wang, Fan; Zheng, Yuanyuan; Chen, Kan; Li, Sainan; Abudumijiti, Huerxidan; Zhou, Zheng; Wang, Jianrong; Lu, Wenxia; Zhu, Rong; Yang, Jing; Zhang, Huawei; Yin, Qin; Wang, Chengfen; Zhou, Yuqing; Lu, Jie; Zhou, Yingqun; Guo, Chuanyong

    2015-01-01

    Objective Astaxanthin, a potent antioxidant, exhibits a wide range of biological activities, including antioxidant, atherosclerosis and antitumor activities. However, its effect on concanavalin A (ConA)-induced autoimmune hepatitis remains unclear. The aim of this study was to investigate the protective effects of astaxanthin on ConA-induced hepatitis in mice, and to elucidate the mechanisms of regulation. Materials and Methods Autoimmune hepatitis was induced in in Balb/C mice using ConA (25 mg/kg), and astaxanthin was orally administered daily at two doses (20 mg/kg and 40 mg/kg) for 14 days before ConA injection. Levels of serum liver enzymes and the histopathology of inflammatory cytokines and other maker proteins were determined at three time points (2, 8 and 24 h). Primary hepatocytes were pretreated with astaxanthin (80 μM) in vitro 24 h before stimulation with TNF-α (10 ng/ml). The apoptosis rate and related protein expression were determined 24 h after the administration of TNF-α. Results Astaxanthin attenuated serum liver enzymes and pathological damage by reducing the release of inflammatory factors. It performed anti-apoptotic effects via the descending phosphorylation of Bcl-2 through the down-regulation of the JNK/p-JNK pathway. Conclusion This research firstly expounded that astaxanthin reduced immune liver injury in ConA-induced autoimmune hepatitis. The mode of action appears to be downregulation of JNK/p-JNK-mediated apoptosis and autophagy. PMID:25761053

  19. Forced expression of Hnf4a induces hepatic gene activation through directed differentiation.

    PubMed

    Yahoo, Neda; Pournasr, Behshad; Rostamzadeh, Jalal; Fathi, Fardin

    2016-08-05

    Embryonic stem (ES) cells are capable of unlimited self-renewal and have a diverse differentiation potential. These unique features make ES cells as an attractive source for developmental biology studies. Having the mature hepatocyte in the lab with functional activities is valuable in drug discovery studies. Overexpression of hepatocyte lineage-specific transcription factors (TFs) becomes a promising approach in pluripotent cell differentiation toward liver cells. Many studies generate transgenic ES cell lines to examine the effects of specific TFs overexpression in cell differentiation. In the present report, we have addressed whether a suspension or adherent model of differentiation is an appropriate way to study the role of Hnf4a overexpression. We generated ES cells that carried a doxycycline (Dox)-inducible Hnf4a using lentiviral vectors. The transduced cells were subjected to induced Hnf4a overexpression through both spontaneous and directed differentiation methods. Gene expression analysis showed substantially increased expression of hepatic gene markers, particularly Ttr and endogenous Hnf4a, in transduced cells differentiated by the directed approach. These results demonstrated that forced expression of TFs during directed differentiation would be an appropriate way to study relevant gene activation and the effects of overexpression in the context of hepatic differentiation. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Isofraxidin, a coumarin component improves high-fat diet induced hepatic lipid homeostasis disorder and macrophage inflammation in mice.

    PubMed

    Li, Jian; Li, Xiaofei; Li, Zhike; Zhang, Lu; Liu, Yonggang; Ding, Hong; Yin, Shanye

    2017-08-01

    Isofraxidin (IF) is a coumarin compound produced in the functional foods Siberian ginseng and Apium graveolens. The first objective of this study was to investigate the protective effects and putative methods of IF in combating lipotoxicity in vitro and in vivo. Oleic acid was used to induce lipid turbulence in human hepatoma cells (HepG2). Alterations in triglyceride metabolism, inflammation and oxidative status were monitored. Results show that IF mainly reduced triglyceride accumulation, TNF-α release and ROS activation in metabolic disordered cells. Next, a high-fat diet, which induced a non-alcoholic fatty liver disease, was used to evaluate the therapeutic action of IF. Our results show that treatment with IF significantly inhibited the high-fat diet-induced elevation in body weight, liver weight, lipid metabolism (TG, TC and HDL-C) and hepatic injury in mice. In biochemical terms, treatment with IF resulted in enhanced phosphorylation of AMPKα and ACC, as well as reduced hepatic expression of FAS and HMGC, suggesting that lipogenesis was compromised. We also found robust evidence that treatment with IF significantly depleted infiltrating inflammatory cells (F4/80 + Kupffer cells and CD68 + macrophages) and inflammatory cytokine release (TNFα and IL-6). Moreover, the anti-inflammatory activity in IF-treated hepatic tissue correlated with down-regulation of TLR4 expression and NF-κB transcription. In sum, these results suggest that IF might play a protective role against lipid metabolism disorder induced by a high-fat diet via inhibition of lipid production and inflammation in the liver.

  1. Silymarin and caffeine combination ameliorates experimentally-induced hepatic fibrosis through down-regulation of LPAR1 expression.

    PubMed

    Eraky, Salma M; El-Mesery, Mohamed; El-Karef, Amro; Eissa, Laila A; El-Gayar, Amal M

    2018-05-01

    Lysophosphatidic acid is a lipid mediator that is supposed to be implicated in hepatic fibrosis. Silymarin and caffeine are natural compounds known for their anti-inflammatory and antioxidant effects. Our study aimed to explore the effect of silymarin, caffeine, and their combination on lysophosphatidic acid receptor 1 (LPAR1) pathway in thioacetamide (TAA)-induced hepatic fibrosis. Hepatic fibrosis was induced in male Sprague-Dawley rats by intraperitoneal injection of 200 mg/kg of TAA twice a week for 8 weeks. Silymarin (50 mg/kg), caffeine (50 mg/kg), and their combination (50 mg/kg silymarin + 50 mg/kg caffeine) were orally given to rats every day for 8 weeks along with TAA injection. Liver functions were measured. Histopathological examination of liver tissues was performed using hematoxylin and eosin and Masson's trichrome staining. mRNA expressions of LPAR1, transforming growth factor beta 1 (TGF-β1), connective tissue growth factor (CTGF), and alpha smooth muscle actin (α-SMA) were measured using RT-PCR. LPAR1 tissue expression was scored using immunohistochemistry. Silymarin, caffeine, and their combination significantly improved liver function. They caused significant decrease in fibrosis and necro-inflammatory scores. Combination of silymain and caffeine caused a significant decrease in the necro-inflammatory score than the single treatment with silymarin or caffeine. In addition, silymarin, caffeine, and their combination significantly decreased hepatic LPAR1, TGF-β1, CTGF, and α-SMA gene expressions and LPAR1 tissue expression. Silymarin, caffeine, and their combination protect against liver fibrosis through down-regulation of LPAR1, TGF-β1, and CTGF. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  2. Dissociation of hepatic insulin resistance from susceptibility of nonalcoholic fatty liver disease induced by a high-fat and high-carbohydrate diet in mice.

    PubMed

    Asai, Akihiro; Chou, Pauline M; Bu, Heng-Fu; Wang, Xiao; Rao, M Sambasiva; Jiang, Anthony; DiDonato, Christine J; Tan, Xiao-Di

    2014-03-01

    Liver steatosis in nonalcoholic fatty liver disease is affected by genetics and diet. It is associated with insulin resistance (IR) in hepatic and peripheral tissues. Here, we aimed to characterize the severity of diet-induced steatosis, obesity, and IR in two phylogenetically distant mouse strains, C57BL/6J and DBA/2J. To this end, mice (male, 8 wk old) were fed a high-fat and high-carbohydrate (HFHC) or control diet for 16 wk followed by the application of a combination of classic physiological, biochemical, and pathological studies to determine obesity and hepatic steatosis. Peripheral IR was characterized by measuring blood glucose level, serum insulin level, homeostasis model assessment of IR, glucose intolerance, insulin intolerance, and AKT phosphorylation in adipose tissues, whereas the level of hepatic IR was determined by measuring insulin-triggered hepatic AKT phosphorylation. We discovered that both C57BL/6J and DBA/2J mice developed obesity to a similar degree without the feature of liver inflammation after being fed an HFHC diet for 16 wk. C57BL/6J mice in the HFHC diet group exhibited severe pan-lobular steatosis, a marked increase in hepatic triglyceride levels, and profound peripheral IR. In contrast, DBA/2J mice in the HFHC diet group developed only a mild degree of pericentrilobular hepatic steatosis that was associated with moderate changes in peripheral IR. Interestingly, both C57BL/6J and DBA/2J developed severe hepatic IR after HFHC diet treatment. Collectively, these data suggest that the severity of diet-induced hepatic steatosis is correlated to the level of peripheral IR, not with the severity of obesity and hepatic IR. Peripheral rather than hepatic IR is a dominant factor of pathophysiology in nonalcoholic fatty liver disease.

  3. Intraretinal hyperreflective foci on spectral-domain optical coherence tomographic images of patients with retinitis pigmentosa

    PubMed Central

    Kuroda, Masako; Hirami, Yasuhiko; Hata, Masayuki; Mandai, Michiko; Takahashi, Masayo; Kurimoto, Yasuo

    2014-01-01

    Background The purpose of this study was to observe the characteristic findings of spectral-domain optical coherence tomography (SD-OCT) images in the retinas of patients with retinitis pigmentosa and to evaluate their distribution patterns in the early and advanced stages of the disease. Methods A total of 184 patients (368 eyes) with retinitis pigmentosa were observed using SD-OCT. We studied the presence or absence of continuous inner/outer segment (IS/OS) lines, presence of thinning of the retinal pigment epithelium-Bruch’s membrane complex, and distribution patterns of hyperreflective foci in the inner and outer nuclear layers (INL and ONL). Results The IS/OS junction had partially disappeared in 275 eyes, which were at the early stage of retinitis pigmentosa (group X), whereas the junction had totally disappeared in 93, which were at the advanced stage of retinitis pigmentosa (group Y). Hyperreflective foci in the INL were observed in a significantly larger proportion of the eyes in group X than in group Y (90% versus 61%, P<0.001), but hyperreflective foci in the ONL were observed in a significantly larger proportion of eyes in group Y than in group X (100% versus 69%, P<0.001). Conclusion Hyperreflective foci in the INL were more frequently observed in retinas with the early stage of retinitis pigmentosa and hyperreflective foci in the ONL were more frequently observed in the advanced stage. Hyperreflective foci may be indicative of changes in the retinal structure at each stage of retinitis pigmentosa. PMID:24591813

  4. Selective cytoprotective effect of histamine on doxorubicin-induced hepatic and cardiac toxicity in animal models

    PubMed Central

    Lamas, DJMartinel; Nicoud, MB; Sterle, HA; Carabajal, E; Tesan, F; Perazzo, JC; Cremaschi, GA; Rivera, ES; Medina, VA

    2015-01-01

    The aim of the present work was to evaluate the potential protective effect of histamine on Doxorubicin (Dox)-induced hepatic and cardiac toxicity in different rodent species and in a triple-negative breast tumor-bearing mice model. Male Sprague Dawley rats and Balb/c mice were divided into four groups: control (received saline), histamine (5 mg/kg for rats and 1 mg/kg for mice, daily subcutaneous injection starting 24 h before treatment with Dox), Dox (2 mg/kg, intraperitoneally injected three times a week for 2 weeks) and Dox+histamine (received both treatments). Tissue toxicity was evaluated by histopathological studies and oxidative stress and biochemical parameters. The combined effect of histamine and Dox was also investigated in vitro and in vivo in human MDA-MB-231 triple-negative breast cancer model. Heart and liver of Dox-treated animals displayed severe histological damage, loss of tissue weight, increased TBARS levels and DNA damage along with an augment in serum creatine kinase-myocardial band. Pretreatment with histamine prevented Dox-induced tissue events producing a significant preservation of the integrity of both rat and mouse myocardium and liver, through the reduction of Dox-induced oxidative stress and apoptosis. Histamine treatment preserved anti-tumor activity of Dox, exhibiting differential cytotoxicity and increasing the Dox-induced inhibition of breast tumor growth. Findings provide preclinical evidence indicating that histamine could be a promising candidate as a selective cytoprotective agent for the treatment of Dox-induced cardiac and hepatic toxicity, and encourage the translation to clinical practice. PMID:27551485

  5. Carbon monoxide protects against hepatic steatosis in mice by inducing sestrin-2 via the PERK-eIF2α-ATF4 pathway.

    PubMed

    Kim, Hyo Jeong; Joe, Yeonsoo; Kim, Seul-Ki; Park, Se-Ung; Park, Jeongmin; Chen, Yingqing; Kim, Jin; Ryu, Jinhyun; Cho, Gyeong Jae; Surh, Young-Joon; Ryter, Stefan W; Kim, Uh-Hyun; Chung, Hun-Taeg

    2017-09-01

    Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, has emerged as one of the most common causes of chronic liver disease in developed countries over the last decade. NAFLD comprises a spectrum of pathological hepatic changes, including steatosis, steatohepatitis, advanced fibrosis, and cirrhosis. Autophagy, a homeostatic process for protein and organelle turnover, is decreased in the liver during the development of NAFLD. Previously, we have shown that carbon monoxide (CO), a reaction product of heme oxygenase (HO) activity, can confer protection in NAFLD, though the molecular mechanisms remain unclear. We therefore investigated the mechanisms underlying the protective effect of CO on methionine/choline-deficient (MCD) diet-induced hepatic steatosis. We found that CO induced sestrin-2 (SESN2) expression through enhanced mitochondrial ROS production and protected against MCD-induced NAFLD progression through activation of autophagy. SESN2 expression was increased by CO or CO-releasing molecule (CORM2), in a manner dependent on signaling through the protein kinase R-like endoplasmic reticulum kinase (PERK), eukaryotic initiation factor-2 alpha (eIF2α)/ activating transcription factor-4 (ATF4)-dependent pathway. CO-induced SESN2 upregulation in hepatocytes contributed to autophagy induction through activation of 5'-AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) complex I (mTORC1). Furthermore, we demonstrate that CO significantly induced the expression of SESN2 and enhanced autophagy in the livers of MCD-fed mice or in MCD-media treated hepatocytes. Conversely, knockdown of SESN2 abrogated autophagy activation and mTOR inhibition in response to CO. We conclude that CO ameliorates hepatic steatosis through the autophagy pathway induced by SESN2 upregulation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Intrinsic aerobic capacity impacts susceptibility to acute high-fat diet-induced hepatic steatosis.

    PubMed

    Morris, E Matthew; Jackman, Matthew R; Johnson, Ginger C; Liu, Tzu-Wen; Lopez, Jordan L; Kearney, Monica L; Fletcher, Justin A; Meers, Grace M E; Koch, Lauren G; Britton, Stephen L; Rector, R Scott; Ibdah, Jamal A; MacLean, Paul S; Thyfault, John P

    2014-08-15

    Aerobic capacity/fitness significantly impacts susceptibility for fatty liver and diabetes, but the mechanisms remain unknown. Herein, we utilized rats selectively bred for high (HCR) and low (LCR) intrinsic aerobic capacity to examine the mechanisms by which aerobic capacity impacts metabolic vulnerability for fatty liver following a 3-day high-fat diet (HFD). Indirect calorimetry assessment of energy metabolism combined with radiolabeled dietary food was employed to examine systemic metabolism in combination with ex vivo measurements of hepatic lipid oxidation. The LCR, but not HCR, displayed increased hepatic lipid accumulation in response to the HFD despite both groups increasing energy intake. However, LCR rats had a greater increase in energy intake and demonstrated greater daily weight gain and percent body fat due to HFD compared with HCR. Additionally, total energy expenditure was higher in the larger LCR. However, controlling for the difference in body weight, the LCR has lower resting energy expenditure compared with HCR. Importantly, respiratory quotient was significantly higher during the HFD in the LCR compared with HCR, suggesting reduced whole body lipid utilization in the LCR. This was confirmed by the observed lower whole body dietary fatty acid oxidation in LCR compared with HCR. Furthermore, LCR liver homogenate and isolated mitochondria showed lower complete fatty acid oxidation compared with HCR. We conclude that rats bred for low intrinsic aerobic capacity show greater susceptibility for dietary-induced hepatic steatosis, which is associated with a lower energy expenditure and reduced whole body and hepatic mitochondrial lipid oxidation.

  7. Secondhand smoke induces hepatic apoptosis and fibrosis in hamster fetus.

    PubMed

    Huang, Chien-Wei; Horng, Chi-Ting; Huang, Chih-Yang; Cho, Ta-Hsiung; Tsai, Yi-Chang; Chen, Li-Jeng; Hsu, Tsai-Ching; Tzang, Bor-Show

    2016-09-01

    Secondhand smoke (SHS) is an important health issue worldwide. Inhaling SHS during pregnancy could cause abnormalities in the internal tissues of newborns, which may then impair fetal development and even cause severe intrauterine damage and perinatal death. However, the understanding of cytopathic mechanisms of SHS by maternal passive smoking on fetus liver during pregnancy is still limited. This study analyzed the effects of high-dose SHS (SHSH) on fetus liver using a maternal passive smoking animal model. Experiments showed that hepatic matrix metalloproteinase-9 activity and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling-positive cells were significantly increased in livers from fetuses of hamsters treated with SHSH. Similarly, expressions of both extrinsic and intrinsic apoptotic molecules were significantly higher in livers from fetuses of hamsters exposed to SHSH. Additionally, significantly increased inflammatory proteins, including transforming growth factor β, inducible nitric oxide synthase, and interleukin 1β, and fibrotic signaling molecules, including phosphorylated Smad2/3, SP1, and α-smooth muscle actin, were observed in the fetus livers from hamsters treated with SHSH. This study revealed that SHSH not only increased apoptosis through intrinsic and extrinsic pathways in the livers of fetuses from hamsters exposed to SHSH but also augmented hepatic fibrosis via Smad2/3 signaling. © The Author(s) 2015.

  8. Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats.

    PubMed

    Wang, Yan; Seitz, Helmut K; Wang, Xiang-Dong

    2010-03-01

    Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition. Sprague-Dawley rats were first fed ad libitum with Lieber-DeCarli high-fat diet (71% energy from fat) for 6 weeks to induce NASH, as demonstrated previously. Afterwards, these rats were continuously fed with high-fat diet (HFD, 55% total energy from fat) or high fat plus alcohol diet (HFA, 55% energy from fat and 16% energy from alcohol) for an additional 4 weeks. Pathological lesions including fat accumulation and inflammatory foci in liver were examined and graded. Lipid peroxidation and apoptotic hepatocytes in the liver were assessed. The mRNA expressions of tumor necrosis factor-alpha (TNFalpha) and TNF receptor 1 (TNF-R1), Fas death receptor (Fas) and Fas ligant (FasL), IL-1beta and IL-12 were determined by real-time PCR. Protein levels of total and cleaved caspase-3, CYP2E1, Bax, and Bcl-2 were measured by western blotting. The number of hepatic inflammatory foci and apoptotic hepatocytes were significantly increased in rats fed with HFA as compared with those in HFD-fed rats. The aggravated inflammatory response and cellular apoptosis mediated by HFA were associated with elevated mRNA expression of Fas/FasL and cleaved caspase-3 protein. Although no significant differences were observed between HFD and HFA groups, the levels of lipid peroxidation, Bax and Bcl-2 protein concentration, and mRNA levels of other inflammatory cytokines were significantly higher in these 2 groups than those in the control group. These data suggest that even moderate alcohol consumption can cause more hepatic inflammation and cellular apoptosis in a pre-existing NASH condition.

  9. Intermediate hepatobiliary cells predict an increased risk of hepatocarcinogenesis in patients with hepatitis C virus-related cirrhosis.

    PubMed

    Ziol, Marianne; Nault, Jean-Charles; Aout, Mounir; Barget, Nathalie; Tepper, Maryline; Martin, Antoine; Trinchet, Jean-Claude; Ganne-Carrié, Nathalie; Vicaut, Eric; Beaugrand, Michel; N'Kontchou, Gisele

    2010-07-01

    The expression of biliary lineage markers such as cytokeratin (K) 7 by hepatocytes is thought to reflect an altered regeneration pathway recruiting a stem cell compartment, more prone to carcinogenesis. We aimed to investigate the presence of these so-called intermediate hepatobiliary cells (IHC) in liver biopsies of patients with hepatitis C-related cirrhosis and their potential influence on the subsequent occurrence of hepatocellular carcinoma (HCC). From a cohort of patients with hepatitis C-related cirrhosis, prospectively screened for HCC, we retrospectively selected those with a liver biopsy performed for the initial diagnosis of cirrhosis. Presence of IHC was recorded when foci of K7-positive, intermediate-sized hepatocytes were detected. A total of 150 patients were included (87 men; mean age, 57 y; range, 19-84 y; body mass index, 25 kg/m(2)). After a median follow-up period of 4.85 years, HCC was diagnosed in 36 patients (24%). Baseline liver biopsy showed intermediate hepatobiliary cell foci in 61 patients (41%). Intermediate cells co-expressed both hepatocytes markers and the progenitor cell markers Ep-CAM and K19. The presence of intermediate hepatobiliary cells was associated independently with HCC occurrence (Fine and Gray model; hazard ratio, 2.48; 95% confidence interval, 1.24-4.96; P = .01). Other predictors of HCC were diabetes and low platelet count. The HCC annual incidence rate was significantly higher in patients with IHC compared with patients without (8.14% vs 3.12%, Gray's test, P = .003). The aberrant expression of biliary K by hepatocytes in patients with hepatitis C virus-related cirrhosis is related independently to HCC occurrence. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

  10. Forkhead Box O6 (FoxO6) Depletion Attenuates Hepatic Gluconeogenesis and Protects against Fat-induced Glucose Disorder in Mice*

    PubMed Central

    Calabuig-Navarro, Virtu; Yamauchi, Jun; Lee, Sojin; Zhang, Ting; Liu, Yun-Zi; Sadlek, Kelsey; Coudriet, Gina M.; Piganelli, Jon D.; Jiang, Chun-Lei; Miller, Rita; Lowe, Mark; Harashima, Hideyoshi; Dong, H. Henry

    2015-01-01

    Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. FoxO6 is a distinct member of the FoxO subfamily. To elucidate the role of FoxO6 in hepatic gluconeogenesis and assess its contribution to the pathogenesis of fasting hyperglycemia in diabetes, we generated FoxO6 knock-out (FoxO6-KO) mice followed by determining the effect of FoxO6 loss-of-function on hepatic gluconeogenesis under physiological and pathological conditions. FoxO6 depletion attenuated hepatic gluconeogenesis and lowered fasting glycemia in FoxO6-KO mice. FoxO6-deficient primary hepatocytes were associated with reduced capacities to produce glucose in response to glucagon. When fed a high fat diet, FoxO6-KO mice exhibited significantly enhanced glucose tolerance and reduced blood glucose levels accompanied by improved insulin sensitivity. These effects correlated with attenuated hepatic gluconeogenesis in FoxO6-KO mice. In contrast, wild-type littermates developed fat-induced glucose intolerance with a concomitant induction of fasting hyperinsulinemia and hyperglycemia. Furthermore, FoxO6-KO mice displayed significantly diminished macrophage infiltration into liver and adipose tissues, correlating with the reduction of macrophage expression of C-C chemokine receptor 2 (CCR2), a factor that is critical for regulating macrophage recruitment in peripheral tissues. Our data indicate that FoxO6 depletion protected against diet-induced glucose intolerance and insulin resistance by attenuating hepatic gluconeogenesis and curbing macrophage infiltration in liver and adipose tissues in mice. PMID:25944898

  11. Hypoechoic foci on EUS are simple and strong predictive factors for neoplastic gallbladder polyps.

    PubMed

    Cho, Jae Hee; Park, Jeong Youp; Kim, Yoon Jae; Kim, Hee Man; Kim, Hong Jeong; Hong, Sung Pil; Park, Seung Woo; Chung, Jae Bock; Song, Si Young; Bang, Seungmin

    2009-06-01

    EUS is an accurate imaging modality for delineating gallbladder (GB) structures; however, its clinical use in differentiating neoplastic GB polyps from nonneoplastic polyps is limited. Thus, we sought to characterize neoplastic GB polyps by analyzing unique EUS features. Our analysis revealed variably shaped, relatively hypoechoic portions in the core of polyps compared with general background echogenicity. Our purpose was to make a differential diagnosis between neoplastic and nonneoplastic GB polyps of less than 20 mm by use of EUS variables, including hypoechoic foci. Retrospective single-center study. University teaching hospital. Patients (n = 88) underwent preoperative EUS and cholecystectomy for GB polyps smaller than 20 mm. Hypoechoic foci were found in 30 of 33 patients (91%) with neoplastic polyps and 6 of 55 (11%) with nonneoplastic polyps. In a multivariate analysis, hypoechoic foci were the only significant predictive factor for neoplastic polyps (odds ratio [OR] 55.4, 95% CI, 8.26-371, P < .001); the sensitivity and specificity were 90% and 89%, respectively. In addition, polyps >15 mm had an increased risk of malignancy (OR 21.7, 95% CI, 2.35-201, P = .007), as did those with hypoechoic foci (OR 10.9; 95% CI, 1.01-117, P = .049). Retrospective review of selected patients from a tertiary medical center. The presence of hypoechoic foci on EUS is a strong predictive factor for neoplastic polyps. EUS may be useful in developing a treatment strategy for GB polyps.

  12. Fibroblast growth factor 21 participates in adaptation to endoplasmic reticulum stress and attenuates obesity-induced hepatic metabolic stress.

    PubMed

    Kim, Seong Hun; Kim, Kook Hwan; Kim, Hyoung-Kyu; Kim, Mi-Jeong; Back, Sung Hoon; Konishi, Morichika; Itoh, Nobuyuki; Lee, Myung-Shik

    2015-04-01

    Fibroblast growth factor 21 (FGF21) is an endocrine hormone that exhibits anti-diabetic and anti-obesity activity. FGF21 expression is increased in patients with and mouse models of obesity or nonalcoholic fatty liver disease (NAFLD). However, the functional role and molecular mechanism of FGF21 induction in obesity or NAFLD are not clear. As endoplasmic reticulum (ER) stress is triggered in obesity and NAFLD, we investigated whether ER stress affects FGF21 expression or whether FGF21 induction acts as a mechanism of the unfolded protein response (UPR) adaptation to ER stress induced by chemical stressors or obesity. Hepatocytes or mouse embryonic fibroblasts deficient in UPR signalling pathways and liver-specific eIF2α mutant mice were employed to investigate the in vitro and in vivo effects of ER stress on FGF21 expression, respectively. The in vivo importance of FGF21 induction by ER stress and obesity was determined using inducible Fgf21-transgenic mice and Fgf21-null mice with or without leptin deficiency. We found that ER stressors induced FGF21 expression, which was dependent on a PKR-like ER kinase-eukaryotic translation factor 2α-activating transcription factor 4 pathway both in vitro and in vivo. Fgf21-null mice exhibited increased expression of ER stress marker genes and augmented hepatic lipid accumulation after tunicamycin treatment. However, these changes were attenuated in inducible Fgf21-transgenic mice. We also observed that Fgf21-null mice with leptin deficiency displayed increased hepatic ER stress response and liver injury, accompanied by deteriorated metabolic variables. Our results suggest that FGF21 plays an important role in the adaptive response to ER stress- or obesity-induced hepatic metabolic stress.

  13. γH2AX foci on apparently intact mitotic chromosomes: Not signatures of misrejoining events but signals of unresolved DNA damage

    PubMed Central

    Martín, Marta; Terradas, Mariona; Hernández, Laia; Genescà, Anna

    2014-01-01

    The presence of γH2AX foci on apparently intact mitotic chromosomes is controversial because they challenge the assumed relationship between γH2AX foci and DNA double-strand breaks (DSBs). In this work, we show that after irradiation during interphase, a variety of γH2AX foci are scored in mitotic cells. Surprisingly, approximately 80% of the γH2AX foci spread over apparently undamaged chromatin at Terminal or Interstitial positions and they can display variable sizes, thus being classified as Small, Medium and Big foci. Chromosome and chromatid breaks that reach mitosis are spotted with Big (60%) and Medium (30%) Terminal γH2AX foci, but very rarely are they signaled with Small γH2AX foci. To evaluate if Interstitial γH2AX foci might be signatures of misrejoining, an mFISH analysis was performed on the same slides. The results show that Interstitial γH2AX foci lying on apparently intact chromatin do not mark sites of misrejoining, and that misrejoined events were never signaled by a γH2AX foci during mitosis. Finally, when analyzing the presence of other DNA-damage response (DDR) factors we found that all γH2AX foci—regardless their coincidence with a visible break—always colocalized with MRE11, but not with 53BP1. This pattern suggests that these γH2AX foci may be hallmarks of both microscopically visible and invisible DNA damage, in which an active, although incomplete or halted DDR is taking place. PMID:25486563

  14. Relationship between spontaneous γH2AX foci formation and progenitor functions in circulating hematopoietic stem and progenitor cells among atomic-bomb survivors.

    PubMed

    Kajimura, Junko; Kyoizumi, Seishi; Kubo, Yoshiko; Misumi, Munechika; Yoshida, Kengo; Hayashi, Tomonori; Imai, Kazue; Ohishi, Waka; Nakachi, Kei; Weng, Nan-Ping; Young, Lauren F; Shieh, Jae-Hung; Moore, Malcolm A; van den Brink, Marcel R M; Kusunoki, Yoichiro

    2016-05-01

    Accumulated DNA damage in hematopoietic stem cells is a primary mechanism of aging-associated dysfunction in human hematopoiesis. About 70 years ago, atomic-bomb (A-bomb) radiation induced DNA damage and functional decreases in the hematopoietic system of A-bomb survivors in a radiation dose-dependent manner. The peripheral blood cell populations then recovered to a normal range, but accompanying cells derived from hematopoietic stem cells still remain that bear molecular changes possibly caused by past radiation exposure and aging. In the present study, we evaluated radiation-related changes in the frequency of phosphorylated (Ser-139) H2AX (γH2AX) foci formation in circulating CD34-positive/lineage marker-negative (CD34+Lin-) hematopoietic stem and progenitor cells (HSPCs) among 226Hiroshima A-bomb survivors. An association between the frequency of γH2AX foci formation in HSPCs and the radiation dose was observed, but the γH2AX foci frequency was not significantly elevated by past radiation. We found a negative correlation between the frequency of γH2AX foci formation and the length of granulocyte telomeres. A negative interaction effect between the radiation dose and the frequency of γH2AX foci was suggested in a proportion of a subset of HSPCs as assessed by the cobblestone area-forming cell assay (CAFC), indicating that the self-renewability of HSPCs may decrease in survivors who were exposed to a higher radiation dose and who had more DNA damage in their HSPCs. Thus, although many years after radiation exposure and with advancing age, the effect of DNA damage on the self-renewability of HSPCs may be modified by A-bomb radiation exposure. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. Relationship between spontaneous γH2AX foci formation and progenitor functions in circulating hematopoietic stem and progenitor cells among atomic-bomb survivors

    PubMed Central

    Kajimura, Junko; Kyoizumi, Seishi; Kubo, Yoshiko; Misumi, Munechika; Yoshida, Kengo; Hayashi, Tomonori; Imai, Kazue; Ohishi, Waka; Nakachi, Kei; Weng, Nan-ping; Young, Lauren F.; Shieh, Jae-Hung; Moore, Malcolm A.; van den Brink, Marcel R.M.; Kusunoki, Yoichiro

    2016-01-01

    Accumulated DNA damage in hematopoietic stem cells is a primary mechanism of aging-associated dysfunction in human hematopoiesis. About 70 years ago, atomic-bomb (A-bomb) radiation induced DNA damage and functional decreases in the hematopoietic system of A-bomb survivors in a radiation dose-dependent manner. The peripheral blood cell populations then recovered to a normal range, but accompanying cells derived from hematopoietic stem cells still remain that bear molecular changes possibly caused by past radiation exposure and aging. In the present study, we evaluated radiation-related changes in the frequency of phosphorylated (Ser-139) H2AX (γH2AX) foci formation in circulating CD34-positive/lineage marker-negative (CD34 + Lin−) hematopoietic stem and progenitor cells (HSPCs) among 226Hiroshima A-bomb survivors. An association between the frequency of γH2AX foci formation in HSPCs and the radiation dose was observed, but the γH2AX foci frequency was not significantly elevated by past radiation. We found a negative correlation between the frequency of γH2AX foci formation and the length of granulocyte telomeres. A negative interaction effect between the radiation dose and the frequency of γH2AX foci was suggested in a proportion of a subset of HSPCs as assessed by the cobblestone area-forming cell assay (CAFC), indicating that the self-renewability of HSPCs may decrease in survivors who were exposed to a higher radiation dose and who had more DNA damage in their HSPCs. Thus, although many years after radiation exposure and with advancing age, the effect of DNA damage on the self-renewability of HSPCs may be modified by A-bomb radiation exposure. PMID:27169377

  16. Dendrobium candidum Wall. ex Lindl. attenuates CCl4-induced hepatic damage in imprinting control region mice.

    PubMed

    Li, Gui-Jie; Sun, Peng; Wang, Qiang; Qian, Yu; Zhu, Kai; Zhao, Xin

    2014-09-01

    The aim of the present study was to determine the preventive effect of the traditional Chinese medicine, Dendrobium candidum Wall ex Lindl. ( D. candidum ), on CCl 4 -induced hepatic damage in mice. The CCl 4 -induced hepatic damage mice were treated with D. candidum, and the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), triglyceride (TG) and total cholesterol (TC) were determined. In addition, serum cytokine levels of interleukin (IL)-6, IL-12, tumor necrosis factor (TNF)-α and interferon (IFN)-γ were analyzed with kits, while liver tissues were analyzed using hematoxylin and eosin staining and reverse transcription polymerase chain reaction (RT-PCR). Furthermore, the contents of D. candidum were determined by nuclear magnetic resonance (NMR). D. candidum was demonstrated to successfully prevent hepatic damage in mice. The serum levels of AST, ALT and LDH were significantly decreased when the mice were treated with 200 and 400 mg/kg D. candidum, as compared with the control mice (P<0.05). The lowest enzymatic activities were exhibited in the 400 mg/kg D. candidum group, which produced similar results to the positive control drug, silymarin. In addition, in the 400 mg/kg D. candidum group, the highest levels of TG and TC were observed among the treated groups. D. candidum -treated groups also demonstrated reduced levels of the serum proinflammatory cytokines, IL-6, IL-12, TNF-α and IFN-γ. The sections of liver tissue examined during histopathology in the high concentration 400 mg/kg D. candidum group recovered well from CCl 4 damage; however, the sections in the 200 mg/kg D. candidum group revealed necrosis to a more serious degree. RT-PCR analysis was conducted on inflammation-associated genes, including nuclear factor (NF)-κB, IκB-α, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, in the livers of the mice. The 400 mg/kg D. candidum group demonstrated significantly

  17. Hepatoprotective effects of the polysaccharide isolated from Tarphochlamys affinis (Acanthaceae) against CCl4-induced hepatic injury.

    PubMed

    Lin, Xing; Liu, Xi; Huang, Quanfang; Zhang, Shijun; Zheng, Li; Wei, Ling; He, Min; Jiao, Yang; Huang, Jianchun; Fu, Shujie; Chen, Zhaoni; Li, Yongwen; Zhuo, Lang; Huang, Renbin

    2012-01-01

    This study was designed to investigate the protective effects of the polysaccharide isolated from Tarphochlamys affinis (PTA) against CCl4-induced hepatotoxicity in rats. Liver injury was induced in rats by the administration of CCl4 twice a week for 2 weeks. During the experiment, the model group received CCl4 only; the treatment groups received various drugs plus CCl4, whereas the normal control group received an equal volume of saline. Compared with the CCl4 group, PTA significantly decreased the activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) in the serum and increased the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) in the liver. Moreover, the content of hepatic malondialdehyde (MDA) was reduced. Histological findings also confirmed the anti-hepatotoxic characterisation. In addition, PTA significantly inhibited the proinflammatory mediators, such as prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and myeloperoxidase (MPO). Further investigation showed that the inhibitory effect of PTA on the pro-inflammatory cytokines was associated with the down-regulation of nuclear factor-kappa B (NF-κB). In brief, our results show that the protective effect of PTA against CCl4-induced hepatic injury may rely on its ability to reduce oxidative stress and suppress inflammatory responses.

  18. L-arginine reverses alterations in drug disposition induced by spinal cord injury by increasing hepatic blood flow.

    PubMed

    Vertiz-Hernandez, Antonio; Castaneda-Hernandez, Gilberto; Martinez-Cruz, Angelina; Cruz-Antonio, Leticia; Grijalva, Israel; Guizar-Sahagun, Gabriel

    2007-12-01

    High hepatic extraction drugs--such as phenacetin, methylprednisolone, and cyclosporine--exhibit an increased bioavailability after acute spinal cord injury (SCI) due to an impaired clearance. For these drugs, metabolic clearance depends on hepatic blood flow. Thus, it is possible that pharmacokinetic alterations can be reversed by increasing liver perfusion. Therefore, we evaluated the effect of L-arginine, a nitric oxide precursor, on the pharmacokinetics of a prototype drug with high hepatic extraction, and on hepatic microvascular blood flow (MVBF) after acute SCI. Pharmacokinetics of i.v. phenacetin was studied in rats 24 h after a severe T-5 spinal cord contusion; animals being pretreated with L-arginine 100 mg/kg i.v. or vehicle. MVBF was assessed under similar experimental conditions using laser Doppler flowmetry. SCI significantly altered phenacetin pharmacokinetics. Clearance was significantly reduced, resulting in a prolonged half-life and an increase in bioavailability, while volume of distribution was decreased. Pharmacokinetic alterations were reversed when injured rats were pretreated with L -arginine. It was also observed that L-arginine significantly increased hepatic MVBF in injured rats, notwithstanding it exhibited a limited effect on sham-injured animals. Our data hence suggest that L-arginine is able to reverse SCI-induced alterations in phenacetin pharmacokinetics due to an impaired hepatic MVBF, likely by increased nitric oxide synthesis leading to vasodilation. Further studies are warranted to examine the potential usefulness of nitric oxide supplementation in a clinical setting.

  19. SGLT5 Reabsorbs Fructose in the Kidney but Its Deficiency Paradoxically Exacerbates Hepatic Steatosis Induced by Fructose

    PubMed Central

    Fukuzawa, Taku; Fukazawa, Masanori; Ueda, Otoya; Shimada, Hideaki; Kito, Aki; Kakefuda, Mami; Kawase, Yosuke; Wada, Naoko A.; Goto, Chisato; Fukushima, Naoshi; Jishage, Kou-ichi; Honda, Kiyofumi; King, George L.; Kawabe, Yoshiki

    2013-01-01

    Although excessive fructose intake is epidemiologically linked with dyslipidemia, obesity, and diabetes, the mechanisms regulating plasma fructose are not well known. Cells transfected with sodium/glucose cotransporter 5 (SGLT5), which is expressed exclusively in the kidney, transport fructose in vitro; however, the physiological role of this transporter in fructose metabolism remains unclear. To determine whether SGLT5 functions as a fructose transporter in vivo, we established a line of mice lacking the gene encoding SGLT5. Sodium-dependent fructose uptake disappeared in renal brush border membrane vesicles from SGLT5-deficient mice, and the increased urinary fructose in SGLT5-deficient mice indicated that SGLT5 was the major fructose reabsorption transporter in the kidney. From this, we hypothesized that urinary fructose excretion induced by SGLT5 deficiency would ameliorate fructose-induced hepatic steatosis. To test this hypothesis we compared SGLT5-deficient mice with wild-type mice under conditions of long-term fructose consumption. Paradoxically, however, fructose-induced hepatic steatosis was exacerbated in the SGLT5-deficient mice, and the massive urinary fructose excretion was accompanied by reduced levels of plasma triglycerides and epididymal fat but fasting hyperinsulinemia compared with fructose-fed wild-type mice. There was no difference in food consumption, water intake, or plasma fructose between the two types of mice. No compensatory effect by other transporters reportedly involved in fructose uptake in the liver and kidney were indicated at the mRNA level. These surprising findings indicated a previously unrecognized link through SGLT5 between renal fructose reabsorption and hepatic lipid metabolism. PMID:23451068

  20. Pegylated interferon de novo-induce autoimmune haemolytic anaemia in chronic hepatitis C patient.

    PubMed

    Said, Ashraf; Elbahrawy, Ashraf; Alfiomy, Mohamed; Abdellah, Mohamed; Shahat, Khaled; Salah, Mohamed; Mostafa, Sadek; Elwassief, Ahmed; Aboelfotoh, Attef; Abdelhafeez, Hafez; El-Sherif, Assem

    2011-08-11

    A 55-year-old Egyptian woman with chronic hepatitis C undergoing treatment with pegylated interferon (Peg-IFN) alfa-2a plus ribavirin was referred to our hospital on November 2010 with prolonged easy fatigability and an attack of syncope; she had no prior history of autoimmune disorders or allergy. Laboratory investigations documented the presence of Peg-IFN induced autoimmune haemolytic anaemia and autoimmune thyroiditis. Intravenous γ globulin (IVGG) failed to correct the autoimmune process; on the other hand steroid therapy dramatically corrected both haematological and thyroid values, and step down the immune process. Our report indicated that Peg-IFN de novo-induce autoimmune haemolysis, documenting a previous report. IVGG failed to step down the immune process in our case.

  1. IP-10 protects while MIP-2 promotes experimental anesthetic hapten - induced hepatitis

    PubMed Central

    Njoku, Dolores B.; Li, Zhaoxia; Mellerson, Jenelle L; Sharma, Rajni; Talor, Monica V.; Barat, Nicole; Rose, Noel R.

    2009-01-01

    MIP-2 and IFN-γ inducible protein-10 (IP-10) and their respective receptors, CXCR2 and CXCR3, modulate tissue inflammation by recruiting neutrophils or T cells from the spleen or bone marrow. Yet, how these chemokines modulate diseases such as immune-mediated drug-induced liver injury (DILI) is essentially unknown. To investigate how chemokines modulate experimental DILI in our model we used susceptible BALB/c (WT) and IL-4−/− (KO) mice that develop significantly reduced hepatitis and splenic T cell priming to anesthetic haptens and self proteins following TFA-S100 immunizations. We detected CXCR2+ splenic granulocytes in all mice two weeks following immunizations; by 3 weeks, MIP-2 levels (p<0.001) and GR1+ cells were elevated in WT livers, suggesting MIP-2-recruited granulocytes. Elevated splenic CXCR3+ CD4+T cells were identified after 2 weeks in KO mice indicating elevated IP-10 levels which were confirmed during T cell priming. This result suggested that IP-10 reduced T cell priming to critical DILI antigens. Increased T cell proliferation following co-culture of TFA-S100-primed WT splenocytes with anti-IP-10 (p<0.05) confirmed that IP-10 reduced T cell priming to CYP2E1 and TFA. We propose that MIP-2 promotes and IP-10 protects against the development of hepatitis and T cell priming in this murine model. PMID:19131211

  2. Assessment of contrast-enhanced ultrasonography of the hepatic vein for detection of hemodynamic changes associated with experimentally induced portal hypertension in dogs.

    PubMed

    Morishita, Keitaro; Hiramoto, Akira; Michishita, Asuka; Takagi, Satoshi; Hoshino, Yuki; Itami, Takaharu; Lim, Sue Yee; Osuga, Tatsuyuki; Nakamura, Sayuri; Ochiai, Kenji; Nakamura, Kensuke; Ohta, Hiroshi; Yamasaki, Masahiro; Takiguchi, Mitsuyoshi

    2017-04-01

    OBJECTIVE To assess the use of contrast-enhanced ultrasonography (CEUS) of the hepatic vein for the detection of hemodynamic changes associated with experimentally induced portal hypertension in dogs. ANIMALS 6 healthy Beagles. PROCEDURES A prospective study was conducted. A catheter was surgically placed in the portal vein of each dog. Hypertension was induced by intraportal injection of microspheres (10 to 15 mg/kg) at 5-day intervals via the catheter. Microsphere injections were continued until multiple acquired portosystemic shunts were created. Portal vein pressure (PVP) was measured through the catheter. Contrast-enhanced ultrasonography was performed before and after establishment of hypertension. Time-intensity curves were generated from the region of interest in the hepatic vein. Perfusion variables measured for statistical analysis were hepatic vein arrival time, time to peak, time to peak phase (TTPP), and washout ratio. The correlation between CEUS variables and PVP was assessed by use of simple regression analysis. RESULTS Time to peak and TTPP were significantly less after induction of portal hypertension. Simple regression analysis revealed a significant negative correlation between TTPP and PVP. CONCLUSIONS AND CLINICAL RELEVANCE CEUS was useful for detecting hemodynamic changes associated with experimentally induced portal hypertension in dogs, which was characterized by a rapid increase in the intensity of the hepatic vein. Furthermore, TTPP, a time-dependent variable, provided useful complementary information for predicting portal hypertension. IMPACT FOR HUMAN MEDICINE Because the method described here induced presinusoidal portal hypertension, these results can be applied to idiopathic portal hypertension in humans.

  3. Wheatgrass-Derived Polysaccharide Has Antiinflammatory, Anti-Oxidative and Anti-Apoptotic Effects on LPS-Induced Hepatic Injury in Mice.

    PubMed

    Nepali, Sarmila; Ki, Hyeon-Hui; Lee, Ji-Hyun; Lee, Hoon-Yeon; Kim, Dae-Ki; Lee, Young-Mi

    2017-07-01

    Hepatic injury occurs frequently during sepsis, and polysaccharides isolated from plants have been reported to have antiinflammatory and antioxidant effects in various models. However, the effect of wheatgrass-derived polysaccharide (WGP) has not been previously studied. In the present study, we investigated the effect of WGP on lipopolysaccharide (LPS)-induced hepatic injury in mice. Mice were pre-treated with WGP (100 or 200 mg/kg daily for 2 days) and then challenged with LPS (1 mg/kg, intraperitoneal), and sacrificed after 12 h. Wheatgrass-derived polysaccharide decreased serum aminotransferase levels and histological changes as compared with LPS-challenged mice. Wheatgrass-derived polysaccharide also significantly inhibited LPS-induced pro-inflammatory cytokine up-regulation and improved the oxidative status of liver tissues. Furthermore, these effects were found to be mediated by the suppression of the transcriptional activity of nuclear factor-kappa B (NF-κB), due to inhibitions of transforming growth factor beta (TGF-β)-activated kinase (TAK)-1 phosphorylation and inhibition of kappa B (IκB)-α degradation. In addition, WGP inhibited the activations of mitogen-activated protein kinases (MAPKs). Wheatgrass-derived polysaccharide also attenuated hepatic cell death by modulating caspase-3 and apoptosis associated mitochondrial proteins, such as, B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax). Taken together, WGP possesses antiinflammatory, anti-oxidant and anti-apoptotic activity and ameliorates LPS-induced liver injury in mice. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  4. Autoimmune hepatitis.

    PubMed

    Vergani, D; Mieli-Vergani, G

    1996-01-01

    Autoimmune hepatitis is an inflammatory liver disease in which the immune system is believed to orchestrate an immune attack onto the liver cell. Current knowledge suggests that both T helper 1 (TH1) and TH2 programmes are involved in the generation of the liver damage. Release of TH2 cytokines leads to the production of autoantibodies to the hepatocyte membrane that recruit killer cells. TH1 cytokines induce macrophage activation which contributes to hepatocyte destruction. Patients commonly possess the "autoimmune" HLA A1/B8/DR3 haplotype and a silent gene at the C4A locus with consequent partial deficiency of the complement component C4. Two main types of autoimmune hepatitis are recognised according to the presence of circulating non-organ specific autoantibodies. Patients with smooth muscle antibody and/or antinuclear antibody may be adults or children, while patients with antiliver kidney microsomal type 1 (LKM1) antibody are usually children or very young adults. In both types there is a preponderance of females. LKM1 antibody is also present in a proportion of adult patients, mainly male, with chronic hepatitis C virus infection. This observation originally led to the suggestion that hepatitis C virus may be the cause of this form of autoimmune hepatitis, but several studies have shown that the epitopes target of the LKM1 antibody in autoimmune hepatitis and chronic hepatitis C virus infection differ. Although autoimmune hepatitis responds satisfactorily to immunosuppression in the short term, progression to cirrhosis is frequent. It is hoped that ongoing research will provide a better understanding of the pathogenic mechanisms of liver damage leading to a more effective and specific mode of treatment.

  5. Abacavir-induced fulminant hepatic failure in a HIV/HCV co-infected patient.

    PubMed

    Haas, Christopher; Ziccardi, Mary Rodriguez; Borgman, Jody

    2015-12-15

    Abacavir hypersensitivity is a rare, yet significant adverse reaction that results in a spectrum of physical and laboratory abnormalities, and has been postulated to stem from a variety of aetiological factors. The major histocompatibility complex haplotype human leucocyte antigen (HLA)-B5701 is a significant risk factor in development of hypersensitivity reactions, yet only 55% of HLA-B5701+ individuals develop such reactions, suggesting a multifactorial aetiology. Nevertheless, prospective screening and avoidance of abacavir in these patients has limited adverse events. Within this spectrum of adverse events, abacavir-induced liver toxicity is exceedingly rare and reported events have ranged from mild elevations of aminotransferases to fulminant hepatic failure. We report the case of a 50-year-old Caucasian woman with a history significant for HIV, hepatitis C virus and a HLA-B5701+ status, transferred to our emergency department in a hypotensive state and found to have acute liver failure, acute renal failure and significant rhabdomyolysis following a change of highly active antiretroviral therapy regimen. 2015 BMJ Publishing Group Ltd.

  6. Hepatitis C virus infection can mimic type 1 (antinuclear antibody positive) autoimmune chronic active hepatitis.

    PubMed Central

    Pawlotsky, J M; Deforges, L; Bretagne, S; André, C; Métreau, J M; Thiers, V; Zafrani, E S; Goossens, M; Duval, J; Mavier, J P

    1993-01-01

    Hepatitis C virus (HCV) has been shown to induce anti-liver-kidney microsomal-1 (LKM1) antibody positive chronic active hepatitis, simulating type 2 autoimmune chronic active hepatitis. The cases of five patients presenting with features of type 1 (antinuclear antibody positive) autoimmune chronic active hepatitis and extrahepatic autoimmune manifestations, in whom immunosuppressive treatment had no effect on liver disease are presented. In these patients, HCV infection could be shown by the presence in serum of anti-HCV antibodies and HCV-RNA detected by polymerase chain reaction. These cases suggest the following: (a) chronic HCV infection can mimic type 1, as well as type 2, autoimmune chronic active hepatitis; (b) HCV infection might be systematically sought in patients presenting with features of type 1 autoimmune chronic active hepatitis, with special care in patients who are unresponsive to immunosuppressive treatment. Images Figure PMID:7686122

  7. Human hepatic lipase overexpression in mice induces hepatic steatosis and obesity through promoting hepatic lipogenesis and white adipose tissue lipolysis and fatty acid uptake.

    PubMed

    Cedó, Lídia; Santos, David; Roglans, Núria; Julve, Josep; Pallarès, Victor; Rivas-Urbina, Andrea; Llorente-Cortes, Vicenta; Laguna, Joan Carles; Blanco-Vaca, Francisco; Escolà-Gil, Joan Carles

    2017-01-01

    Human hepatic lipase (hHL) is mainly localized on the hepatocyte cell surface where it hydrolyzes lipids from remnant lipoproteins and high density lipoproteins and promotes their hepatic selective uptake. Furthermore, hepatic lipase (HL) is closely associated with obesity in multiple studies. Therefore, HL may play a key role on lipid homeostasis in liver and white adipose tissue (WAT). In the present study, we aimed to evaluate the effects of hHL expression on hepatic and white adipose triglyceride metabolism in vivo. Experiments were carried out in hHL transgenic and wild-type mice fed a Western-type diet. Triglyceride metabolism studies included β-oxidation and de novo lipogenesis in liver and WAT, hepatic triglyceride secretion, and adipose lipoprotein lipase (LPL)-mediated free fatty acid (FFA) lipolysis and influx. The expression of hHL promoted hepatic triglyceride accumulation and de novo lipogenesis without affecting triglyceride secretion, and this was associated with an upregulation of Srebf1 as well as the main genes controlling the synthesis of fatty acids. Transgenic mice also exhibited more adiposity and an increased LPL-mediated FFA influx into the WAT without affecting glucose tolerance. Our results demonstrate that hHL promoted hepatic steatosis in mice mainly by upregulating de novo lipogenesis. HL also upregulated WAT LPL and promoted triglyceride-rich lipoprotein hydrolysis and adipose FFA uptake. These data support the important role of hHL in regulating hepatic lipid homeostasis and confirm the broad cardiometabolic role of HL.

  8. Human hepatic lipase overexpression in mice induces hepatic steatosis and obesity through promoting hepatic lipogenesis and white adipose tissue lipolysis and fatty acid uptake

    PubMed Central

    Cedó, Lídia; Santos, David; Roglans, Núria; Julve, Josep; Pallarès, Victor; Rivas-Urbina, Andrea; Llorente-Cortes, Vicenta; Laguna, Joan Carles

    2017-01-01

    Human hepatic lipase (hHL) is mainly localized on the hepatocyte cell surface where it hydrolyzes lipids from remnant lipoproteins and high density lipoproteins and promotes their hepatic selective uptake. Furthermore, hepatic lipase (HL) is closely associated with obesity in multiple studies. Therefore, HL may play a key role on lipid homeostasis in liver and white adipose tissue (WAT). In the present study, we aimed to evaluate the effects of hHL expression on hepatic and white adipose triglyceride metabolism in vivo. Experiments were carried out in hHL transgenic and wild-type mice fed a Western-type diet. Triglyceride metabolism studies included β-oxidation and de novo lipogenesis in liver and WAT, hepatic triglyceride secretion, and adipose lipoprotein lipase (LPL)-mediated free fatty acid (FFA) lipolysis and influx. The expression of hHL promoted hepatic triglyceride accumulation and de novo lipogenesis without affecting triglyceride secretion, and this was associated with an upregulation of Srebf1 as well as the main genes controlling the synthesis of fatty acids. Transgenic mice also exhibited more adiposity and an increased LPL-mediated FFA influx into the WAT without affecting glucose tolerance. Our results demonstrate that hHL promoted hepatic steatosis in mice mainly by upregulating de novo lipogenesis. HL also upregulated WAT LPL and promoted triglyceride-rich lipoprotein hydrolysis and adipose FFA uptake. These data support the important role of hHL in regulating hepatic lipid homeostasis and confirm the broad cardiometabolic role of HL. PMID:29244870

  9. Objective scoring of transformed foci in BALB/c 3T3 cell transformation assay by statistical image descriptors.

    PubMed

    Urani, C; Corvi, R; Callegaro, G; Stefanini, F M

    2013-09-01

    In vitro cell transformation assays (CTAs) have been shown to model important stages of in vivo carcinogenesis and have the potential to predict carcinogenicity in humans. Advantages of CTAs are their ability of revealing both genotoxic and non-genotoxic carcinogens while reducing both experimental costs and the number of animals used. The endpoint of the CTA is foci formation, and requires classification under light microscopy based on morphology. Thus current limitations for the wide adoption of the assay partially depend on a fair degree of subjectivity in foci scoring. An objective evaluation may be obtained after separating foci from background monolayer in the digital image, and quantifying values of statistical descriptors which are selected to capture eye-scored morphological features. The aim of this study was to develop statistical descriptors to be applied to transformed foci of BALB/c 3T3, which cover foci size, multilayering and invasive cell growth into the background monolayer. Proposed descriptors were applied to a database of 407 foci images to explore the numerical features, and to illustrate open problems and potential solutions. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Effects of 4-nonylphenol on oxidant/antioxidant balance system inducing hepatic steatosis in male rat.

    PubMed

    Kourouma, Ansoumane; Keita, Hady; Duan, Peng; Quan, Chao; Bilivogui, Koikoi Kebe; Qi, Suqin; Christiane, Ndjiembi Adjonga; Osamuyimen, Aidogie; Yang, Kedi

    2015-01-01

    An emerging literature suggests that early life exposure to 4-nonylphenol (4-NP), a widespread endocrine disrupting chemical, may increase the risk of metabolic syndrome. In this study, we investigated the hypothesis that intraperitoneal administration of 4-NP induces hepatic steatosis in rat. 24 male Sprague-Dawley rats were administered with 4-NP (0, 2, 10 and 50 mg/kg b.wt) in corn oil for 30 days. Liver histology, biochemical analysis and gene expression profiling were examined. After treatment, abnormal liver morphology and function were observed in the 4-NP-treated rat, and significant changes in gene expression an indicator of hepatic steatosis and apoptosis were observed compared with controls. Up-regulated genes involved in apoptosis, hepatotoxity and oxidative stress, increased ROS and decrease of antioxidant enzyme were observed in the 4-NP exposed rat. Extensive fatty accumulation in liver section and elevated serum GOT, GPT, LDH and γ-GT were also observed. Incidence and severity of liver steatosis was scored and taken into consideration (steatosis, ballooning and lobular inflammation). Hepatocytes apoptosis could promote NAFLD progression; Fas/FasL, TNF-α and Caspase-9 mRNA activation were important contributing factors to hepatic steatosis. These findings provide the first evidence that 4-NP affects the gene expression related to liver hepatotoxicity, which is correlated with hepatic steatosis.

  11. [Protective effects of agmatine on lipopolysaccharide -induced acute hepatic injury in mice].

    PubMed

    Li, Xuan -fei; Fan, Xia; Zheng, Zhi-hua; Yang, Xue; Liu, Zheng; Gong, Jian-ping; Liang, Hua-ping

    2013-12-01

    To observe the effect of agmatine ( AGM) on lipopolysaccharide ( LPS )-induced acute hepatic injury in mice, and to explore its related mechanism. Sixty C57BU6 mice were randomly divided into control group ( n = 20, with intra-peritoneal injection of phosphate buffer saline 10 mg/kg), model group ( n = 20, with intra-peritoneal injection of LPS 10 mg/kg), and AGM group (n=20, with intra-peritoneal injection of LPS 10 mg/kg and AGM 200 mg/kg). Ten mice in each group were sacrificed at 6 hours and 24 hours, respectively, after modeling, blood samples were collected for the determination of tumor necrosis factor-a ( TNF -a) and interleukin ( IL-113 and IL-6) by enzyme linked immunosorbent assay (ELISA) at 6 hours after modeling , and for determination of alanine aminotransferase (ALT), aspartate transaminase (AST) and total bilirubin (TBil) by automatic biochemistry analyzer at 24 hours after modeling. Hepatic homogenate was also collected for determining the endo nuclear nuclear factor-KB ( NF -KB) p65 by Western blotting at 6 hours after modeling, and for observation of pathological changes at 24 hours after modeling. At 6 hours after modeling, .the mice in model group became lethargic and quiet, and their food and water assumption was reduced, but AGM was found to be able to greatly improve the general status of animals in AGM group. AGM was found to lower the contents of serum TNF-a ( IJ.g/L: 296.3 ± 42.5 vs. 627.2 ± 81.3, t=7.327, P=0.002), IL-113 ( f.Lg/L: 109.1 ± 12.3 vs. 264.2 ± 18.8, t= 11.958, P=0.001), IL-6 ( mg/L: 11.4 ± 1.9 vs. 23.6 ± 2.5, t=6.729, P=0.003), ALT (U!L: 107.9 ± 8.5 vs. 189.9 ± 13.6, t=8.856, P=0.001 ), AST (UIL: 347.4 ± 24.9 vs. 716.8 ± 60.4, t=9.793, P=0.001) and TBil ( f.Lmol!L: 8.3 ± 0.9 vs. 10.6 ± 0.5, t=3.869, P=0.018) in mice with acute hepatic injury induced by LPS. AGM also depressed TNF -a ( ng/g: 287.4 ± 32.5 vs. 461.5 ± 31.4, t=6.673, P= 0.003), IL-113 (pg/g: 146.7 ± 13.5 vs. 351.6 ± 28.7, t=11.190, P=0.001) and

  12. An ω-3-enriched diet alone does not attenuate CCl4-induced hepatic fibrosis.

    PubMed

    Harris, Todd R; Kodani, Sean; Yang, Jun; Imai, Denise M; Hammock, Bruce D

    2016-12-01

    Exposure to the halogenated hydrocarbon carbon tetrachloride (CCl 4 ) leads to hepatic lipid peroxidation, inflammation and fibrosis. Dietary supplementation of ω-3 fatty acids has been increasingly advocated as being generally anti-inflammatory, though its effect in models of liver fibrosis is mixed. This raises the question of whether diets high in ω-3 fatty acids will result in a greater sensitivity or resistance to liver fibrosis as a result of environmental toxicants like CCl 4 . In this study, we fed CCl 4 -treated mice a high ω-3 diet (using a mix of docosahexaenoic acid and eicosapentaenoic acid ethyl esters). We also co-administered an inhibitor of soluble epoxide hydrolase, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which has been shown to boost anti-inflammatory epoxy fatty acids that are produced from both ω-3 and ω-6 dietary lipids. We showed that soluble epoxide inhibitors reduced CCl 4 -induced liver fibrosis. Three major results were obtained. First, the ω-3-enriched diet did not attenuate CCl 4 -induced liver fibrosis as judged by collagen deposition and collagen mRNA expression. Second, the ω-3-enriched diet raised hepatic tissue levels of several inflammatory lipoxygenase metabolites and prostaglandins, including PGE2. Third, treatment with TPPU in drinking water in conjunction with the ω-3-enriched diet resulted in a reduction in liver fibrosis compared to all other groups. Taken together, these results indicate that dietary ω-3 supplementation alone did not attenuate CCl 4 -induced liver fibrosis. Additionally, oxylipin signaling molecules may play role in the CCl 4 -induced liver fibrosis in the high ω-3 diet groups. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. An ω-3 enriched diet alone does not attenuate CCl4-induced hepatic fibrosis

    PubMed Central

    Harris, Todd R.; Kodani, Sean; Yang, Jun; Imai, Denise M.; Hammock, Bruce D.

    2016-01-01

    Exposure to the halogenated hydrocarbon carbon tetrachloride (CCl4) leads to hepatic lipid peroxidation, inflammation, and fibrosis. Dietary supplementation of ω-3 fatty acids has been increasingly advocated as being generally anti-inflammatory, though its effect in models of liver fibrosis is mixed. This raises the question of whether diets high in ω-3 fatty acids will result in a greater sensitivity or resistance to liver fibrosis as a result of environmental toxicants like CCl4. In this study we fed CCl4-treated mice a high ω-3 diet (using a mix of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) ethyl esters). We also co-administered an inhibitor of soluble epoxide hydrolase, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), which has been shown to boost anti-inflammatory epoxy fatty acids that are produced from both ω-3 and ω-6 dietary lipids. In this study, we showed that soluble epoxide inhibitors reduced CCl4-induced liver fibrosis. Three major results were obtained. First, the ω-3 enriched diet did not attenuate CCl4-induced liver fibrosis as judged by collagen deposition and collagen mRNA expression. Second, the ω-3 enriched diet raised hepatic tissue levels of several inflammatory lipoxygenase metabolites and prostaglandins, including PGE2. Third, treatment with TPPU in drinking water in conjunction with the ω-3 enriched diet resulted in a reduction in liver fibrosis compared to all other groups. Taken together, these results indicate that dietary ω-3 supplementation alone did not attenuate CCl4-induced liver fibrosis. Additionally, oxylipin signaling molecules may play role in the CCl4-induced liver fibrosis in the high ω-3 diet groups. PMID:27732914

  14. Metabolic profiles and bile acid extraction rate in the liver of cows with fasting-induced hepatic lipidosis.

    PubMed

    Mohamed, T; Oikawa, S; Iwasaki, Y; Mizunuma, Y; Takehana, K; Endoh, D; Kurosawa, T; Sato, H

    2004-04-01

    This study was designed to monitor lipid profile in the portal and hepatic blood of cows with fasting-induced hepatic lipidosis, and to compare the results with those in the jugular blood. The work was also carried out to investigate bile acid (BA) in these vessels, and further to investigate BA extraction rate in the liver. Five cows were equipped with catheters in the portal, hepatic and jugular veins (day 0), fasted for 4 days (day 1-day 4) and then refed (day 5-day 11). Before morning feeding, blood was sampled before, during and after fasting from the catheterized vessels. In the portal blood, the concentration of non-esterified fatty acids (NEFA) showed a progressive increase and at day 5 there was an approximate twofold rise. Increased NEFA concentrations were also found similarly in the other two veins. At day 5, beta-hydroxybutyrate (BHBA) in the portal, hepatic and jugular blood rose to 197, 190 and 186% of the pre-fasting value, respectively. However, the concentrations of NEFA and BHBA in the three veins gradually returned to pre-fasting concentration during the refeeding period. Compared with the pre-fasting value at day 0, the content of liver triglyceride (TG) increased significantly at day 5 (P < 0.01). In the liver, the hepatic extraction rate of BA dropped from 3.1 times pre-fasting to 2.2 times during fasting. There were no significant differences in the concentrations of glucose, TG, total cholesterol, cholesterol esters, free cholesterol and phospholipids. The results of the current study show that metabolic alterations occur in the portal, hepatic and jugular veins during induction of hepatic lipidosis in cows, and mostly metabolites, with exception of BA concentration, run parallel. The decreased BA extraction rate in the liver of fasted cows was considered to reflect hepatic cell impairment caused by TG accumulation. Hopefully, the findings, at least in part, contribute to the explanation of the pathophysiology of hepatic lipidosis in dairy

  15. Identification of hepatic fibroblast growth factor 21 as a mediator in 17β-estradiol-induced white adipose tissue browning.

    PubMed

    Hua, Lun; Zhuo, Yong; Jiang, Dandan; Li, Jing; Huang, Xiaohua; Zhu, Yingguo; Li, Zhen; Yan, Lijun; Jin, Chao; Jiang, Xuemei; Che, Lianqiang; Fang, Zhengfeng; Lin, Yan; Xu, Shengyu; Li, Jian; Feng, Bin; Wu, De

    2018-05-02

    Both ovarian E2 and hepatic fibroblast growth factor 21 (FGF21) are critical for energy homeostasis and white adipose tissue browning. Estrogen receptor α (ERα) is abundantly expressed in liver. However, whether FGF21 has a role in E2-induced white adipose tissue browning remains uncertain. In this study, we showed that hepatic Fgf21 expression and secretion during estrus cycle changed with the tetradian oscillatory secretion of circulation E2 in adult, female mice, with their peak expressions and secretions at the proestrus. In addition, exogenous E2 robustly stimulated liver Fgf21 expression and elevated serum FGF21 concentrations, which induced browning gene expression and reduced the tissue weight in subcutaneous white adipose in mice with ovariectomies. The inhibitor of mammalian target of rapamycin (mTOR) and of ERα blocked the induction effect of E2 on the expression of Fgf21 in primary hepatocytes, which revealed that E2 might stimulate FGF21 expression via the ERα-mTOR pathway. Furthermore, FGF21 liver-specific deficiency abolished E2-induced white adipose browning in mice with ovariectomies. This study indicates that ovarian E2 increased liver FGF21 expression directly, which in turn, functioned as an endocrine signal to influence inguinal white adipose tissue browning.-Hua, L., Zhuo, Y., Jiang, D., Li, Jin., Huang, X., Zhu, Y., Li, Z., Yan, L., Jin, C., Jiang, X., Che, L., Fang, Z., Lin, Y., Xu, S. Li, Jia., Feng, B., Wu, D. Identification of hepatic fibroblast growth factor 21 as a mediator in 17β-estradiol-induced white adipose tissue browning.

  16. Effect of Pterocarpus santalinus bark, on blood glucose, serum lipids, plasma insulin and hepatic carbohydrate metabolic enzymes in streptozotocin-induced diabetic rats.

    PubMed

    Kondeti, Vinay Kumar; Badri, Kameswara Rao; Maddirala, Dilip Rajasekhar; Thur, Sampath Kumar Mekala; Fatima, Shaik Sameena; Kasetti, Ramesh Babu; Rao, Chippada Appa

    2010-05-01

    The present study was designed to investigate the effect of bark of Pterocarpus santalinus, an ethnomedicinal plant, on blood glucose, plasma insulin, serum lipids and the activities of hepatic glucose metabolizing enzymes in streptozotocin-induced diabetic rats. Streptozotocin-induced diabetic rats were treated (acute/short-term and long-term) with ethyl acetate:methanol fractions of ethanolic extract of the bark of P. santalinus. Fasting blood glucose, HbA(1C), plasma insulin and protein were estimated before and after the treatment, along with hepatic glycogen, and activities of hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase and glucose-6-phosphate dehydrogenase. Further anti-hyperlipidemic activity was studied by measuring the levels of serum lipids and lipoproteins. Phytochemical analysis of active fraction showed the presence of flavonoids, glycosides and phenols. Biological testing of the active fraction demonstrated a significant antidiabetic activity by reducing the elevated blood glucose levels and glycosylated hemoglobin, improving hyperlipidemia and restoring the insulin levels in treated experimental induced diabetic rats. Further elucidation of mechanism of action showed improvement in the hepatic carbohydrate metabolizing enzymes after the treatment. Our present investigation suggests that active fraction of ethanolic extract of bark of P. santalinus decreases streptozotocin induced hyperglycemia by increasing glycolysis and decreasing gluconeogenesis. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  17. Overcoming diabetes-induced hyperglycemia through inhibition of hepatic phosphoenolpyruvate carboxykinase (GTP) with RNAi.

    PubMed

    Gómez-Valadés, Alicia G; Vidal-Alabró, Anna; Molas, Maria; Boada, Jordi; Bermúdez, Jordi; Bartrons, Ramon; Perales, José C

    2006-02-01

    Phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) is the rate-controlling enzyme in gluconeogenesis. In diabetic individuals, altered rates of gluconeogenesis are responsible for increased hepatic glucose output and sustained hyperglycemia. Liver-specific inhibition of PEPCK has not been assessed to date as a treatment for diabetes. We have designed a therapeutic, vector-based RNAi approach to induce posttranscriptional gene silencing of hepatic PEPCK using nonviral gene delivery. A transient reduction of PEPCK enzymatic activity (7.6 +/- 0.6 vs 9.7 +/- 1.1 mU/mg, P < 0.05) that correlated with decreased protein content of up to 50% was achieved using this strategy in diabetic mice. PEPCK partial silencing was sufficient to demonstrate lowered blood glucose (218 +/- 26 vs 364 +/- 33 mg/dl, P < 0.001) and improved glucose tolerance together with decreased circulating FFA (0.89 +/- 0.10 vs 1.44 +/- 0.11 mEq/dl, P < 0.001) and TAG (65 +/- 11 vs 102 +/- 16 mg/dl, P < 0.01), in the absence of liver steatosis or lactic acidosis. SREBP1c was down-regulated in PEPCK-silenced animals, suggesting a role for this pathway in the alterations of lipid metabolism. These data reinforce the significance of PEPCK in sustaining diabetes-induced hyperglycemia and validate liver-specific intervention at the level of PEPCK for diabetes gene therapy.

  18. Phosphorylation of NS5A Serine-235 is essential to hepatitis C virus RNA replication and normal replication compartment formation

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Eyre, Nicholas S., E-mail: nicholas.eyre@adelaide.edu.au; Centre for Cancer Biology, SA Pathology, Adelaide; Hampton-Smith, Rachel J.

    Hepatitis C virus (HCV) NS5A protein is essential for HCV RNA replication and virus assembly. Here we report the identification of NS5A phosphorylation sites Ser-222, Ser-235 and Thr-348 during an infectious HCV replication cycle and demonstrate that Ser-235 phosphorylation is essential for HCV RNA replication. Confocal microscopy revealed that both phosphoablatant (S235A) and phosphomimetic (S235D) mutants redistribute NS5A to large juxta-nuclear foci that display altered colocalization with known replication complex components. Using electron microscopy (EM) we found that S235D alters virus-induced membrane rearrangements while EM using ‘APEX2’-tagged viruses demonstrated S235D-mediated enrichment of NS5A in irregular membranous foci. Finally, using amore » customized siRNA screen of candidate NS5A kinases and subsequent analysis using a phospho-specific antibody, we show that phosphatidylinositol-4 kinase III alpha (PI4KIIIα) is important for Ser-235 phosphorylation. We conclude that Ser-235 phosphorylation of NS5A is essential for HCV RNA replication and normal replication complex formation and is regulated by PI4KIIIα. - Highlights: • NS5A residues Ser-222, Ser-235 and Thr-348 are phosphorylated during HCV infection. • Phosphorylation of Ser-235 is essential to HCV RNA replication. • Mutation of Ser-235 alters replication compartment localization and morphology. • Phosphatidylinositol-4 kinase III alpha is important for Ser-235 phosphorylation.« less

  19. Cultured Mycelium Cordyceps sinensis allevi¬ates CCl4-induced liver inflammation and fibrosis in mice by activating hepatic natural killer cells.

    PubMed

    Peng, Yuan; Huang, Kai; Shen, Li; Tao, Yan-yan; Liu, Cheng-hai

    2016-02-01

    Recent evidence shows that cultured mycelium Cordyceps sinensis (CMCS) effectively protects against liver fibrosis in mice. Here, we investigated whether the anti-fibrotic action of CMCS was related to its regulation of the activity of hepatic natural killer (NK) cells in CCl4-treated mice. C57BL/6 mice were injected with 10% CCl4 (2 mL/kg, ip) 3 times per week for 4 weeks, and received CMCS (120 mg·kg(-1)·d(-1), ig) during this period. In another part of experiments, the mice were also injected with an NK cell-deleting antibody ASGM-1 (20 μg, ip) 5 times in the first 3 weeks. After the mice were sacrificed, serum liver function, and liver inflammation, hydroxyproline content and collagen deposition were assessed. The numbers of hepatic NK cells and expression of NKG2D (activation receptor of NK cells) on isolated liver lymphocytes were analyzed using flow cytometry. Desmin expression and cell apoptosis in liver tissues were studied using desmin staining and TUNEL assay, respectively. The levels of α-SMA, TGF-β, RAE-1δ and RAE-1ε in liver tissues were determined by RT-qPCR. In CCl4-treated mice, CMCS administration significantly improved liver function, attenuated liver inflammation and fibrosis, and increased the numbers of hepatic NK cells and expression level of NKG2D on hepatic NK cells. Furthermore, CMCS administration significantly decreased desmin expression in liver tissues, and increased TUNEL staining adjacent to hepatic stellate cells. Injection with NK cell-deleting ASGM-1 not only diminished the numbers of hepatic NK cells, but also greatly accelerated liver inflammation and fibrosis in CCl4-treated mice. In CCl4-treated mice with NK cell depletion, CMCS administration decelerated the rate of liver fibrosis development, and mildly upregulated the numbers of hepatic NK cells but without changing NKG2D expression. CMCS alleviates CCl4-induced liver inflammation and fibrosis via promoting activation of hepatic NK cells. CMCS partially reverses ASGM

  20. Hepatic Transcriptome Profiles of Mice with Diet-Induced Nonalcoholic Steatohepatitis Treated with Astaxanthin and Vitamin E

    PubMed Central

    Kobori, Masuko; Takahashi, Yumiko; Sakurai, Mutsumi; Ni, Yinhua; Chen, Guanliang; Nagashimada, Mayumi; Kaneko, Shuichi; Ota, Tsuguhito

    2017-01-01

    Astaxanthin alleviates hepatic lipid accumulation and peroxidation, inflammation, and fibrosis in mice with high-cholesterol, high-cholate, and high-fat (CL) diet-induced nonalcoholic steatohepatitis (NASH). It has been proposed as a potential new treatment to inhibit the progression of NASH in humans. In this study, we compared hepatic gene expression profiles after treatment with astaxanthin or the antioxidant vitamin E in mice with CL diet-induced NASH. Comprehensive gene expression analyses of the livers of mice fed a standard, CL, or CL diet containing astaxanthin or vitamin E for 12 weeks were performed using a DNA microarray. Both astaxanthin and vitamin E effectively improved gene expression associated with eukaryotic initiation factor-2 (EIF2) signaling, which is suppressed in NASH by endoplasmic reticulum (ER) stress in the liver. However, astaxanthin did not improve the expression of genes associated with mitochondrial dysfunction. Astaxanthin, but not vitamin E, was predicted to suppress the actions of ligand-dependent nuclear receptors peroxisome proliferator-activated receptors, (PPAR) α (PPARA) and PPARδ (PPARD), and to affect related molecules. Establishing a new therapy using astaxanthin will require elucidation of astaxanthin’s molecular action on the functions of PPARα and related molecules in the livers of mice with diet-induced NASH. PMID:28282876

  1. Origins of recently emerged foci of the tick Dermacentor reticulatus in central Europe inferred from molecular markers.

    PubMed

    Kloch, Agnieszka; Mierzejewska, Ewa J; Karbowiak, Grzegorz; Slivinska, Kateryna; Alsarraf, Mohammed; Rodo, Anna; Kowalec, Maciej; Dwużnik, Dorota; Didyk, Yuliya M; Bajer, Anna

    2017-04-15

    The ornate dog tick Dermacentor reticulatus is vector of several blood parasites, including Babesia canis, a causative agent of babesiosis. The geographical range of D. reticulatus in Europe is discontinuous with a gap separating eastern and western macroregions. New foci observed in several locations in western and central Europe were considered an expansion of the western population, including foci in western Poland. In the present paper we used molecular markers to identify the origins of these foci, and we compared their genetic polymorphism to D. reticulatus collected in sites situated within the eastern population. The overall polymorphism in mt 16S rDNA was low, and all sites from the western population shared the same haplotype suggesting the expansion in this area. In the marker 5.8S rDNA-ITS2 we found no differences in polymorphism between sites from eastern Poland (eastern population), and newly emerged foci in western Poland considered a putative expansion zone of the western population. However, the sites from western Poland differed considerably from nearby German site. Our results show that foci in western Poland could not have originated from D. reticulatus from the western population, as previously thought. We found that the state border following river hinders considerably gene flow between adjacent sites what suggest that natural dispersal of D. reticulatus by wildlife is unlikely, and the emergence of new foci should rather be contributed to human-associated dispersal. We propose that livestock, and pets travelling with their owners are the most probable source of new foci, and they can easily transfer ticks within a country but not between countries. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Intra-Hepatic Depletion of Mucosal-Associated Invariant T Cells in Hepatitis C Virus-Induced Liver Inflammation.

    PubMed

    Bolte, Fabian J; O'Keefe, Ashley C; Webb, Lauren M; Serti, Elisavet; Rivera, Elenita; Liang, T Jake; Ghany, Marc; Rehermann, Barbara

    2017-11-01

    controls. Anti-viral therapy rapidly decreased liver inflammation and MAIT cell activation and cytotoxicity, and increased the MAIT cell frequency among intra-hepatic but not blood T cells. The MAIT cell response to T-cell receptor-mediated stimulation did not change during the 12 weeks of antiviral therapy. In analyses of paired blood and liver samples from patients with chronic HCV infection before, during, and after antiviral therapy with sofosbuvir and velpatasvir, we found that intrahepatic MAIT cells are activated by monocyte-derived cytokines and depleted in HCV-induced liver inflammation. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

  3. Forkhead Box O6 (FoxO6) Depletion Attenuates Hepatic Gluconeogenesis and Protects against Fat-induced Glucose Disorder in Mice.

    PubMed

    Calabuig-Navarro, Virtu; Yamauchi, Jun; Lee, Sojin; Zhang, Ting; Liu, Yun-Zi; Sadlek, Kelsey; Coudriet, Gina M; Piganelli, Jon D; Jiang, Chun-Lei; Miller, Rita; Lowe, Mark; Harashima, Hideyoshi; Dong, H Henry

    2015-06-19

    Excessive endogenous glucose production contributes to fasting hyperglycemia in diabetes. FoxO6 is a distinct member of the FoxO subfamily. To elucidate the role of FoxO6 in hepatic gluconeogenesis and assess its contribution to the pathogenesis of fasting hyperglycemia in diabetes, we generated FoxO6 knock-out (FoxO6-KO) mice followed by determining the effect of FoxO6 loss-of-function on hepatic gluconeogenesis under physiological and pathological conditions. FoxO6 depletion attenuated hepatic gluconeogenesis and lowered fasting glycemia in FoxO6-KO mice. FoxO6-deficient primary hepatocytes were associated with reduced capacities to produce glucose in response to glucagon. When fed a high fat diet, FoxO6-KO mice exhibited significantly enhanced glucose tolerance and reduced blood glucose levels accompanied by improved insulin sensitivity. These effects correlated with attenuated hepatic gluconeogenesis in FoxO6-KO mice. In contrast, wild-type littermates developed fat-induced glucose intolerance with a concomitant induction of fasting hyperinsulinemia and hyperglycemia. Furthermore, FoxO6-KO mice displayed significantly diminished macrophage infiltration into liver and adipose tissues, correlating with the reduction of macrophage expression of C-C chemokine receptor 2 (CCR2), a factor that is critical for regulating macrophage recruitment in peripheral tissues. Our data indicate that FoxO6 depletion protected against diet-induced glucose intolerance and insulin resistance by attenuating hepatic gluconeogenesis and curbing macrophage infiltration in liver and adipose tissues in mice. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  4. Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A2 and diet-induced obesity

    PubMed Central

    Labonté, Eric D.; Pfluger, Paul T.; Cash, James G.; Kuhel, David G.; Roja, Juan C.; Magness, Daniel P.; Jandacek, Ronald J.; Tschöp, Matthias H.; Hui, David Y.

    2010-01-01

    Decrease in fat catabolic rate on consuming a high-fat diet contributes to diet-induced obesity. This study used group 1B phospholipase A2 (Pla2g1b)-deficient mice, which are resistant to hyperglycemia, to test the hypothesis that Pla2g1b and its lipolytic product lysophospholipid suppress hepatic fat utilization and energy metabolism in promoting diet-induced obesity. The metabolic consequences of hypercaloric diet, including body weight gain, energy expenditure, and fatty acid oxidation, were compared between Pla2g1b+/+ and Pla2g1b−/− mice. The Pla2g1b−/− mice displayed normal energy balance when fed chow, but were resistant to obesity when challenged with a hypercaloric diet. Obesity resistance in Pla2g1b−/− mice is due to their ability to maintain elevated energy expenditure and core body temperature when subjected to hypercaloric diet, which was not observed in Pla2g1b+/+ mice. The Pla2g1b−/− mice also displayed increased postprandial hepatic fat utilization due to increased expression of peroxisome proliferator-activated receptor (PPAR)-α, PPAR-δ, PPAR-γ, cd36/Fat, and Ucp2, which coincided with reduced postprandial plasma lysophospholipid levels. Lysophospholipids produced by Pla2g1b hydrolysis suppress hepatic fat utilization and down-regulate energy expenditure, thereby preventing metabolically beneficial adaptation to a high-fat diet exposure in promoting diet-induced obesity and type 2 diabetes.—Labonté, E. D., Pfluger, P. T., Cash, J. G., Kuhel, D. G., Rojas, J. C., Magness, D. P., Jandacek, R. J., Tschöp, M. H., Hui, D. Y. Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A2 and diet-induced obesity. PMID:20215528

  5. Activation of AMPK by berberine induces hepatic lipid accumulation by upregulation of fatty acid translocase CD36 in mice

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Choi, You-Jin; Lee, Kang-Yo; Jung, Seung-Hwan

    Emerging evidence has shown that berberine has a protective effect against metabolic syndrome such as obesity and type II diabetes mellitus by activating AMP-activated protein kinase (AMPK). AMPK induces CD36 trafficking to the sarcolemma for fatty acid uptake and oxidation in contracting muscle. However, little is known about the effects of AMPK on CD36 regulation in the liver. We investigated whether AMPK activation by berberine affects CD36 expression and fatty acid uptake in hepatocytes and whether it is linked to hepatic lipid accumulation. Activation of AMPK by berberine or transduction with adenoviral vectors encoding constitutively active AMPK in HepG2 andmore » mouse primary hepatocytes increased the expression and membrane translocation of CD36, resulting in enhanced fatty acid uptake and lipid accumulation as determined by BODIPY-C16 and Nile red fluorescence, respectively. Activation of AMPK by berberine induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and subsequently induced CCAAT/enhancer-binding protein β (C/EBPβ) binding to the C/EBP-response element in the CD36 promoter in hepatocytes. In addition, hepatic CD36 expression and triglyceride levels were increased in normal diet-fed mice treated with berberine, but completely prevented when hepatic CD36 was silenced with adenovirus containing CD36-specific shRNA. Taken together, prolonged activation of AMPK by berberine increased CD36 expression in hepatocytes, resulting in fatty acid uptake via processes linked to hepatocellular lipid accumulation and fatty liver. - Highlights: • Berberine increases the expression and membrane translocation of CD36 in hepatocytes. • The increase of CD36 results in enhanced fatty acid uptake and lipid accumulation. • Berberine-induced fatty liver is mediated by AMPK-ERK-C/EBPβ pathway. • CD36-specific shRNA inhibited berberine-induced lipid accumulation in liver.« less

  6. Protective effects of seed melon extract on CCl4-induced hepatic fibrosis in mice.

    PubMed

    Zhan, Yuan-Yuan; Wang, Jin-Hui; Tian, Xing; Feng, Shi-Xiu; Xue, Lin; Tian, Li-Ping

    2016-12-04

    Citrullus lanatus ssp. vulgaris var. megalaspermus Lin et Chao, was also known as watermelon belongs to family Cucurbitaceae, variously used as healthy food and in the treatment of liver and lungs problems. Currently, Citrullus lanatus has become a major economic crop of medicinal and edible effects with regional characteristics. This study was designed to evaluate the hepatoprotective and antioxidant activity of the seed melon (Citrullus lanatus ssp. vulgaris var. megalaspermus Lin et Chao) extract (SME) against carbon tetrachloride (CCl 4 ) induced hepatic fibrosis in mice. In this study, mice were randomly divided into 7 groups, including normal control, model, silymarin tablets as the positive control, SME 100, 200, 400, and 800mg/kg. After 8 weeks, activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglycerides (TG), hyaluronic acid (HA) and laminin (LN) were checked. The levels of antioxidant enzymes such as superoxide dismutase (SOD), glutataion (GSH) and glutathione peroxidase (GSH-Px) were determined after SME administration. The hydroxyproline (HYP) levels, malondialdehyde (MDA) levels and histopathologic examinations of hepatocyte fibrosis were also determined. Additionally, effects of SME on alpha-smooth muscle actin (α-SMA) and transforming growth factor beta-1(TGF-β1) protein expressions were determined. We found that SME could significantly lower the serum levels of hepatic enzyme markers AST, ALT, HA and LN (P<0.01). Compared with the CCl 4 -only treatment group, levels of hepatic SOD and GSH-Px were significantly increased, and the MDA levels were remarkably decreased in mice treated by SME at medium dose (400mg/kg) and high dose (800mg/kg) (P<0.01). A histological examination of the liver showed that lesions, including necrosis, lymphocyte infiltration and fatty degeneration, were partially healed by treatment with SME. The results of protein expressions studies displayed that SME could inhibit α-SMA and TGF

  7. Progression and Regression of Hepatic Lesions in a Mouse Model of NASH Induced by Dietary Intervention and Its Implications in Pharmacotherapy.

    PubMed

    Ding, Zhi-Ming; Xiao, Yue; Wu, Xikun; Zou, Haixia; Yang, Shurong; Shen, Yiyun; Xu, Juehua; Workman, Heather C; Usborne, Amy L; Hua, Haiqing

    2018-01-01

    Understanding of the temporal changes of hepatic lesions in the progression and regression of non-alcoholic steatohepatitis (NASH) is vital to elucidation of the pathogenesis of NASH, and critical to the development of a strategy for NASH pharmacotherapy. There are challenges in studying hepatic lesion progression and regression in NASH patients due to the slow development of NASH in humans, one being the requirement for multiple biopsies during the longitudinal follow-up. Here we studied lesion progression and regression in the diet-induced animal model of NASH by application or removal of the pathogenic diet for multiple time periods. Male C57BL/6 mice fed Western diet developed progressive hepatic steatosis/macrovesicular vacuolation, inflammation, and hepatocyte degeneration, as well as perisinusoidal fibrosis and occasionally portal fibrosis as early as 2 months after initiation of the Western diet. In the same period, the mice exhibited elevated ALT (alanine aminotransferase) and AST (aspartate aminotransferase) enzyme activities, CK18 (cytokeratin-18), PIIINP (N-terminal propeptide of type III collagen), and TIMP-1 (tissue inhibitor of metalloproteinase-1). Hepatic steatosis diminished rapidly when the Western diet was replaced by normal rodent chow diet and hepatic inflammation and hepatocyte degeneration were also reduced. Interestingly, perisinusoidal fibrosis and portal fibrosis regressed 8 months after chow diet replacement. To understand pharmacotherapy for NASH, mice with established NASH hepatic lesions were treated with either FXR agonist obeticholic acid (Ocaliva), or CCR2/5 antagonist Cenicriviroc. Similar to the diet replacement, metabolic modulator Ocaliva markedly reduced steatosis/macrovesicular vacuolation, hepatic inflammation, and hepatocyte degeneration effectively, but exhibited no significant effect on liver fibrosis. Anti-inflammation drug Cenicriviroc, on the other hand, markedly decreased inflammation and hepatocyte degeneration, and

  8. Detecting hepatic steatosis using ultrasound-induced thermal strain imaging: an ex vivo animal study

    NASA Astrophysics Data System (ADS)

    Mahmoud, Ahmed M.; Ding, Xuan; Dutta, Debaditya; Singh, Vijay P.; Kim, Kang

    2014-02-01

    Hepatic steatosis or fatty liver disease occurs when lipids accumulate within the liver and can lead to steatohepatitis, cirrhosis, liver cancer and eventual liver failure requiring liver transplant. Conventional brightness mode (B-mode) ultrasound (US) is the most common noninvasive diagnostic imaging modality used to diagnose hepatic steatosis in clinics. However, it is mostly subjective or requires a reference organ such as the kidney or spleen with which to compare. This comparison can be problematic when the reference organ is diseased or absent. The current work presents an alternative approach to noninvasively detecting liver fat content using US-induced thermal strain imaging (US-TSI). This technique is based on the difference in the change in the speed of sound as a function of temperature between water- and lipid-based tissues. US-TSI was conducted using two system configurations including a mid-frequency scanner with a single linear array transducer (5-14 MHz) for both imaging and heating and a high-frequency (13-24 MHz) small animal imaging system combined with a separate custom-designed US heating transducer array. Fatty livers (n = 10) with high fat content (45.6 ± 11.7%) from an obese mouse model and control livers (n = 10) with low fat content (4.8 ± 2.9%) from wild-type mice were embedded in gelatin. Then, US imaging was performed before and after US induced heating. Heating time periods of ˜3 s and ˜9.2 s were used for the mid-frequency imaging and high-frequency imaging systems, respectively, to induce temperature changes of approximately 1.5 °C. The apparent echo shifts that were induced as a result of sound speed change were estimated using 2D phase-sensitive speckle tracking. Following US-TSI, histology was performed to stain lipids and measure percentage fat in the mouse livers. Thermal strain measurements in fatty livers (-0.065 ± 0.079%) were significantly (p < 0.05) higher than those measured in control livers (-0.124 ± 0

  9. Detecting hepatic steatosis using ultrasound-induced thermal strain imaging: an ex vivo animal study

    PubMed Central

    Mahmoud, Ahmed M.; Ding, Xuan; Dutta, Debaditya; Singh, Vijay P.; Kim, Kang

    2014-01-01

    Hepatic steatosis or fatty liver disease occurs when lipids accumulate within the liver and can lead to steatohepatitis, cirrhosis, liver cancer, and eventual liver failure requiring liver transplant. Conventional brightness mode (B-mode) ultrasound (US) is the most common noninvasive diagnostic imaging modality used to diagnose hepatic steatosis in clinics. However, it is mostly subjective or requires a reference organ such as the kidney or spleen with which to compare. This comparison can be problematic when the reference organ is diseased or absent. The current work presents an alternative approach to noninvasively detecting liver fat content using ultrasound-induced thermal strain imaging (US-TSI). This technique is based on the difference in the change in the speed of sound as a function of temperature between water- and lipid-based tissues. US-TSI was conducted using two system configurations including a mid-frequency scanner with a single linear array transducer (5-14 MHz) for both imaging and heating and a high-frequency (13-24 MHz) small animal imaging system combined with a separate custom-designed US heating transducer array. Fatty livers (n=10) with high fat content (45.6 ± 11.7%) from an obese mouse model and control livers (n=10) with low fat content (4.8± 2.9%) from wild-type mice were embedded in gelatin. Then, US imaging was performed before and after US induced heating. Heating time periods of ~3 s and ~9.2 s were used for the mid-frequency imaging and high-frequency imaging systems, respectively to induce temperature changes of approximately 1.5 °C. The apparent echo shifts that were induced as a result of sound speed change were estimated using 2D phase-sensitive speckle tracking. Following US-TSI, histology was performed to stain lipids and measure percentage fat in the mouse livers. Thermal strain measurements in fatty livers (−0.065±0.079%) were significantly (p<0.05) higher than those measured in control livers (−0.124±0

  10. Adenoviral Gene Transfer of Hepatic Stimulator Substance Confers Resistance Against Hepatic Ischemia–Reperfusion Injury by Improving Mitochondrial Function

    PubMed Central

    Jiang, Shu-Jun; Li, Wen

    2013-01-01

    Abstract Hepatic stimulator substance (HSS) has been suggested to protect liver cells from various toxins. However, the precise role of HSS in hepatic ischemia–reperfusion (I/R) injury remains unknown. This study aims to elucidate whether overexpression of HSS could attenuate hepatic ischemia–reperfusion injury and its possible mechanisms. Both in vivo hepatic I/R injury in mice and in vitro hypoxia–reoxygenation (H/R) in a cell model were used to evaluate the effect of HSS protection after adenoviral gene transfer. Moreover, a possible mitochondrial mechanism of HSS protection was investigated. Efficient transfer of the HSS gene into liver inhibited hepatic I/R injury in mice, as evidenced by improvement in liver function tests, the preservation of hepatic morphology, and a reduction in hepatocyte apoptosis. HSS overexpression also inhibited H/R-induced cell death, as detected by cell viability and cell apoptosis assays. The underlying mechanism of this hepatic protection might involve the attenuation of mitochondrial dysfunction and mitochondrial-dependent cell apoptosis, as shown by the good preservation of mitochondrial ultrastructure, mitochondrial membrane potential, and the inhibition of cytochrome c leakage and caspase activity. Moreover, the suppression of H/R-induced mitochondrial ROS production and the maintenance of mitochondrial respiratory chain complex activities may participate in this mechanism. This new function of HSS expands the possibility of its application for the prevention of I/R injury, such as hepatic resection and liver transplantation in clinical practice. PMID:23461564

  11. Pegylated interferon de novo-induce autoimmune haemolytic anaemia in chronic hepatitis C patient

    PubMed Central

    Said, Ashraf; Elbahrawy, Ashraf; Alfiomy, Mohamed; Abdellah, Mohamed; Shahat, Khaled; Salah, Mohamed; Mostafa, Sadek; Elwassief, Ahmed; Aboelfotoh, Attef; Abdelhafeez, Hafez; El-Sherif, Assem

    2011-01-01

    A 55-year-old Egyptian woman with chronic hepatitis C undergoing treatment with pegylated interferon (Peg-IFN) alfa-2a plus ribavirin was referred to our hospital on November 2010 with prolonged easy fatigability and an attack of syncope; she had no prior history of autoimmune disorders or allergy. Laboratory investigations documented the presence of Peg-IFN induced autoimmune haemolytic anaemia and autoimmune thyroiditis. Intravenous γ globulin (IVGG) failed to correct the autoimmune process; on the other hand steroid therapy dramatically corrected both haematological and thyroid values, and step down the immune process. Our report indicated that Peg-IFN de novo-induce autoimmune haemolysis, documenting a previous report. IVGG failed to step down the immune process in our case. PMID:22688484

  12. An Inducible Transgenic Mouse Model for Immune Mediated Hepatitis Showing Clearance of Antigen Expressing Hepatocytes by CD8+ T Cells

    PubMed Central

    Cebula, Marcin; Ochel, Aaron; Hillebrand, Upneet; Pils, Marina C.; Schirmbeck, Reinhold; Hauser, Hansjörg; Wirth, Dagmar

    2013-01-01

    The liver has the ability to prime immune responses against neo antigens provided upon infections. However, T cell immunity in liver is uniquely modulated by the complex tolerogenic property of this organ that has to also cope with foreign agents such as endotoxins or food antigens. In this respect, the nature of intrahepatic T cell responses remains to be fully characterized. To gain deeper insight into the mechanisms that regulate the CD8+ T cell responses in the liver, we established a novel OVA_X_CreERT2 mouse model. Upon tamoxifen administration OVA antigen expression is observed in a fraction of hepatocytes, resulting in a mosaic expression pattern. To elucidate the cross-talk of CD8+ T cells with antigen-expressing hepatocytes, we adoptively transferred Kb/OVA257-264-specific OT-I T cells to OVA_X_CreERT2 mice or generated triple transgenic OVA_X CreERT2_X_OT-I mice. OT-I T cells become activated in OVA_X_CreERT2 mice and induce an acute and transient hepatitis accompanied by liver damage. In OVA_X_CreERT2_X_OT-I mice, OVA induction triggers an OT-I T cell mediated, fulminant hepatitis resulting in 50% mortality. Surviving mice manifest a long lasting hepatitis, and recover after 9 weeks. In these experimental settings, recovery from hepatitis correlates with a complete loss of OVA expression indicating efficient clearance of the antigen-expressing hepatocytes. Moreover, a relapse of hepatitis can be induced upon re-induction of cured OVA_X_CreERT2_X_OT-I mice indicating absence of tolerogenic mechanisms. This pathogen-free, conditional mouse model has the advantage of tamoxifen inducible tissue specific antigen expression that reflects the heterogeneity of viral antigen expression and enables the study of intrahepatic immune responses to both de novo and persistent antigen. It allows following the course of intrahepatic immune responses: initiation, the acute phase and antigen clearance. PMID:23869228

  13. High fat diet-induced modifications in membrane lipid and mitochondrial-membrane protein signatures precede the development of hepatic insulin resistance in mice

    PubMed Central

    Kahle, M.; Schäfer, A.; Seelig, A.; Schultheiß, J.; Wu, M.; Aichler, M.; Leonhardt, J.; Rathkolb, B.; Rozman, J.; Sarioglu, H.; Hauck, S.M.; Ueffing, M.; Wolf, E.; Kastenmueller, G.; Adamski, J.; Walch, A.; Hrabé de Angelis, M.; Neschen, S.

    2014-01-01

    Objective Excess lipid intake has been implicated in the pathophysiology of hepatosteatosis and hepatic insulin resistance. Lipids constitute approximately 50% of the cell membrane mass, define membrane properties, and create microenvironments for membrane-proteins. In this study we aimed to resolve temporal alterations in membrane metabolite and protein signatures during high-fat diet (HF)-mediated development of hepatic insulin resistance. Methods We induced hepatosteatosis by feeding C3HeB/FeJ male mice an HF enriched with long-chain polyunsaturated C18:2n6 fatty acids for 7, 14, or 21 days. Longitudinal changes in hepatic insulin sensitivity were assessed via the euglycemic-hyperinsulinemic clamp, in membrane lipids via t-metabolomics- and membrane proteins via quantitative proteomics-analyses, and in hepatocyte morphology via electron microscopy. Data were compared to those of age- and litter-matched controls maintained on a low-fat diet. Results Excess long-chain polyunsaturated C18:2n6 intake for 7 days did not compromise hepatic insulin sensitivity, however, induced hepatosteatosis and modified major membrane lipid constituent signatures in liver, e.g. increased total unsaturated, long-chain fatty acid-containing acyl-carnitine or membrane-associated diacylglycerol moieties and decreased total short-chain acyl-carnitines, glycerophosphocholines, lysophosphatidylcholines, or sphingolipids. Hepatic insulin sensitivity tended to decrease within 14 days HF-exposure. Overt hepatic insulin resistance developed until day 21 of HF-intervention and was accompanied by morphological mitochondrial abnormalities and indications for oxidative stress in liver. HF-feeding progressively decreased the abundance of protein-components of all mitochondrial respiratory chain complexes, inner and outer mitochondrial membrane substrate transporters independent from the hepatocellular mitochondrial volume in liver. Conclusions We assume HF-induced modifications in membrane lipid

  14. Restorative effects of hydroxysafflor yellow A on hepatic function in an experimental regression model of hepatic fibrosis induced by carbon tetrachloride

    PubMed Central

    Li, Yanuo; Shi, Yan; Sun, Yan; Liu, Luying; Bai, Xianyong; Wang, Dong; Li, Hongxing

    2017-01-01

    Hepatic fibrosis is a reversible pathological process, in which fibrotic tissue is excessively deposited in the liver during the repair process that follows hepatic injury. Early prevention or treatment of hepatic fibrosis has great significance on the treatment of chronic hepatic diseases. Hydroxysafflor yellow A (HSYA) is a water-soluble monomer extracted from safflower, which serves numerous pharmacological roles. However, it remains to be elucidated how HSYA regulates hepatic fibrogenesis. The aim of the present study was to reveal the possible mechanisms underlying the effects of HSYA on the prevention and treatment of hepatic fibrosis. A rat model of hepatic fibrosis was established in the present study, and the rats were administered various doses of HSYA. The effects of HSYA on pathological alterations of the liver tissue in rats with hepatic fibrosis were observed using hematoxylin-eosin staining and Masson staining. In order to explore the anti-hepatic fibrosis effects and underlying mechanisms of HSYA, serum levels, and hepatic function and hepatic fibrosis indices were evaluated. The results demonstrated that HSYA can improve the general condition of rats with hepatic fibrosis and relieve cellular swelling of the liver, fatty degeneration, necrosis, inflammatory cell infiltration and fibroplastic proliferation. Subsequent to administration of HSYA, globulin was increased during hepatic fibrosis caused by tetrachloromethane. However, total cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase and levels of hyaluronic acid, laminin, procollagen III N-terminal peptide, collagen type IV and hydroxyproline were significantly reduced. The results additionally demonstrated that HSYA could enhance superoxide dismutase activity and reduce malondialdehyde levels, inhibiting lipid peroxidation caused by free radicals. PMID:27909717

  15. Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice.

    PubMed

    Cheng, Licai; Yu, Yinghua; Szabo, Alexander; Wu, Yizhen; Wang, Hongqin; Camer, Danielle; Huang, Xu-Feng

    2015-05-01

    The consumption of diets rich in saturated fat largely contributes to the development of obesity in modern societies. A diet high in saturated fats can induce inflammation and impair leptin signaling in the hypothalamus. However, the role of saturated fatty acids on hypothalamic leptin signaling, and hepatic glucose and lipid metabolism remains largely undiscovered. In this study, we investigated the effects of intracerebroventricular (icv) administration of a saturated fatty acid, palmitic acid (PA, C16:0), on central leptin sensitivity, hypothalamic leptin signaling, inflammatory molecules and hepatic energy metabolism in C57BL/6J male mice. We found that the icv administration of PA led to central leptin resistance, evidenced by the inhibition of central leptin's suppression of food intake. Central leptin resistance was concomitant with impaired hypothalamic leptin signaling (JAK2-STAT3, PKB/Akt-FOXO1) and a pro-inflammatory response (TNF-α, IL1-β, IL-6 and pIκBa) in the mediobasal hypothalamus and paraventricular hypothalamic nuclei. Furthermore, the pre-administration of icv PA blunted the effect of leptin-induced decreases in mRNA expression related to gluconeogenesis (G6Pase and PEPCK), glucose transportation (GLUT2) and lipogenesis (FAS and SCD1) in the liver of mice. Therefore, elevated central PA concentrations can induce pro-inflammatory responses and leptin resistance, which are associated with disorders of energy homeostasis in the liver as a result of diet-induced obesity. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Chardonnay grape seed flour ameliorates hepatic steatosis and insulin resistance via altered hepatic gene expression for oxidative stress, inflammation, and lipid and ceramide synthesis in diet-induced obese mice

    USDA-ARS?s Scientific Manuscript database

    Diet-induced obese (DIO) mice were fed high-fat (HF) diets containing either partially defatted flavonoid-rich Chardonnay grape seed flour (ChrSd) or microcrystalline cellulose (MCC, control) for 5 weeks in order to determine whether ChrSd improved insulin resistance and the pathogenesis of hepatic ...

  17. Organochloride pesticides induced hepatic ABCG5/G8 expression and lipogenesis in Chinese patients with gallstone disease

    PubMed Central

    Ji, Guixiang; Xu, Cheng; Sun, Haidong; Liu, Qian; Hu, Hai; Gu, Aihua; Jiang, Zhao-Yan

    2016-01-01

    Background Organochlorine pesticides (OCPs) are one kind of persistent organic pollutants. Although they are reported to be associated with metabolic disorders, the underlying mechanism is unclear. We explored the association of OCPs with gallstone disease and its influence on hepatic lipid metabolism. Materials and Methods OCPs levels in omentum adipose tissues from patients with and without gallstone disease between 2008 and 2011 were measured by GC-MS. Differences of gene expression involved in hepatic lipid metabolism and hepatic lipids content were compared in liver biopsies between groups with high and low level of OCPs. Using HepG2 cell lines, the influence on hepatic lipid metabolism by individual OCP was evaluated in vitro. Results In all patients who were from non-occupational population, there were high levels of β-hexachlorocyclohexane (β-HCH) and p',p'-dichloroethylene (p',p'-DDE) accumulated in adipose tissues. Both β-HCH and p', p'-DDE levels were significantly higher in adipose tissues from patients with gallstone disease (294.3± 313.5 and 2222± 2279 ng/g of lipid) than gallstone-free controls (282.7± 449.0 and 2025±2664 ng/g of lipid, P< 0.01) and they were strongly related with gallstone disease (P for trend = 0.0004 and 0.0138). Furthermore, higher OCPs in adipose tissue led to increase in the expression of hepatic cholesterol transporters ABCG5 and G8 (+34% and +27%, P< 0.01) and higher cholesterol saturation index in gallbladder bile, and induced hepatic fatty acids synthesis, which was further confirmed in HepG2 cells. Conclusion OCPs might enhance hepatic secretion of cholesterol into bile via ABCG5/G8 which promoting gallstone disease as well as lipogenesis. PMID:27203212

  18. Distinct kinetics of DNA repair protein accumulation at DNA lesions and cell cycle-dependent formation of γH2AX- and NBS1-positive repair foci.

    PubMed

    Suchánková, Jana; Kozubek, Stanislav; Legartová, Soňa; Sehnalová, Petra; Küntziger, Thomas; Bártová, Eva

    2015-12-01

    The DNA damage response is a fundamental, well-regulated process that occurs in the genome to recognise DNA lesions. Here, we studied kinetics of proteins involved in DNA repair pathways and their recruitment to DNA lesions during the cell cycle. In non-irradiated and irradiated cells, we analysed the distribution pattern and spatiotemporal dynamics of γH2AX, 53BP1, BMI1, MDC1, NBS1, PCNA, coilin and BRCA1 proteins. We observed that spontaneous and irradiation-induced foci (IRIF) demonstrated a high abundance of phosphorylated H2AX, which was consistent with 53BP1 and BMI1 protein accumulation. However, NBS1 and MDC1 proteins were recruited to nuclear bodies (NBs) to a lesser extent. Irradiation by γ-rays significantly increased the number of 53BP1- and γH2AX-positive IRIF, but cell cycle-dependent differences were only observed for γH2AX-positive foci in both non-irradiated and γ-irradiated cells. In non-irradiated cells, the G2 phase was characterised by an increased number of spontaneous γH2AX-foci; this increase was more pronounced after γ-irradiation. Cells in G2 phase had the highest number of γH2AX-positive foci. Similarly, γ-irradiation increased the number of NBS1-positive NBs only in G2 phase. Moreover, NBS1 accumulated in nucleoli after γ-irradiation showed the slowest recovery after photobleaching. Analysis of protein accumulation kinetics at locally induced DNA lesions showed that in HeLa cells, BMI1, PCNA and coilin were rapidly recruited to the lesions, 10-15 s after UVA-irradiation, whereas among the other proteins studied, BRCA1 demonstrated the slowest recruitment: BRCA1 appeared at the lesion 20 min after local micro-irradiation by UVA laser. We show that the kinetics of the accumulation of selected DNA repair-related proteins is protein specific at locally induced DNA lesions, and that the formation of γH2AX- and NBS1-positive foci, but not 53BP1-positive NBs, is cell cycle dependent in HeLa cells. Moreover, γH2AX is the most

  19. Integrative Genomic Analysis of Coincident Cancer Foci Implicates CTNNB1 and PTEN Alterations in Ductal Prostate Cancer.

    PubMed

    Gillard, Marc; Lack, Justin; Pontier, Andrea; Gandla, Divya; Hatcher, David; Sowalsky, Adam G; Rodriguez-Nieves, Jose; Vander Griend, Donald; Paner, Gladell; VanderWeele, David

    2017-12-08

    Ductal adenocarcinoma of the prostate is an aggressive subtype, with high rates of biochemical recurrence and overall poor prognosis. It is frequently found coincident with conventional acinar adenocarcinoma. The genomic features driving evolution to its ductal histology and the biology associated with its poor prognosis remain unknown. To characterize genomic features distinguishing ductal adenocarcinoma from coincident acinar adenocarcinoma foci from the same patient. Ten patients with coincident acinar and ductal prostate cancer underwent prostatectomy. Laser microdissection was used to separately isolate acinar and ductal foci. DNA and RNA were extracted, and used for integrative genomic and transcriptomic analyses. Single nucleotide mutations, small indels, copy number estimates, and expression profiles were identified. Phylogenetic relationships between coincident foci were determined, and characteristics distinguishing ductal from acinar foci were identified. Exome sequencing, copy number estimates, and fusion genes demonstrated coincident ductal and acinar adenocarcinoma diverged from a common progenitor, yet they harbored distinct alterations unique to each focus. AR expression and activity were similar in both histologies. Nine of 10 cases had mutually exclusive CTNNB1 hotspot mutations or phosphatase and tensin homolog (PTEN) alterations in the ductal component, and these were absent in the acinar foci. These alterations were associated with changes in expression in WNT- and PI3K-pathway genes. Coincident ductal and acinar histologies typically are clonally related and thus arise from the same cell of origin. Ductal foci are enriched for cases with either a CTNNB1 hotspot mutation or a PTEN alteration, and are associated with WNT- or PI3K-pathway activation. These alterations are mutually exclusive and may represent distinct subtypes. The aggressive subtype ductal adenocarcinoma is closely related to conventional acinar prostate cancer. Ductal foci

  20. [THE EPIZOOTIC AND EPIDEMIC ACTIVITY OF NATURAL TULAREMIA FOCI OF DIFFERENT LANDSCAPE EPIDEMIOLOGICAL TYPES IN 2009-2014].

    PubMed

    Meshcheryakova, I S; Mikhailova, T V; Demidova, T N; Kormilitsyna, M I

    2016-01-01

    to assess the present state of the natural tularemia foci of different landscape epidemiological types, by using individual focal areas as an example. Epizootological monitoring and epidemiological analysis were conducted in the areas of natural tularemia foci of tundra (Wrangel Island), meadow-field (Central Federal District of the Russian Federation), flood-swamp (Arkhangelsk Region, Khanty-Mansi Autonomous District), and steppe (Mongolii) types. Small mammals (organs, blood), tularemia patients' sera, and environniental objects were examined. Molecular genetic and immune serological diagnostic assays were used. The incidence of tularemia in the past decade was analyzed using the maps for the epidemiological examinations of tularemia cases and medical reports. The natural foci of tularemia were established to continue to actively operate. There were 2913 cases of tularemia in the Russian Federation in 2001 to 2014. The flood-swamp natural foci, in which there were summer transmissive tularemia outbreaks, the largest of high occurred in Khanti-Mansiysk in 2013 when a total of 1005 people fell ill, are a special epidemic hazard. Analysis of the tularemia outbreaks suggests that there is a need for continuous epizootological monitoring of the areas of natural tularemia foci for the timely prediction and prevention of epidemic complications. It is noted that there is an unfounded reduction in the scope of preventive measures, and immunoprevention in particular, and a weaker control of the antitularemia immune status in the population residing in the area of active natural foci of tularemia.

  1. Nephrolithiasis and Osteomalacia associated with adefovir-induced Fanconi syndrome in a patient with hepatitis B.

    PubMed

    Lin, Jueying; Zhuo, Yufeng; Zhang, Dongdong

    2017-08-29

    An increasing number of case reports suggest that acquired renal Fanconi syndrome may be associated with prolonged use of adefovir against hepatitis B virus. Renal Fanconi syndrome is an uncommon disease, and its complication with nephrolithiasis is quite rare. Herein, we report a rare coexistence of nephrolithiasis and acquired renal Fanconi syndrome in a chronic hepatitis B-positive patient with prolonged adefovir therapy. The patient presented with osteomalacia and nephrolithiasis. Consequently, extracorporeal shock-wave lithotripsy and left double-J ureteral stent insertion were considered for obstructive nephropathy, which was caused by nephrolithiasis. However, osteomalacia had been misdiagnosed as osteoporosis before admission to our hospital. On admission, a complexity of multiple fractures, hypophosphataemia, glycosuria without hyperglycaemia and non-anion-gap metabolic acidosis indicated a diagnosis of acquired renal Fanconi syndrome induced by adefovir. After switching from adefovir to entecavir, the patient's symptoms and laboratory findings improved significantly. The mechanism responsible for nephrolithiasis in renal Fanconi syndrome is still unclear. We recommend regularly monitoring renal function and serum calcium and serum phosphate to prevent renal Fanconi syndrome during the prolonged use of adefovir for hepatitis B virus.

  2. Hepatitis B virus infection and vaccine-induced immunity in Madrid (Spain).

    PubMed

    Pedraza-Flechas, Ana María; García-Comas, Luis; Ordobás-Gavín, María; Sanz-Moreno, Juan Carlos; Ramos-Blázquez, Belén; Astray-Mochales, Jenaro; Moreno-Guillén, Santiago

    2014-01-01

    To estimate the prevalence of hepatitis B virus (HBV) infection and vaccine-induced immunity in the region of Madrid, and to analyze their evolution over time. An observational, analytical, cross-sectional study was carried out in the population aged 16-80 years between 2008 and 2009. This was the last of four seroprevalence surveys in the region of Madrid. The prevalence of HBV infection and vaccine-induced immunity was estimated using multivariate logistic models and were compared with the prevalences in the 1989, 1993 and 1999 surveys. In the population aged 16-80 years, the prevalence of HBV infection was 11.0% (95% CI: 9.8-12.3) and that of chronic infection was 0.7% (95% CI: 0.5-1.1). The prevalence of vaccine-induced immunity in the population aged 16-20 years was 73.0% (95% CI: 70.0-76.0). Compared with previous surveys, there was a decrease in the prevalence of HBV infection. Based on the prevalence of chronic infection (<1%), Madrid is a region with low HBV endemicity. Preventive strategies against HBV should especially target the immigrant population. Copyright © 2013. Published by Elsevier Espana.

  3. Docosahexaenoic Acid Attenuates Hepatic Inflammation, Oxidative Stress, and Fibrosis without Decreasing Hepatosteatosis in a Ldlr−/− Mouse Model of Western Diet-Induced Nonalcoholic Steatohepatitis123

    PubMed Central

    Depner, Christopher M.; Philbrick, Kenneth A.; Jump, Donald B.

    2013-01-01

    The incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has increased in parallel with the incidence of obesity. While both NAFLD and NASH are characterized by hepatosteatosis, NASH is characterized by hepatic damage, inflammation, oxidative stress, and fibrosis. We previously reported that feeding Ldlr−/− mice a high-fat, high-cholesterol diet containing menhaden oil attenuated several markers of NASH, including hepatosteatosis, inflammation, and fibrosis. Herein, we test the hypothesis that DHA [22:6 (n-3)] is more effective than EPA [20:5 (n-3)] at preventing Western diet (WD)-induced NASH in Ldlr−/− mice. Mice were fed the WD supplemented with either olive oil (OO), EPA, DHA, or EPA + DHA for 16 wk. WD + OO feeding induced a severe NASH phenotype, characterized by robust hepatosteatosis, inflammation, oxidative stress, and fibrosis. Whereas none of the C20–22 (n-3) fatty acid treatments prevented WD-induced hepatosteatosis, all 3 (n-3) PUFA-containing diets significantly attenuated WD-induced inflammation, fibrosis, and hepatic damage. The capacity of dietary DHA to suppress hepatic markers of inflammation (Clec4F, F4/80, Trl4, Trl9, CD14, Myd88), fibrosis (Procol1α1, Tgfβ1), and oxidative stress (NADPH oxidase subunits Nox2, p22phox, p40phox, p47phox, p67phox) was significantly greater than dietary EPA. The effects of DHA on these markers paralleled DHA-mediated suppression of hepatic Fads1 mRNA abundance and hepatic arachidonic acid content. Because DHA suppression of NASH markers does not require a reduction in hepatosteatosis, dietary DHA may be useful in combating NASH in obese humans. PMID:23303872

  4. Emodin Decreases Hepatic Hypoxia-Inducible Factor-1[Formula: see text] by Inhibiting its Biosynthesis.

    PubMed

    Ma, Feifei; Hu, Lijuan; Yu, Ming; Wang, Feng

    2016-01-01

    Hypoxia-inducible factor-1 (HIF-1) is an [Formula: see text] dimeric transcription factor. Because HIF-1[Formula: see text] is instable with oxygen, HIF-1 is scarce in normal mammalian cells. However, HIF-1[Formula: see text] is expressed in pathological conditions such as cancer and obesity. Inhibiting HIF-1[Formula: see text] may be of therapeutic value for these pathologies. Here, we investigated whether emodin, derived from the herb of Rheum palmatum L, which is also known as Chinese rhubarb, and is native to China, regulates HIF-1[Formula: see text] expression. Male C57BL/6 mice without or with diet-induced obesity were treated with emodin for two weeks, while control mice were treated with vehicle. HIF-1[Formula: see text] expression was determined by Western blot. We found that emodin inhibited obesity-induced HIF-1[Formula: see text] expression in liver and skeletal muscle but did not regulate HIF-1[Formula: see text] expression in the kidneys or in intra-abdominal fat. In vitro, emodin inhibited HIF-1[Formula: see text] expression in human HepG2 hepatic cells and Y1 adrenocortical cells. Further, we investigated the mechanisms of HIF-1[Formula: see text] expression in emodin-treated HepG2 cells. First, we found that HIF-1[Formula: see text] had normal stability in the presence of emodin. Thus, emodin did not decrease HIF-1[Formula: see text] by stimulating its degradation. Importantly, emodin decreased the activity of the signaling pathways that led to HIF-1[Formula: see text] biosynthesis. Interestingly, emodin increased HIF-1[Formula: see text] mRNA in HepG2 cells. This may be a result of feedback in response to the emodin-induced decrease in the protein of HIF-1[Formula: see text]. In conclusion, emodin decreases hepatic HIF-1[Formula: see text] by inhibiting its biosynthesis.

  5. Fish oil alleviated high-fat diet-induced non-alcoholic fatty liver disease via regulating hepatic lipids metabolism and metaflammation: a transcriptomic study.

    PubMed

    Yuan, Fahu; Wang, Hualin; Tian, Yu; Li, Qi; He, Lei; Li, Na; Liu, Zhiguo

    2016-02-01

    Intake of fish oil rich in n-3 polyunsaturated fatty acids (PUFAs) is believed to be beneficial against development of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanisms remain unclear. This study was to gain further understanding of the potential mechanisms of the protective effects of fish oil against NAFLD. Ten male Sprague-Dawley rats were fed a control diet (CON), a Western style high-fat and high-cholesterol diet (WD), or a WD diet containing fish oil (FOH) for 16 weeks respectively. The development of liver steatosis and fibrosis were verified by histological and biochemical examination. Hepatic transcriptome were extracted for RNA-seq analysis, and particular results were confirmed by real-time polymerase chain reaction (PCR). The consumption of fish oil significantly ameliorated WD-induced dyslipidemia, transaminase elevation, hepatic steatosis, inflammatory infiltration, and fibrosis. Hepatic RNA-Seq analysis showed that long-term intake of fish oil restored the expression of circadian clock-related genes per2 and per3, which were reduced in WD fed animals. Fish oil consumption also corrected the expression levels of genes involved in fatty acid and cholesterol metabolism, such as Srebf1, Fasn, Scd1, Insig2, Cd36, Cyp7a1, Abcg5, Abcg8 and Pcsk9. Moreover, the expression levels of pro-inflammation genes Mcp1, Socs2, Sema4a, and Cd44 in the FOH group were lower than that of WD group, implying that fish oil protects the liver against WD-induced hepatic inflammation. The present study demonstrates fish oil protects against WD-induced NALFD via improving lipid metabolism and ameliorating hepatic inflammation. Our findings add to the current understanding on the benefits of n-3 PUFAs against NAFLD.

  6. Experimental study of electrolysis-induced hepatic necrosis.

    PubMed

    Robertson, G S; Wemyss-Holden, S A; Dennison, A R; Hall, P M; Baxter, P; Maddern, G J

    1998-09-01

    One of the most promising but unexplored methods for treating patients with irresectable liver tumours is electrolysis. This study examined the effect of increasing 'current dose' on the volume of the lesion induced in normal rat liver. A direct current generator, connected to platinum electrodes implanted in the rat liver, was used to examine the effect of (1) varying current doses from 1 to 5 coulombs and (2) electrode separation (2 or 20 mm), on the volume of liver necrosis. There was a significant correlation (P < 0.001) between the current dose and the volume of necrosis produced for each electrode separation. Placing the electrodes 2 mm apart resulted in smaller total volumes of necrosis than placing them 20 mm apart when anode lesions were significantly larger than cathode lesions (P< 0.05). Liver enzymes (aspartate aminotransferase, alanine aminotransferase) were significantly raised 1 day after treatment (P < 0.001) and predicted the total volume of hepatic necrosis (P < 0.001). Predictable and reproducible areas of liver necrosis are produced with electrolysis. If these results extrapolate to larger animal models, this technique has potential for patients with irresectable primary and secondary liver tumours.

  7. Liver Failure due to Acute Viral Hepatitis (A-E).

    PubMed

    Manka, Paul; Verheyen, Jens; Gerken, Guido; Canbay, Ali

    2016-04-01

    Viral hepatitis is still one of the key causes of acute liver failure (ALF) in the world. A selective literature search of the PubMed database was conducted, including current studies, reviews, meta-analyses, and guidelines. We obtained an overview of ALF due to viral hepatitis in terms of epidemiology, course, and treatment options. Most fulminant viral courses are reported after infection with hepatitis A, B, and B/D, but not with hepatitis C. Hepatitis E is also known to cause ALF but has not gained much attention in recent years. However, more and more autochthonous hepatitis E virus infections have been recently observed in Europe. Reactivation of hepatitis B virus (HBV) under immunosuppressive conditions, such as after intensive chemotherapy, is also an increasing problem. For most viral-induced cases of ALF, liver transplantation represented the only therapeutic option in the past. Today, immediate treatment of HBV-induced ALF with nucleotide or nucleoside analogs is well tolerated and beneficially affects the course of the disease. Although numbers in Western European countries are decreasing rapidly, reliable diagnostic screening for hepatitis A-E is necessary to identify the etiology and to determine those most at risk of developing ALF.

  8. Involvement of hepatic peroxisome proliferator-activated receptor α/γ in the therapeutic effect of osthole on high-fat and high-sucrose-induced steatohepatitis in rats.

    PubMed

    Zhao, Xi; Xue, Jie; Wang, Xiao-Li; Zhang, Yan; Deng, Min; Xie, Mei-Lin

    2014-09-01

    Our previous studies have indicated that osthole may be a dual agonist of peroxisome proliferator-activated receptor (PPAR) α/γ and decrease the hepatic lipid accumulation. But there has been no report about therapeutic effect on steatohepatitis. In the present study, we investigated the action of osthole and its potential mechanisms. The rats with steatohepatitis induced by orally feeding high-fat and high-sucrose emulsion were given osthole 5-20 mg/kg for 4 weeks. The results showed that after treatment with osthole, the serum alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglyceride (TG), and free fatty acid (FFA) levels, the hepatic TG, FFA, tumor necrosis factor-α, monocyte chemotactic protein-1, interleukin-6, and interleukin-8 contents, and the hepatic weight and liver index were lowered, especially in the osthole 20 mg/kg group. The histological evaluation of liver specimens demonstrated that osthole might improve the hepatic steatosis and inflammation. At the same time, osthole treatment increased the hepatic protein expressions of PPARα/γ and lipoprotein lipase, and decreased the hepatic protein expressions of nuclear factor-κB, sterol regulatory element-binding protein-1c, fatty acid synthase, and diacylglycerol acyltransferase. These findings demonstrate that osthole is effective in treating rat steatohepatitis, and the PPARα/γ may be involved in the osthole-induced modulation of hepatic lipogenic gene expressions and inflammatory cytokine production. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Developmental bisphenol A (BPA) exposure leads to sex-specific modification of hepatic gene expression and epigenome at birth that may exacerbate high-fat diet-induced hepatic steatosis.

    PubMed

    Strakovsky, Rita S; Wang, Huan; Engeseth, Nicki J; Flaws, Jodi A; Helferich, William G; Pan, Yuan-Xiang; Lezmi, Stéphane

    2015-04-15

    Developmental bisphenol A (BPA) exposure increases adulthood hepatic steatosis with reduced mitochondrial function. To investigate the potential epigenetic mechanisms behind developmental BPA-induced hepatic steatosis, pregnant Sprague-Dawley rats were dosed with vehicle (oil) or BPA (100μg/kg/day) from gestational day 6 until postnatal day (PND) 21. After weaning, offspring were either challenged with a high-fat (HF; 45% fat) or remained on a control (C) diet until PND110. From PND60 to 90, both BPA and HF diet increased the fat/lean ratio in males only, and the combination of BPA and HF diet appeared to cause the highest ratio. On PND110, Oil-HF, BPA-C, and BPA-HF males had higher hepatic lipid accumulation than Oil-C, with microvesicular steatosis being marked in the BPA-HF group. Furthermore, on PND1, BPA increased and modified hepatic triglyceride (TG) and free fatty acid (FFA) compositions in males only. In PND1 males, BPA increased hepatic expression of FFA uptake gene Fat/Cd36, and decreased the expression of TG synthesis- and β-oxidation-related genes (Dgat, Agpat6, Cebpα, Cebpβ, Pck1, Acox1, Cpt1a, Cybb). BPA altered DNA methylation and histone marks (H3Ac, H4Ac, H3Me2K4, H3Me3K36), and decreased the binding of several transcription factors (Pol II, C/EBPβ, SREBP1) within the male Cpt1a gene, the key β-oxidation enzyme. In PND1 females, BPA only increased the expression of genes involved in FFA uptake and TG synthesis (Lpl, Fasn, and Dgat). These data suggest that developmental BPA exposure alters and reprograms hepatic β-oxidation capacity in males, potentially through the epigenetic regulation of genes, and further alters the response to a HF diet. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury.

    PubMed

    Jiao, Shu-Fan; Sun, Kai; Chen, Xiao-Jing; Zhao, Xue; Cai, Ning; Liu, Yan-Jun; Xu, Long-Mei; Kong, Xian-Ming; Wei, Li-Xin

    2014-01-08

    Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection. Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors. These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci.

  11. Inhibition of tumor necrosis factor alpha reduces the outgrowth of hepatic micrometastasis of colorectal tumors in a mouse model of liver ischemia-reperfusion injury

    PubMed Central

    2014-01-01

    Background Patients with colorectal cancer (CRC) often develop liver metastases, in which case surgery is considered the only potentially curative treatment option. However, liver surgery is associated with a risk of ischemia-reperfusion (IR) injury, which is thought to promote the growth of colorectal liver metastases. The influence of IR-induced tumor necrosis factor alpha (TNF-α) elevation in the process still is unknown. To investigate the role of TNF-α in the growth of pre-existing micrometastases in the liver following IR, we used a mouse model of colorectal liver metastases. In this model, mice received IR treatment seven days after intrasplenic injections of colorectal CT26 cells. Prior to IR treatment, either TNF-α blocker Enbrel or low-dose TNF-α, which could inhibit IR-induced TNF-α elevation, was administered by intraperitoneal injection. Results Hepatic IR treatment significantly promoted CT26 tumor growth in the liver, but either Enbrel or low-dose TNF-α pretreatment reversed this trend. Further studies showed that the CT26 + IR group prominently increased the levels of ALT and AST, liver necrosis, inflammatory infiltration and the expressions of hepatic IL-6, MMP9 and E-selectin compared to those of CT26 group. Inhibition of TNF-α elevation remarkably attenuated the increases of these liver inflammatory damage indicators and tumor-promoting factors. Conclusion These findings suggested that inhibition of TNF-α elevation delayed the IR-enhanced outgrowth of colorectal liver metastases by reducing IR-induced inflammatory damage and the formation of tumor-promoting microenvironments. Both Enbrel and low-dose TNF-α represented the potential therapeutic approaches for the protection of colorectal liver metastatic patients against IR injury-induced growth of liver micrometastases foci. PMID:24397824

  12. Ginger extract modulates Pb-induced hepatic oxidative stress and expression of antioxidant gene transcripts in rat liver.

    PubMed

    Mohamed, Omnia Ismail; El-Nahas, Abeer Fekry; El-Sayed, Yasser Said; Ashry, Khaled Mohamed

    2016-07-01

    Spices and herbs are recognized sources of natural antioxidants that can protect from oxidative stress, thus play an important role in chemoprevention of liver diseases. Ginger is used worldwide primarily as a spicy condiment. This study evaluated the ability of ginger extract (GE) to ameliorate oxidative-hepatic toxicity induced by lead acetate (PbAc) in rats. Five groups of animals were used: group I kept as control; groups II, IV, and V received PbAc (1 ppm in drinking water daily for 6 weeks, and kept for an additional 2 weeks without PbAc exposure); group III treated orally with GE (350 mg/kg body weight, 4 d per week) for 6 weeks; group IV (protective) received GE for 2 weeks before and simultaneously with PbAc; and group V (treatment) received GE for 2 weeks after PbAc exposure. GC-MS analysis of GE revealed its content of gingerol (7.09%), quercetin (3.20%), dl-limonene (0.96%), and zingiberene (0.18%). Treatment of PbAc-treated rats with GE has no effect on hepatic Pb concentrations. However, it maintained serum aspartate aminotransferase level, increased hepatic glutathione (157%), glutathione S-transferase (GST) (228%), glutathione peroxidase (GPx) (138%) and catalase (CAT) (112%) levels, and reduced hepatic malondialdehyde (80%). Co-treatment of PbAc group with GE upregulated mRNA expression of antioxidant genes: GST-α1 (1.4-fold), GPx1 (1.8-fold), and CAT (8-fold), while post-treatment with GE upregulated only mRNA expression of GPx1 (1.5-fold). GE has an antioxidant protective efficacy against PbAc-induced hepatotoxicity, which appears more effective than its therapeutic application. However, the changes in antioxidant gene expression were not reflected at the protein level.

  13. [Alternatives to femtosecond laser technology: subnanosecond UV pulse and ring foci for creation of LASIK flaps].

    PubMed

    Vogel, A; Freidank, S; Linz, N

    2014-06-01

    In refractive corneal surgery femtosecond (fs) lasers are used for creating LASIK flaps, dissecting lenticules and for astigmatism correction by limbal incisions. Femtosecond laser systems are complex and expensive and cutting precision is compromised by the large focal length associated with the commonly used infrared (IR) wavelengths. Based on investigations of the cutting dynamics, novel approaches for corneal dissection using ultraviolet A (UVA) picosecond (ps) pulses and ring foci from vortex beams are presented. Laser-induced bubble formation in corneal stroma was investigated by high-speed photography at 1-50 million frames/s. Using Gaussian and vortex beams of UVA pulses with durations between 200 and 850 ps the laser energy needed for easy removal of flaps created in porcine corneas was determined and the quality of the cuts by scanning electron microscopy was documented. Cutting parameters for 850 ps are reported also for rabbit eyes. The UV-induced and mechanical stress were evaluated for Gaussian and vortex beams. The results show that UVA picosecond lasers provide better cutting precision than IR femtosecond lasers, with similar processing times. Cutting energy decreases by >50 % when the laser pulse duration is reduced to 200 ps. Vortex beams produce a short, donut-shaped focus allowing efficient and precise dissection along the corneal lamellae which results in a dramatic reduction of the absorbed energy needed for cutting and of mechanical side effects as well as in less bubble formation in the cutting plane. A combination of novel approaches for corneal dissection provides the option to replace femtosecond lasers by compact UVA microchip laser technology. Ring foci are also of interest for femtosecond laser surgery, especially for improved lenticule excision.

  14. Effect of purified diets and phenobarbital withdrawal on the phenotypic stability of altered hepatic foci (AHF)

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Glauert, H.P.; Schwarz, M.; Pitot, H.C.

    1986-03-05

    The effect of the short-term withdrawal of phenobarbital (PB) and of the feeding of purified diets during the long-term withdrawal of PB on the stability of AHF were studied. In both experiments, female CD rats initially received an intragastric dose of diethylnitrosamine (10 mg/kg) 20 hours after being subjected to partial hepatectomy. In the short-term study, rats were fed 0.05% PB in a cereal-based diet for 6 months; at this time, half of the rats were killed whereas the other half were withdrawn from PB for 10 days before sacrifice. Withdrawing PB for 10 days resulted in a decrease inmore » the number and volume of AHF, particularly those which stained positively for gamma-glutamyltranspeptidase (GGT). In the long-term experiment, rats were fed 0.05% PB in a cereal-based diet containing PB and fed either a low-fat or a high-fat purified diet without PB for 8 months. At this time, the number and volume of AHF were much less than that seen at the time of PB withdrawal, and the distribution of phenotypes was altered: the percentage of foci containing GGT as a marker decreased dramatically. These results indicate that the observable number and total volume of AHF rapidly decrease after the withdrawal of PB from rats fed a cereal-based diet and that the feeding of purified diets after such PB withdrawal does not result in the reappearance of AHF.« less

  15. A novel therapeutic hepatitis B vaccine induces cellular and humoral immune responses and breaks tolerance in hepatitis B virus (HBV) transgenic mice.

    PubMed

    Buchmann, Pascale; Dembek, Claudia; Kuklick, Larissa; Jäger, Clemens; Tedjokusumo, Raindy; von Freyend, Miriam John; Drebber, Uta; Janowicz, Zbigniew; Melber, Karl; Protzer, Ulrike

    2013-02-06

    Therapeutic vaccines are currently being developed for chronic hepatitis B and C. As an alternative to long-term antiviral treatment or to support only partially effective therapy, they should activate the patient's immune system effectively to fight and finally control the virus. A paradigm of therapeutic vaccination is the potent induction of T-cell responses against key viral antigens - besides activation of a humoral immune response. We have evaluated the potential of a novel vaccine formulation comprising particulate hepatitis B surface (HBsAg) and core antigen (HBcAg), and the saponin-based ISCOMATRIX™ adjuvant for its ability to stimulate T and B cell responses in C57BL/6 mice and its ability to break tolerance in syngeneic HBV transgenic (HBVtg) mice. In C57BL/6 mice, the vaccine induced multifunctional HBsAg- and HBcAg-specific CD8+ T cells detected by staining for IFNγ, TNFα and IL-2, as well as high antibody titers against both antigens. Vaccination of HBVtg animals induced potent HBsAg- and HBcAg-specific CD8+ T-cell responses in spleens and HBcAg-specific CD8+ T-cell responses in livers as well as anti-HBs seroconversion two weeks post injection. Vaccination further reduced HBcAg expression in livers of HBVtg mice without causing liver damage. In summary, this study demonstrates therapeutic efficacy of a novel vaccine formulation in a mouse model of immunotolerant, chronic HBV infection. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Experimental induction of hepatic lipidosis in cats.

    PubMed

    Biourge, V C; Groff, J M; Munn, R J; Kirk, C A; Nyland, T G; Madeiros, V A; Morris, J G; Rogers, Q R

    1994-09-01

    The effect of long-term voluntary fasting on hematologic variables, biochemical profiles, and liver histologic findings was assessed in 15 obese cats (> 40% overweight). Clinical signs and laboratory results consistent with hepatic lipidosis were observed in 12 of 15 cats after 5 to 7 weeks of fasting, and were associated with 30 to 35% reduction of initial body weight. Histologic examination of successive liver biopsy specimens revealed that obesity was not associated with liver parenchymal lipid accumulation, but that fasting resulted in lipidosis in all 15 cats. The long-term fast was associated with an early (after 2 to 4 weeks of fasting) and significant (P < 0.05) reduction in serum urea, glucose, and albumin concentrations, and RBC mass. Fasting for 5 to 7 weeks was associated with a significant (P < 0.05) increase in hepatic-associated enzyme activities and in total and direct serum bilirubin concentrations. Significant (P < 0.05) changes in serum alkaline phosphatase developed as early as 3 weeks before the onset of hyperbilirubinemia. Except for development of hepatic lipidosis, cats appeared to tolerate the fast without other adverse effect. This study confirmed that long-term fasting may induce clinical hepatic lipidosis in obese cats. Fasting appears to induce a syndrome of hepatic lipidosis that is indistinguishable from feline idiopathic hepatic lipidosis and may be an appropriate model to study the pathophysiologic features and treatment of hepatic lipidosis.

  17. Protection against high-fat diet-induced obesity in Helz2-deficient male mice due to enhanced expression of hepatic leptin receptor.

    PubMed

    Yoshino, Satoshi; Satoh, Tetsurou; Yamada, Masanobu; Hashimoto, Koshi; Tomaru, Takuya; Katano-Toki, Akiko; Kakizaki, Satoru; Okada, Shuichi; Shimizu, Hiroyuki; Ozawa, Atsushi; Tuchiya, Takafumi; Ikota, Hayato; Nakazato, Yoichi; Mori, Munemasa; Matozaki, Takashi; Sasaki, Tsutomu; Kitamura, Tadahiro; Mori, Masatomo

    2014-09-01

    Obesity arises from impaired energy balance, which is centrally coordinated by leptin through activation of the long form of leptin receptor (Leprb). Obesity causes central leptin resistance. However, whether enhanced peripheral leptin sensitivity could overcome central leptin resistance remains obscure. A peripheral metabolic organ targeted by leptin is the liver, with low Leprb expression. We here show that mice fed a high-fat diet (HFD) and obese patients with hepatosteatosis exhibit increased expression of hepatic helicase with zinc finger 2, a transcriptional coactivator (Helz2), which functions as a transcriptional coregulator of several nuclear receptors, including peroxisome proliferator-activated receptor γ in vitro. To explore the physiological importance of Helz2, we generated Helz2-deficient mice and analyzed their metabolic phenotypes. Helz2-deficient mice showing hyperleptinemia associated with central leptin resistance were protected against HFD-induced obesity and had significantly up-regulated hepatic Leprb expression. Helz2 deficiency and adenovirus-mediated liver-specific exogenous Leprb overexpression in wild-type mice significantly stimulated hepatic AMP-activated protein kinase on HFD, whereas Helz2-deficient db/db mice lacking functional Leprb did not. Fatty acid-β oxidation was increased in Helz2-deficeint hepatocytes, and Helz2-deficient mice revealed increased oxygen consumption and decreased respiratory quotient in calorimetry analyses. The enhanced hepatic AMP-activated protein kinase energy-sensing pathway in Helz2-deficient mice ameliorated hyperlipidemia, hepatosteatosis, and insulin resistance by reducing lipogenic gene expression and stimulating lipid-burning gene expression in the liver. These findings together demonstrate that Helz2 deficiency ameliorates HFD-induced metabolic abnormalities by stimulating endogenous hepatic Leprb expression, despite central leptin resistance. Hepatic HELZ2 might be a novel target molecule for

  18. [Effects of pirfenidone on hepatic fibrosis in mice induced by carbon tetrachloride].

    PubMed

    Xiao, Min; Qu, Xiao-Hu; Lv, Jv-Ping; Shi, Yang; Li, Chang-Xi; Xie, Ke-Jian

    2016-04-08

    To investigate the effects of pirfenidone on CCl4-induced liver fibrosis in mice. After 8-week feeding, 40 healthy male SPF ICR mice were randomly divided into 4 groups:liver fibrosis group (CCL 4 group), low doses of Pirfenidone group (PFD-L group), high doses of Pirfenidone group (PFD-H group) and control group. The mice in CCL 4 group, low doses of Pirfenidone group (PFD-L group), high doses of Pirfenidone group (PFD-H group) were injected intraperitoneally with 0.4 ml 10% CCL 4 solution dissolved in soybean oil. Then the PFD-L and PFD-H groups were treated with 120 mg and 240 mg PFD via gastric gavage, respectively. Control group was injected with same volume of saline. Alanine aminotransferase(ALT), aspartate aminotransferase(AST), alkaline phosphatase(ALP) in serum were tested with automatic biochemistry analyzer and the pathologic changes of liver tissue were examined by HE staining. Furthermore, we identi-fied hyaluronic acids(HA), laminin(LN), collagentype IV(IV-C) in serum using radioimmunoassay and the expression of smooth muscle acti-nalpha(α-SMA) related gene in liver was tested by real-time fluorescence quantitative PCR. Compared with control group, hepatic lobules in CCL 4 mice were damaged significantly, collagenous fiber was deposited obviously, and counterfeit hepatic lobules formed. The serum levels of ALT, AST, ALP were increased obviously ( P <0.05) with the enhancement of HA, LN, IV-C in serum ( P <0.05) and the ex-pression of α-SMA related gene ( P <0.05). Compared to CCL 4 -treated mice, the serum levels of ALT, AST, ALP in PFD-L and PFD-H groups were decreased, HA, LN, IV-C in PFD-L and PFD-H mice went down obviously,and the expression of α-SMA related gene was con-trolled ( P <0.05). From pathological observation, we found the degree of liver fibrosis in PFD-L mice was reduced and collagenous fiber was decreased, only a little counterfeit hepatic lobule could be found. Cell arrangement in PFD-H mice recovered, the structural of hepatic

  19. Apparent diffusive motion of centrin foci in living cells: implications for diffusion-based motion in centriole duplication

    NASA Astrophysics Data System (ADS)

    Rafelski, Susanne M.; Keller, Lani C.; Alberts, Jonathan B.; Marshall, Wallace F.

    2011-04-01

    The degree to which diffusion contributes to positioning cellular structures is an open question. Here we investigate the question of whether diffusive motion of centrin granules would allow them to interact with the mother centriole. The role of centrin granules in centriole duplication remains unclear, but some proposed functions of these granules, for example, in providing pre-assembled centriole subunits, or by acting as unstable 'pre-centrioles' that need to be captured by the mother centriole (La Terra et al 2005 J. Cell Biol. 168 713-22), require the centrin foci to reach the mother. To test whether diffusive motion could permit such interactions in the necessary time scale, we measured the motion of centrin-containing foci in living human U2OS cells. We found that these centrin foci display apparently diffusive undirected motion. Using the apparent diffusion constant obtained from these measurements, we calculated the time scale required for diffusion to capture by the mother centrioles and found that it would greatly exceed the time available in the cell cycle. We conclude that mechanisms invoking centrin foci capture by the mother, whether as a pre-centriole or as a source of components to support later assembly, would require a form of directed motility of centrin foci that has not yet been observed.

  20. Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model.

    PubMed

    Tokunaga, Yuko; Osawa, Yosuke; Ohtsuki, Takahiro; Hayashi, Yukiko; Yamaji, Kenzaburo; Yamane, Daisuke; Hara, Mitsuko; Munekata, Keisuke; Tsukiyama-Kohara, Kyoko; Hishima, Tsunekazu; Kojima, Soichi; Kimura, Kiminori; Kohara, Michinori

    2017-03-23

    Chronic hepatitis C virus (HCV) infection is one of the major causes of serious liver diseases, including liver cirrhosis. There are no anti-fibrotic drugs with efficacy against liver cirrhosis. Wnt/β-catenin signaling has been implicated in the pathogenesis of a variety of tissue fibrosis. In the present study, we investigated the effects of a β-catenin/CBP (cyclic AMP response element binding protein) inhibitor on liver fibrosis. The anti-fibrotic activity of PRI-724, a selective inhibitor of β-catenin/CBP, was assessed in HCV GT1b transgenic mice at 18 months after HCV genome expression. PRI-724 was injected intraperitoneally or subcutaneously in these mice for 6 weeks. PRI-724 reduced liver fibrosis, which was indicated by silver stain, Sirius Red staining, and hepatic hydroxyproline levels, in HCV mice while attenuating αSMA induction. PRI-724 led to increased levels of matrix metalloproteinase (MMP)-8 mRNA in the liver, along with elevated levels of intrahepatic neutrophils and macrophages/monocytes. The induced intrahepatic neutrophils and macrophages/monocytes were identified as the source of MMP-8. In conclusion, PRI-724 ameliorated HCV-induced liver fibrosis in mice. We hypothesize that inhibition of hepatic stellate cells activation and induction of fibrolytic cells expressing MMP-8 contribute to the anti-fibrotic effects of PRI-724. PRI-724 is a drug candidate which possesses anti-fibrotic effect.

  1. Involvement of AMP-activated protein kinase in beneficial effects of betaine on high-sucrose diet-induced hepatic steatosis

    PubMed Central

    Song, Zhenyuan; Deaciuc, Ion; Zhou, Zhanxiang; Song, Ming; Chen, Theresa; Hill, Daniell; McClain, Craig J.

    2014-01-01

    Although simple steatosis was originally thought to be a pathologically inert histological change, fat accumulation in the liver may play a critical role not only in disease initiation, but also in the progression to nonalcoholic steatohepatitis and cirrhosis. Therefore, prevention of fat accumulation in the liver may be an effective therapy for multiple stages of nonalcoholic fatty liver disease (NAFLD). Promising beneficial effects of betaine supplementation on human NAFLD have been reported in some pilot clinical studies; however, data related to betaine therapy in NAFLD are limited. In this study, we examined the effects of betaine on fat accumulation in the liver induced by high-sucrose diet and evaluated mechanisms by which betaine could attenuate or prevent hepatic steatosis in this model. Male C57BL/6 mice weighing 20 ± 0.5 g (means ± SE) were divided into four groups (8 mice per group) and started on one of four treatments: standard diet (SD), SD+betaine, high-sucrose diet (HS), and HS + betaine. Betaine was supplemented in the drinking water at a concentration of 1% (wt/vol) (anhydrous). Long-term feeding of high-sucrose diet to mice caused significant hepatic steatosis accompanied by markedly increased lipogenic activity. Betaine significantly attenuated hepatic steatosis in this animal model, and this change was associated with increased activation of hepatic AMP-activated protein kinase (AMPK) and attenuated lipogenic capability (enzyme activities and gene expression) in the liver. Our findings are the first to suggest that betaine might serve as a therapeutic tool to attenuate hepatic steatosis by targeting the hepatic AMPK system. PMID:17702954

  2. Serum PAI-1 and PAI-1 4G/5G Polymorphism in Hepatitis C Virus-Induced Cirrhosis and Hepatitis C Virus-Induced Hepatocellular Carcinoma Patients.

    PubMed

    El Edel, Rawhia H; Essa, Enas Said; Essa, Abdallah S; Hegazy, Sara A; El Rowedy, Dalia I

    2016-11-01

    Association between variable agent-induced hepatocellular carcinoma (HCC) and both PAI-1 4G/5G polymorphism and plasminogen activator inhibitor (PAI-1) levels compared to healthy controls have been reported in earlier studies. We aimed to assess serum PAI-1 and PAI-1 4G/5G polymorphism in hepatitis C virus (HCV)-induced HCC, HCV-induced liver cirrhosis, and viral infection-free apparently healthy control subjects. Forty nine HCC, 52 cirrhosis, and 105 controls were genotyped for PAI-1 4G/5G using an allele-specific polymerase chain reaction analysis. In addition, for 31 HCC, 24 cirrhosis, and 28 controls, serum PAI-1 level was measured by enzyme-linked immunosorbent assay (ELISA). There was no significant difference in PAI-1 4G/5G genotype distribution between cirrhosis and controls (p = 0.33, p = 0.15, and p = 0.38 for the codominant, dominant, and recessive models, respectively) or between HCC and cirrhosis (p = 0.5, p = 0.24, and p = 0.69 for the codominant, dominant, and recessive models, respectively). Serum PAI-1 was significantly higher in cirrhosis than controls and significantly lower in HCC than cirrhosis (p < 0.001 for both). Serum PAI-1 did not differ significantly among the three PAI-1 4G/5G genotypes in controls, cirrhosis, and HCC (p = 0.29, p = 0.28, and p = 0.73 respectively). We documented higher serum PAI-1 in HCV-induced HCC than viral infection-free controls, but interestingly, lower than HCV-induced liver cirrhosis patients. This was not genotype related. Further studies will be needed to clearly elucidate the underlying mechanism.

  3. Mangiferin, a Natural Xanthone, Protects Murine Liver in Pb(II) Induced Hepatic Damage and Cell Death via MAP Kinase, NF-κB and Mitochondria Dependent Pathways

    PubMed Central

    Pal, Pabitra Bikash; Sinha, Krishnendu; Sil, Parames C.

    2013-01-01

    One of the most well-known naturally occurring environmental heavy metals, lead (Pb) has been reported to cause liver injury and cellular apoptosis by disturbing the prooxidant-antioxidant balance via oxidative stress. Several studies, on the other hand, reported that mangiferin, a naturally occurring xanthone, has been used for a broad range of therapeutic purposes. In the present study, we, therefore, investigated the molecular mechanisms of the protective action of mangiferin against lead-induced hepatic pathophysiology. Lead [Pb(II)] in the form of Pb(NO3)2 (at a dose of 5 mg/kg body weight, 6 days, orally) induced oxidative stress, hepatic dysfunction and cell death in murine liver. Post treatment of mangiferin at a dose of 100 mg/kg body weight (6 days, orally), on the other hand, diminished the formation of reactive oxygen species (ROS) and reduced the levels of serum marker enzymes [alanine aminotranferase (ALT) and alkaline phosphatase (ALP)]. Mangiferin also reduced Pb(II) induced alterations in antioxidant machineries, restored the mitochondrial membrane potential as well as mutual regulation of Bcl-2/Bax. Furthermore, mangiferin inhibited Pb(II)-induced activation of mitogen-activated protein kinases (MAPKs) (phospho-ERK 1/2, phosphor-JNK phospho- p38), nuclear translocation of NF-κB and apoptotic cell death as was evidenced by DNA fragmentation, FACS analysis and histological assessment. In vitro studies using hepatocytes as the working model also showed the protective effect of mangiferin in Pb(II) induced cytotoxicity. All these beneficial effects of mangiferin contributes to the considerable reduction of apoptotic hepatic cell death induced by Pb(II). Overall results demonstrate that mangiferin exhibit both antioxidative and antiapoptotic properties and protects the organ in Pb(II) induced hepatic dysfunction. PMID:23451106

  4. Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein.

    PubMed

    Rosmorduc, O; Sirma, H; Soussan, P; Gordien, E; Lebon, P; Horisberger, M; Bréchot, C; Kremsdorf, D

    1999-05-01

    Chronic hepatitis B treatment has been significantly improved by interferon (IFN) treatment. However, some studies have suggested that hepatitis B virus (HBV) might have a direct effect on the resistance to IFN. Defective particles, generated by spliced HBV RNA and associated with chronic hepatitis B, have been previously characterized; expression of these particles leads to cytoplasmic accumulation of the capsid protein. The aim of this study was to investigate the role of these defective genomes in IFN resistance. The global antiviral activity of IFN was studied by virus yield reduction assays, the expression of three IFN-induced antiviral proteins was analysed by Western blotting and confocal microscopy, and the regulation of MxA gene expression was studied by Northern blotting and the luciferase assay, in Huh7 cells transfected with a complete or the defective HBV genome. Results showed that the expression of the defective genome reduces the antiviral activity of IFN and that this modulation involves a selective inhibition of MxA protein induction by the HBV capsid protein. Our results also show the trans-suppressive effect of the HBV capsid on the MxA promoter, which might participate in this phenomenon. In conclusion, this study shows a direct interplay between the IFN-sensitive pathway and the capsid protein and might implicate this defective HBV genome in virus persistence.

  5. Photoacoustic Tomography of Human Hepatic Malignancies Using Intraoperative Indocyanine Green Fluorescence Imaging

    PubMed Central

    Miyata, Akinori; Ishizawa, Takeaki; Kamiya, Mako; Shimizu, Atsushi; Kaneko, Junichi; Ijichi, Hideaki; Shibahara, Junji; Fukayama, Masashi; Midorikawa, Yutaka; Urano, Yasuteru; Kokudo, Norihiro

    2014-01-01

    Recently, fluorescence imaging following the preoperative intravenous injection of indocyanine green has been used in clinical settings to identify hepatic malignancies during surgery. The aim of this study was to evaluate the ability of photoacoustic tomography using indocyanine green as a contrast agent to produce representative fluorescence images of hepatic tumors by visualizing the spatial distribution of indocyanine green on ultrasonographic images. Indocyanine green (0.5 mg/kg, intravenous) was preoperatively administered to 9 patients undergoing hepatectomy. Intraoperatively, photoacoustic tomography was performed on the surface of the resected hepatic specimens (n = 10) under excitation with an 800 nm pulse laser. In 4 hepatocellular carcinoma nodules, photoacoustic imaging identified indocyanine green accumulation in the cancerous tissue. In contrast, in one hepatocellular carcinoma nodule and five adenocarcinoma foci (one intrahepatic cholangiocarcinoma and 4 colorectal liver metastases), photoacoustic imaging delineated indocyanine green accumulation not in the cancerous tissue but rather in the peri-cancerous hepatic parenchyma. Although photoacoustic tomography enabled to visualize spatial distribution of ICG on ultrasonographic images, which was consistent with fluorescence images on cut surfaces of the resected specimens, photoacoustic signals of ICG-containing tissues decreased approximately by 40% even at 4 mm depth from liver surfaces. Photoacoustic tomography using indocyanine green also failed to identify any hepatocellular carcinoma nodules from the body surface of model mice with non-alcoholic steatohepatitis. In conclusion, photoacoustic tomography has a potential to enhance cancer detectability and differential diagnosis by ultrasonographic examinations and intraoperative fluorescence imaging through visualization of stasis of bile-excreting imaging agents in and/or around hepatic tumors. However, further technical advances are needed

  6. Photoacoustic tomography of human hepatic malignancies using intraoperative indocyanine green fluorescence imaging.

    PubMed

    Miyata, Akinori; Ishizawa, Takeaki; Kamiya, Mako; Shimizu, Atsushi; Kaneko, Junichi; Ijichi, Hideaki; Shibahara, Junji; Fukayama, Masashi; Midorikawa, Yutaka; Urano, Yasuteru; Kokudo, Norihiro

    2014-01-01

    Recently, fluorescence imaging following the preoperative intravenous injection of indocyanine green has been used in clinical settings to identify hepatic malignancies during surgery. The aim of this study was to evaluate the ability of photoacoustic tomography using indocyanine green as a contrast agent to produce representative fluorescence images of hepatic tumors by visualizing the spatial distribution of indocyanine green on ultrasonographic images. Indocyanine green (0.5 mg/kg, intravenous) was preoperatively administered to 9 patients undergoing hepatectomy. Intraoperatively, photoacoustic tomography was performed on the surface of the resected hepatic specimens (n = 10) under excitation with an 800 nm pulse laser. In 4 hepatocellular carcinoma nodules, photoacoustic imaging identified indocyanine green accumulation in the cancerous tissue. In contrast, in one hepatocellular carcinoma nodule and five adenocarcinoma foci (one intrahepatic cholangiocarcinoma and 4 colorectal liver metastases), photoacoustic imaging delineated indocyanine green accumulation not in the cancerous tissue but rather in the peri-cancerous hepatic parenchyma. Although photoacoustic tomography enabled to visualize spatial distribution of ICG on ultrasonographic images, which was consistent with fluorescence images on cut surfaces of the resected specimens, photoacoustic signals of ICG-containing tissues decreased approximately by 40% even at 4 mm depth from liver surfaces. Photoacoustic tomography using indocyanine green also failed to identify any hepatocellular carcinoma nodules from the body surface of model mice with non-alcoholic steatohepatitis. In conclusion, photoacoustic tomography has a potential to enhance cancer detectability and differential diagnosis by ultrasonographic examinations and intraoperative fluorescence imaging through visualization of stasis of bile-excreting imaging agents in and/or around hepatic tumors. However, further technical advances are needed

  7. Promotion of hepatic preneoplastic lesions in male B6C3F1 mice by unleaded gasoline.

    PubMed Central

    Standeven, A M; Wolf, D C; Goldsworthy, T L

    1995-01-01

    In previous studies, unleaded gasoline (UG) vapor was found to be a liver tumor promoter and hepatocarcinogen in female mice, but UG was not a hepatocarcinogen in male mice. However, UG vapor had similar transient mitogenic effects in nonlesioned liver of both male and female mice under the conditions of the cancer bioassay. We used an initiation-promotion protocol to determine whether UG vapor acts as a liver tumor promoter in male mice and to examine proliferative effects that may be critical to tumor development. Twelve-day-old male B6C3F1 mice were injected with N-nitrosodiethylamine (DEN; 5 mg/kg, intraperitoneally) or vehicle. Starting at 5-7 weeks of age, mice were exposed by inhalation 6 hr/day, 5 days/week for 16 weeks to 0 or 2046 ppm of PS-6 blend UG. UG treatment caused a significant 2.3-fold increase in the number of macroscopic hepatic masses in DEN-initiated mice, whereas no macroscopic masses were observed in non-initiated mice. Altered hepatic foci (AHF), which were predominantly basophilic in phenotype, were found almost exclusively in DEN-initiated mice. UG treatment significantly increased both the mean volume (threefold) and the volume fraction (twofold) of the AHF without increasing the number of AHF per unit area. UG also induced hepatic pentoxyresorufin-O-dealkylase (PROD) activity, a marker of CYP2B, by more than 12-fold over control with or without DEN cotreatment. To study hepatocyte proliferative effects of UG, we treated mice with 5-bromo-2'-deoxyuridine (BrdU) via osmotic pump for 3 days before necropsy and measured hepatocyte BrdU labeling index (LI) in AHF and nonlesioned liver.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1. PMID:7588481

  8. Apigenin protects against alcohol-induced liver injury in mice by regulating hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression.

    PubMed

    Wang, Feng; Liu, Jin-Cheng; Zhou, Rui-Jun; Zhao, Xi; Liu, Mei; Ye, Hua; Xie, Mei-Lin

    2017-09-25

    Alcohol is a major cause of liver injury, and there are currently no ideal pharmacological reagents that can prevent or reverse this disease. Apigenin is one of the most common flavonoids present in numerous plants and has many beneficial effects. But whether or not apigenin may protect against alcohol-induced liver injury remains unknown. Our aim was to examine the effect and potential mechanisms. The experimental mice were given 56% erguotou wine or simultaneously given apigenin 150-300 mg/kg by gavage for 30 days. The results showed that in the apigenin-treated mice, the expression of hepatic cytochrome P450 2E1 (CYP2E1) and nuclear factor kappa B proteins as well as contents of hepatic malondialdehyde and tumor necrosis factor-alpha were reduced, while the levels of hepatic reduced glutathione, glutathione reductase, glutathione peroxidase, and glutathione S-transferase were increased, especially in the 300 mg/kg group. A significant change in hepatic steatosis was also observed in the apigenin 300 mg/kg group. Apigenin pretreatment could increase the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) and carnitine palmitoyltransferase-1 proteins, and decrease the expression of hepatic sterol regulatory element binding protein-1c, fatty acid synthase, and diacylglycerol acyltransferase proteins. These findings demonstrated that apigenin might exert a protective effect on alcohol-induced liver injury, and its mechanisms might be related to the regulations of hepatic CYP2E1-mediated oxidative stress and PPARα-mediated lipogenic gene expression. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism.

    PubMed

    Pathak, Preeti; Liu, Hailiang; Boehme, Shannon; Xie, Cen; Krausz, Kristopher W; Gonzalez, Frank; Chiang, John Y L

    2017-06-30

    The bile acid-activated receptors, nuclear farnesoid X receptor (FXR) and the membrane Takeda G-protein receptor 5 (TGR5), are known to improve glucose and insulin sensitivity in obese and diabetic mice. However, the metabolic roles of these two receptors and the underlying mechanisms are incompletely understood. Here, we studied the effects of the dual FXR and TGR5 agonist INT-767 on hepatic bile acid synthesis and intestinal secretion of glucagon-like peptide-1 (GLP-1) in wild-type, Fxr -/- , and Tgr5 -/- mice. INT-767 efficaciously stimulated intracellular Ca 2+ levels, cAMP activity, and GLP-1 secretion and improved glucose and lipid metabolism more than did the FXR-selective obeticholic acid and TGR5-selective INT-777 agonists. Interestingly, INT-767 reduced expression of the genes in the classic bile acid synthesis pathway but induced those in the alternative pathway, which is consistent with decreased taurocholic acid and increased tauromuricholic acids in bile. Furthermore, FXR activation induced expression of FXR target genes, including fibroblast growth factor 15, and unexpectedly Tgr5 and prohormone convertase 1/3 gene expression in the ileum. We identified an FXR-responsive element on the Tgr5 gene promoter. Fxr -/- and Tgr5 -/- mice exhibited reduced GLP-1 secretion, which was stimulated by INT-767 in the Tgr5 -/- mice but not in the Fxr -/- mice. Our findings uncovered a novel mechanism in which INT-767 activation of FXR induces Tgr5 gene expression and increases Ca 2+ levels and cAMP activity to stimulate GLP-1 secretion and improve hepatic glucose and lipid metabolism in high-fat diet-induced obese mice. Activation of both FXR and TGR5 may therefore represent an effective therapy for managing hepatic steatosis, obesity, and diabetes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Adenoviral hepatitis in a female bearded dragon (Amphibolurus barbatus).

    PubMed

    Julian, A F; Durham, P J

    1982-05-01

    A female bearded dragon (Amphibolurus barbatus) died following intermittent periods of inappetance. No significant gross lesions were found at autopsy, but histological examination revealed disordered liver architecture with numerous foci of coagulative necrosis. Eosinophilic intranuclear inclusions were present in many hepatocytes, some epithelial cells of the bile ductules and occasional epithelial cells of renal tubes and glomeruli. Large numbers of viral particles within many nuclei, associated with the intranuclear inclusion were demonstrated by electronmicroscopy. Similar particles, sometimes in paracrystalline arrays, were also seen within membrane-bound vesicles located next to the nuclei and to a lesser degree within the cytoplasm and extracellular spaces. The virus was considered to be an adenovirus on the basis of its size, morphology, site of formation and lack of envelopment. It was considered to he the cause of the hepatitis.

  11. Activation of AMPK by berberine induces hepatic lipid accumulation by upregulation of fatty acid translocase CD36 in mice.

    PubMed

    Choi, You-Jin; Lee, Kang-Yo; Jung, Seung-Hwan; Kim, Hyung Sik; Shim, Gayong; Kim, Mi-Gyeong; Oh, Yu-Kyoung; Oh, Seon-Hee; Jun, Dae Won; Lee, Byung-Hoon

    2017-02-01

    Emerging evidence has shown that berberine has a protective effect against metabolic syndrome such as obesity and type II diabetes mellitus by activating AMP-activated protein kinase (AMPK). AMPK induces CD36 trafficking to the sarcolemma for fatty acid uptake and oxidation in contracting muscle. However, little is known about the effects of AMPK on CD36 regulation in the liver. We investigated whether AMPK activation by berberine affects CD36 expression and fatty acid uptake in hepatocytes and whether it is linked to hepatic lipid accumulation. Activation of AMPK by berberine or transduction with adenoviral vectors encoding constitutively active AMPK in HepG2 and mouse primary hepatocytes increased the expression and membrane translocation of CD36, resulting in enhanced fatty acid uptake and lipid accumulation as determined by BODIPY-C16 and Nile red fluorescence, respectively. Activation of AMPK by berberine induced the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and subsequently induced CCAAT/enhancer-binding protein β (C/EBPβ) binding to the C/EBP-response element in the CD36 promoter in hepatocytes. In addition, hepatic CD36 expression and triglyceride levels were increased in normal diet-fed mice treated with berberine, but completely prevented when hepatic CD36 was silenced with adenovirus containing CD36-specific shRNA. Taken together, prolonged activation of AMPK by berberine increased CD36 expression in hepatocytes, resulting in fatty acid uptake via processes linked to hepatocellular lipid accumulation and fatty liver. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. FOCIS: A forest classification and inventory system using LANDSAT and digital terrain data

    NASA Technical Reports Server (NTRS)

    Strahler, A. H.; Franklin, J.; Woodcook, C. E.; Logan, T. L.

    1981-01-01

    Accurate, cost-effective stratification of forest vegetation and timber inventory is the primary goal of a Forest Classification and Inventory System (FOCIS). Conventional timber stratification using photointerpretation can be time-consuming, costly, and inconsistent from analyst to analyst. FOCIS was designed to overcome these problems by using machine processing techniques to extract and process tonal, textural, and terrain information from registered LANDSAT multispectral and digital terrain data. Comparison of samples from timber strata identified by conventional procedures showed that both have about the same potential to reduce the variance of timber volume estimates over simple random sampling.

  13. Agmatine protects rat liver from nicotine-induced hepatic damage via antioxidative, antiapoptotic, and antifibrotic pathways.

    PubMed

    El-Sherbeeny, Nagla A; Nader, Manar A; Attia, Ghalia M; Ateyya, Hayam

    2016-12-01

    Tobacco smoking with its various forms is a global problem with proved hazardous effects to human health. The present work was planned to study the defending role of agmatine (AGM) on hepatic oxidative stress and damage induced by nicotine in rats. Thirty-two rats divided into four groups were employed: control group, nicotine-only group, AGM group, and AGM-nicotine group. Measurements of serum hepatic biochemical markers, lipid profile, and vascular cell adhesion molecule-1 were done. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) activity, and nitrate/nitrite (NOx) levels were estimated in the liver homogenates. Immunohistochemistry for Bax and transforming growth factor beta (TGF-β1) and histopathology of the liver were also included. Data of the study demonstrated that nicotine administration exhibited marked liver deterioration, an increase in liver enzymes, changes in lipid profile, and an elevation in MDA with a decline in levels of SOD, GSH, and NOx (nitrate/nitrite). Also, levels of proapoptotic Bax and profibrotic TGF-β1 showed marked elevation in the liver. AGM treatment to rats in nicotine-only group ameliorated all the previous changes. These findings indicate that AGM could successfully overcome the nicotine-evoked hepatic oxidative stress and tissue injury, apoptosis, and fibrosis.

  14. Zingiber mioga reduces weight gain, insulin resistance and hepatic gluconeogenesis in diet-induced obese mice

    PubMed Central

    LEE, DA-HYE; AHN, JIYUN; JANG, YOUNG JIN; HA, TAE-YOUL; JUNG, CHANG HWA

    2016-01-01

    Zingiber mioga is a perennial herb belonging to the ginger family (Zingiberaceae) that is used medicinally to treat cough and rheumatism in China and consumed throughout Japan. The aim of the present study was to investigate the anti-obesity effects of Z. mioga following extraction with distilled water or 70% ethanol. In 3T3-L1 preadipocyte cells, Z. mioga water extract (ZMW) markedly inhibited adipogenesis, whereas the ethanol extract had no effect. In addition, we conducted ZMW feeding experiments (0.25 or 0.5% ZMW) in high-fat diet (HFD)-fed mice to examine the anti-obesity effects of Z. mioga in vivo. Body weight and serum triglyceride and cholesterol levels significantly decreased in the HFD + ZMW 0.5% group. Notably, ZMW decreased liver weight but not adipose tissue weight. Furthermore, insulin resistance and hepatic mRNA expression of gluconeogenic genes, such as phosphoenolpyruvate carboxykinase and G6Pase, were improved in the HFD + ZMW 0.5% group. Furthermore, ZMW treatment decreased hepatic lipogenic gene expression; however, it did not alter adipogenesis in fat tissue, suggesting that ZMW inhibits hepatosteatosis through the suppression of lipogenesis. ZMW improved HFD-induced hepatic inflammation. Collectively, the present findings suggest that ZMW may serve as a new and promising strategy for the treatment of hepatosteatosis. PMID:27347064

  15. Hepatitis B virus enhances cisplatin-induced hepatotoxicity via a mechanism involving suppression of glucose-regulated protein of 78 Kda.

    PubMed

    Zhang, Xiaoxue; Zhang, Rui; Yang, HuiOu; Xiang, Qian; Jiang, Qing; He, Qi; Zhang, Ting; Chen, Chen; Zhu, Huifen; Wang, Qiang; Ning, Qin; Li, Yiwu; Lei, Ping; Shen, Guanxin

    2016-07-25

    Cisplatin is a classical platinum-based chemotherapeutic drug used in the treatment of many cancer types, including hepatocellular carcinoma (HCC). The application of cisplatin is significantly limited by its toxicity, which may be affected by various biological factors. Persistence of Hepatitis B virus (HBV) infection leads to HCC development and may be associated with higher incidence of severe hepatitis during chemotherapy. However, whether HBV alters the susceptibility of hepatocytes to cisplatin remains poorly understood. Here, we demonstrate that HBV transfection enhanced cisplatin-induced hepatotoxicity via a mechanism involving suppression of glucose-regulated protein of 78 KDa (Grp78), a major stress-induced chaperone that localizes to the endoplasmic reticulum. Silencing Grp78 gene increased the susceptibility of HepG2 to cisplatin by activating caspase-3. Grp78 expression was down-regulated by HBV infection both in vitro and in liver tissues of patients. We compared the cisplatin sensitivity of hepatoma cells either expressing (HepG2.2.15 cells) or not expressing the entire Hepatitis B Virus genome (HepG2). HepG2.2.15 cells showed increased sensitivity to cisplatin and a higher apoptosis rate. Overexpression of Grp78 counteracted the increase of sensitivity of HepG2.215 cells to cisplatin. Furthermore, we found that HBV disrupted Grp78 synthesis in response to cisplatin stimulation, which may trigger severe and prolonged endoplasmic reticulum (ER) stress that can induce cellular apoptosis. Our findings provide new information into the effect of HBV in the modulation of Grp78 expression, and, consequently on cisplatin-induced hepatotoxicity during viral infection. Copyright © 2016. Published by Elsevier Ireland Ltd.

  16. Hepatic alveolar echinococcosis: correlative US and CT study

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Didier, D.; Weiler, S.; Rohmer, P.

    1985-01-01

    A total of 24 cases of hepatic alveolar echinococcosis (HAE) due to Echinococcus multilocularis was assessed by US and CT. The diagnosis was confirmed in all cases by immunologic and histologic study. Both US and CT patterns of HAE showed changes of liver morphology in both contour and size. Abnormal areas of parenchyma were nodular or in fields, irregular, heterogeneous, and basically echogenic. Clustered microcalcifications were encountered within the abnormal parenchymal fields in 50% of cases, and necrotized zones occurred in 40% of cases. Dilatation of intrahepatic bile ducts was commonly seen, especially on US; hilar involvement was frequent. Follow-upmore » by both techniques can display increases of primary lesions, occurrence of new foci, and local or regional extensions. Precise evaluations of the lesions arising from correlative use of US and CT permits adequate therapeutic management.« less

  17. Persistence of Gamma-H2AX Foci in Irradiated Bronchial Cells Correlates with Susceptibility to Radiation Associated Lung Cancer in Mice

    NASA Technical Reports Server (NTRS)

    Ochola, Donasian O.; Sharif, Rabab; Bedford, Joel S.; Keefe, Thomas J.; Kato, Takamitsu A.; Fallgren, Christina M.; Demant, Peter; Costes, Sylvain V.; Weil, Michael M.

    2018-01-01

    The risk of developing radiation-induced lung cancer differs between different strains of mice, but the underlying cause of the strain differences is unknown. Strains of mice also differ in their ability to efficiently repair DNA double strand breaks resulting from radiation exposure. We phenotyped mouse strains from the CcS/Dem recombinant congenic strain set for their efficacy in repairing DNA double strand breaks during protracted radiation exposures. We monitored persistent gamma-H2AX radiation induced foci (RIF) 24 hours after exposure to chronic gamma-rays as a surrogate marker for repair deficiency in bronchial epithelial cells for 17 of the CcS/Dem strains and the BALB/cHeN founder strain. We observed a very strong correlation R2 = 79.18%, P < 0.001) between the level of persistent RIF and radiogenic lung cancer percent incidence measured in the same strains. Interestingly, spontaneous levels of foci in non-irradiated strains also showed good correlation with lung cancer incidence (R2=32.74%, P =0.013). These results suggest that genetic differences in DNA repair capacity largely account for differing susceptibilities to radiation-induced lung cancer among CcS/Dem mouse strains and that high levels of spontaneous DNA damage is also a relatively good marker of cancer predisposition. In a smaller pilot study, we found that the repair capacity measured in peripheral blood leucocytes also correlated well with radiogenic lung cancer susceptibility, raising the possibility that such phenotyping assay could be used to detect radiogenic lung cancer susceptibility in humans.

  18. Hepatic FTO expression is increased in NASH and its silencing attenuates palmitic acid-induced lipotoxicity.

    PubMed

    Lim, Andrea; Zhou, Jin; Sinha, Rohit A; Singh, Brijesh K; Ghosh, Sujoy; Lim, Kiat-Hon; Chow, Pierce Kah-Hoe; Woon, Esther C Y; Yen, Paul M

    2016-10-21

    Non-alcoholic steatohepatitis (NASH) is one of the most common causes of liver failure worldwide. It is characterized by excess fat accumulation, inflammation, and increased lipotoxicity in hepatocytes. Currently, there are limited treatment options for NASH due to lack of understanding of its molecular etiology. In the present study, we demonstrate that the expression of fat mass and obesity associated gene (FTO) is significantly increased in the livers of NASH patients and in a rodent model of NASH. Furthermore, using human hepatic cells, we show that genetic silencing of FTO protects against palmitate-induced oxidative stress, mitochondrial dysfunction, ER stress, and apoptosis in vitro. Taken together, our results show that FTO may have a deleterious role in hepatic cells during lipotoxic conditions, and strongly suggest that up-regulation of FTO may contribute to the increased liver damage in NASH. Copyright © 2016 Elsevier Inc. All rights reserved.

  19. Aqueous Extract of Gynura Bicolor Attenuated Hepatic Steatosis, Glycative, Oxidative, and Inflammatory Injury Induced by Chronic Ethanol Consumption in Mice.

    PubMed

    Yin, Mei-Chin; Wang, Zhi-Hong; Liu, Wen-Hu; Mong, Mei-Chin

    2017-11-01

    Gynura bicolor leaf aqueous extract (GAE) is rich in phytochemicals including phenolic acids, flavonoids, carotenoids, and anthocyanins. Effects of GAE upon hepatic injury in mice with chronic ethanol intake were examined. Lieber-DeCarli liquid diet with ethanol was used to induce hepatic lipid accumulation, oxidative, glycative, and inflammatory injury. GAE at 0.25% or 0.5% was added in feeds, and supplied to mice consumed Lieber-DeCarli liquid diet with ethanol for 6 wk. Blood and liver were collected for analyses. Results showed that ethanol increased plasma and hepatic triglyceride and cholesterol content, and affected plasma levels of insulin, adiponectin, leptin, and ghrelin. GAE at both doses decreased lipid accumulation, and at high dose improved hormones abnormality. Histological data revealed that GAE supplement mitigated hepatic lipid deposit. Ethanol increased plasma N ε -(carboxyethymethyl)-lysine and pentosidine levels. GAE at high doses lowered those glycative factors. Ethanol depleted glutathione content, increased CYP2E1 activity and reactive oxygen species production, and reduced the activity of glutathione peroxide, glutathione reductase and catalase in liver. GAE supplement at both doses reversed these alterations and attenuated hepatic oxidative stress. GAE supplement also at both doses decreased hepatic inflammatory cytokines release in ethanol treated mice. These findings support that leaves of G. bicolor is a functional food with liver protective activities against ethanol. © 2017 Institute of Food Technologists®.

  20. Establishment of a γ-H2AX foci-based assay to determine biological dose of radon to red bone marrow in rats

    PubMed Central

    Wang, Jing; He, Linfeng; Fan, Dunhuang; Ding, Defang; Wang, Xufei; Gao, Yun; Zhang, Xuxia; Li, Qiang; Chen, Honghong

    2016-01-01

    The biodosimetric information is critical for assessment of cancer risk in populations exposed to high radon. However, no tools are available for biological dose estimation following radon exposure. Here, we established a γ-H2AX foci-based assay to determine biological dose to red bone marrow (RBM) in radon-inhaled rats. After 1–3 h of in vitro radon exposure, a specific pattern of γ-H2AX foci, linear tracks with individual p-ATM and p-DNA-PKcs foci, was observed, and the yield of γ-H2AX foci and its linear tracks displayed a linear dose-response manner in both rat peripheral blood lymphocytes (PBLs) and bone-marrow lymphocytes (BMLs). When the cumulative doses of radon inhaled by rats reached 14, 30 and 60 working level months (WLM), the yields of three types of foci markedly increased in both PBLs and BMLs, and γ-H2AX foci-based dose estimates to RBM were 0.97, 2.06 and 3.94 mGy, respectively. Notably, BMLs displayed a more profound increase of three types of foci than PBLs, and the absorbed dose ratio between BMLs and PBLs was similar between rats exposed to 30 and 60 WLM of radon. Taken together, γ-H2AX foci quantitation in PBLs is able to estimate RBM-absorbed doses with the dose-response curve of γ-H2AX foci after in vitro radon exposure and the ratio of RBM- to PBL-absorbed doses in rats following radon exposure. PMID:27445126

  1. Establishment of a γ-H2AX foci-based assay to determine biological dose of radon to red bone marrow in rats

    NASA Astrophysics Data System (ADS)

    Wang, Jing; He, Linfeng; Fan, Dunhuang; Ding, Defang; Wang, Xufei; Gao, Yun; Zhang, Xuxia; Li, Qiang; Chen, Honghong

    2016-07-01

    The biodosimetric information is critical for assessment of cancer risk in populations exposed to high radon. However, no tools are available for biological dose estimation following radon exposure. Here, we established a γ-H2AX foci-based assay to determine biological dose to red bone marrow (RBM) in radon-inhaled rats. After 1-3 h of in vitro radon exposure, a specific pattern of γ-H2AX foci, linear tracks with individual p-ATM and p-DNA-PKcs foci, was observed, and the yield of γ-H2AX foci and its linear tracks displayed a linear dose-response manner in both rat peripheral blood lymphocytes (PBLs) and bone-marrow lymphocytes (BMLs). When the cumulative doses of radon inhaled by rats reached 14, 30 and 60 working level months (WLM), the yields of three types of foci markedly increased in both PBLs and BMLs, and γ-H2AX foci-based dose estimates to RBM were 0.97, 2.06 and 3.94 mGy, respectively. Notably, BMLs displayed a more profound increase of three types of foci than PBLs, and the absorbed dose ratio between BMLs and PBLs was similar between rats exposed to 30 and 60 WLM of radon. Taken together, γ-H2AX foci quantitation in PBLs is able to estimate RBM-absorbed doses with the dose-response curve of γ-H2AX foci after in vitro radon exposure and the ratio of RBM- to PBL-absorbed doses in rats following radon exposure.

  2. A single dose of inactivated hepatitis A vaccine promotes HAV-specific memory cellular response similar to that induced by a natural infection.

    PubMed

    Melgaço, Juliana Gil; Morgado, Lucas Nóbrega; Santiago, Marta Almeida; Oliveira, Jaqueline Mendes de; Lewis-Ximenez, Lia Laura; Hasselmann, Bárbara; Cruz, Oswaldo Gonçalves; Pinto, Marcelo Alves; Vitral, Claudia Lamarca

    2015-07-31

    Based on current studies on the effects of single dose vaccines on antibody production, Latin American countries have adopted a single dose vaccine program. However, no data are available on the activation of cellular response to a single dose of hepatitis A. Our study investigated the functional reactivity of the memory cell phenotype after hepatitis A virus (HAV) stimulation through administration of the first or second dose of HAV vaccine and compared the response to that of a baseline group to an initial natural infection. Proliferation assays showed that the first vaccine dose induced HAV-specific cellular response; this response was similar to that induced by a second dose or an initial natural infection. Thus, from the first dose to the second dose, increase in the frequencies of classical memory B cells, TCD8 cells, and central memory TCD4 and TCD8 cells were observed. Regarding cytokine production, increased IL-6, IL-10, TNF, and IFNγ levels were observed after vaccination. Our findings suggest that a single dose of HAV vaccine promotes HAV-specific memory cell response similar to that induced by a natural infection. The HAV-specific T cell immunity induced by primary vaccination persisted independently of the protective plasma antibody level. In addition, our results suggest that a single dose immunization system could serve as an alternative strategy for the prevention of hepatitis A in developing countries. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Treatment for hepatitis C virus-induced portal hypertension in leukemic children.

    PubMed

    El-Ashry, Rasha; Malek, Hala Abdel; Ghayaty, Essam A Desoky; El-Gendy, Ahmed A; Darwish, Ahmad; Al-Tonbary, Youssef

    2013-01-01

    Children with acute leukemia are at high risk of hepatitis C infection, either by immunosuppression secondary to chemotherapy or by multiple transfusions of blood products during the course of the disease. Hepatitis C virus (HCV) infection constitutes a major problem during management of acute leukemia due to resultant portal hypertension or bleeding esophageal varices. Chronic HCV infection is a major cause of liver cirrhosis and hepatocellular carcinoma in leukemic survivors. The effect of amlodipine treatment on children with acute lymphoblastic leukemia (ALL) having portal hypertension secondary to HCV infection during maintenance chemotherapy has been studied. Sixty male children (mean age 11.83 ± 1.1 years) with ALL in remission and have HCV infection were included. Diagnosis of HCV infection was confirmed by real-time PCR. Thirty patients received 5 mg amlodipine orally per day for 4 weeks and compared to another 30 patients received placebo therapy and 30 age- and sex-matched children as a control group. Amlodipine significantly reduced the elevated portal blood pressure to normal level in doses which did not interfere with mechanism of action of chemotherapy (p ≤ 0.001). Treatment with amlodipine can be used to control portal hypertension in leukemic children having HCV-induced portal hypertension. HCV in leukemics could be virtually eliminated by proper testing of the blood transfusion pool.

  4. Simultaneous Occurrence of Varicella Zoster Virus-Induced Pancreatitis and Hepatitis in a Renal Transplant Recipient: A Case Report and Review of Literature

    PubMed Central

    Chhabra, Puneet; Ranjan, Priyadarshi; Bhasin, Deepak K

    2017-01-01

    Introduction: Gastrointestinal complications are common after renal transplantation, including oral lesions, esophagitis, gastritis, diarrhea, and colon carcinoma. The differential diagnosis is difficult in this scenario because multiple factors such as drugs, infections, and preexisting gastrointestinal disease come into play. Case Presentation: We report a case of varicella zoster virus-induced pancreatitis and hepatitis in a renal transplant recipient. The patient underwent renal transplantation 3 years earlier and now presented with severe pain in the epigastrium radiating to his back and had raised serum lipase levels and skin lesions characteristic of varicella. Liver enzyme levels were also elevated. He was started on a regimen of acyclovir. His pain improved in 24 hours, and liver enzyme levels returned to normal in 48 hours. Discussion: There is a paucity of literature on the simultaneous occurrence of varicella zoster virus-induced hepatitis and pancreatitis in both immunocompetent and immunocompromised patients. Our case highlights the gastrointestinal complications of varicella infection in immunocompromised patients that may precede the characteristic dermatologic manifestations, and the fact that rarely both hepatitis and pancreatitis may be seen. PMID:28333601

  5. Short-chain chlorinated paraffins (SCCPs) induced thyroid disruption by enhancement of hepatic thyroid hormone influx and degradation in male Sprague Dawley rats.

    PubMed

    Gong, Yufeng; Zhang, Haijun; Geng, Ningbo; Xing, Liguo; Fan, Jingfeng; Luo, Yun; Song, Xiaoyao; Ren, Xiaoqian; Wang, Feidi; Chen, Jiping

    2018-06-01

    Short-chain chlorinated paraffins (SCCPs) are known to disturb thyroid hormone (TH) homeostasis in rodents. However, the mechanism remains to be fully characterized. In this study, male Sprague Dawley rats received SCCPs (0, 1, 10, or 100mg/kg/day) via gavage once a day for consecutive 28days. Plasma and hepatic TH concentrations, thyrocyte structure, as well as thyroid and hepatic mRNA and protein levels of genes associated with TH homeostasis were examined. Moreover, we performed molecular docking to predict interactions between constitutive androstane receptor (CAR), a key regulator in xenobiotic-induced TH metabolism, with different SCCP molecules. Exposure to SCCPs significantly decreased the circulating free thyroxine (T 4 ) and triiodothyronine (T 3 ) levels, but increased thyroid-stimulating hormone (TSH) levels by a feedback mechanism. Decreased hepatic T 4 and increased hepatic T 3 levels were also seen after 100mg/kg/day SCCPs exposure. SCCPs didn't show any significant effects on the expression of thyroid TH synthesis genes or thyrocyte structure. However, stimulation effects were observed for mRNA and protein levels of hepatic uridine diphosphoglucuronosyl transferase (UGT) 1A1 and organic anion transporter 2, suggesting an accelerated TH metabolism in rat liver. The increased cytochrome P450 2B1 but not 1A1 mRNA and protein levels indicated that the CAR signaling was activated by SCCPs exposure. According to docking analysis, SCCPs form hydrophobic interactions with CAR and the binding affinity shows dependency on chlorine content. Overall, our data showed that CAR implicated enhancement of hepatic TH influx and degradation could be the main cause for SCCPs induced TH deficiency in male rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. IFN-gamma signaling in the central nervous system controls the course of experimental autoimmune encephalomyelitis independently of the localization and composition of inflammatory foci

    PubMed Central

    2012-01-01

    Background Murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, presents typically as ascending paralysis. However, in mice in which interferon-gamma (IFNγ) signaling is disrupted by genetic deletion, limb paralysis is accompanied by atypical deficits, including head tilt, postural imbalance, and circling, consistent with cerebellar/vestibular dysfunction. This was previously attributed to intense cerebellar and brainstem infiltration by peripheral immune cells and formation of neutrophil-rich foci within the CNS. However, the exact mechanism by which IFNγ signaling prohibits the development of vestibular deficits, and whether the distribution and composition of inflammatory foci within the CNS affects the course of atypical EAE remains elusive. Methods We induced EAE in IFNγ-/- mice and bone marrow chimeric mice in which IFNγR is not expressed in the CNS but is intact in the periphery (IFNγRCNSKO) and vice versa (IFNγRperiKO). Blood-brain barrier permeability was determined by Evans blue intravenous administration at disease onset. Populations of immune cell subsets in the periphery and the CNS were quantified by flow cytometry. CNS tissues isolated at various time points after EAE induction, were analyzed by immunohistochemistry for composition of inflammatory foci and patterns of axonal degeneration. Results Incidence and severity of atypical EAE were more pronounced in IFNγRCNSKO as compared to IFNγRperiKO mice. Contrary to what we anticipated, cerebella/brainstems of IFNγRCNSKO mice were only minimally infiltrated, while the same areas of IFNγRperiKO mice were extensively populated by peripheral immune cells. Furthermore, the CNS of IFNγRperiKO mice was characterized by persistent neutrophil-rich foci as compared to IFNγRCNSKO. Immunohistochemical analysis of the CNS of IFNγ-/- and IFNγR chimeric mice revealed that IFNγ protective actions are exerted through microglial STAT1. Conclusions Alterations in

  7. Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice.

    PubMed

    Honda, Takashi; Ishigami, Masatoshi; Luo, Fangqiong; Lingyun, Ma; Ishizu, Yoji; Kuzuya, Teiji; Hayashi, Kazuhiko; Nakano, Isao; Ishikawa, Tetsuya; Feng, Guo-Gang; Katano, Yoshiaki; Kohama, Tomoya; Kitaura, Yasuyuki; Shimomura, Yoshiharu; Goto, Hidemi; Hirooka, Yoshiki

    2017-04-01

    For successful treatment for nonalcoholic steatohepatitis (NASH), it may be important to treat the individual causative factors. At present, however, there is no established treatment for this disease. Branched-chain amino acids (BCAAs) have been used to treat patients with decompensated cirrhosis. In order to elucidate the mechanisms responsible for the effects of BCAAs on hepatic steatosis and disease progression, we investigated the effects of BCAA supplementation in mice fed a choline-deficient high-fat diet (CDHF), which induces NASH. Male mice were divided into four groups that received (1) choline-sufficient high fat (HF) diet (HF-control), (2) HF plus 2% BCAA in drinking water (HF-BCAA), (3) CDHF diet (CDHF-control), or (4) CDHF-BCAA for 8weeks. We monitored liver injury, hepatic steatosis and cholesterol, gene expression related to lipid metabolism, and hepatic fat accumulation. Serum alanine aminotransferase (ALT) levels and hepatic triglyceride (TG) were significantly elevated in CDHF-control relative to HF-control. Liver histopathology revealed severe steatosis, inflammation, and pericellular fibrosis in CDHF-control, confirming the NASH findings. Serum ALT levels and hepatic TG and lipid droplet areas were significantly lower in CDHF-BCAA than in CDHF-control. Gene expression and protein level of fatty acid synthase (FAS), which catalyzes the final step in fatty acid biosynthesis, was significantly decreased in CDHF-BCAA than in CDHF-control (P<0.05). Moreover, hepatic total and free cholesterol of CDHF-BCAA was significantly lower than those of CDHF-control. BCAA can alleviate hepatic steatosis and liver injury associated with NASH by suppressing FAS gene expression and protein levels. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Role of caspase-1 and interleukin-1{beta} in acetaminophen-induced hepatic inflammation and liver injury

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Williams, C. David; Farhood, Anwar; Jaeschke, Hartmut, E-mail: hjaeschke@kumc.ed

    2010-09-15

    Acetaminophen (APAP) overdose can result in serious liver injury and potentially death. Toxicity is dependent on metabolism of APAP to a reactive metabolite initiating a cascade of intracellular events resulting in hepatocellular necrosis. This early injury triggers a sterile inflammatory response with formation of cytokines and innate immune cell infiltration in the liver. Recently, IL-1{beta} signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1{beta} formation through caspase-1 is critical for the pathophysiology, C57Bl/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1{beta} during APAP overdose (300 mg/kg APAP).more » This intervention did not affect IL-1{beta} gene transcription but prevented the increase in IL-1{beta} plasma levels. However, APAP-induced liver injury and neutrophil infiltration were not affected. Similarly, liver injury and the hepatic neutrophilic inflammation were not attenuated in IL-1-receptor-1 deficient mice compared to wild-type animals. To evaluate the potential of IL-1{beta} to increase injury, mice were given pharmacological doses of IL-1{beta} after APAP overdose. Despite increased systemic activation of neutrophils and recruitment into the liver, there was no alteration in injury. We conclude that endogenous IL-1{beta} formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1{beta}, which induce hepatic neutrophil accumulation and activation, do not enhance APAP-induced liver injury. Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury.« less

  9. Interleukin-28B polymorphisms and interferon gamma inducible protein-10 serum levels in seronegative occult hepatitis C virus infection.

    PubMed

    Bartolomé, Javier; Castillo, Inmaculada; Quiroga, Juan Antonio; Carreño, Vicente

    2016-02-01

    Polymorphisms upstream interleukin (IL)-28B gene and serum levels of interferon gamma inducible protein-10 (IP-10) are associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Patients with seronegative occult HCV infection are anti-HCV and serum HCV-RNA negative but have viral RNA in liver and abnormal values of liver enzymes. We examined if the rs12979860 polymorphism of IL-28B and serum IP-10 levels differ between chronic and seronegative occult CV infection. IL-28B polymorphism was determined with allele specific TaqMan probes in total DNA isolated from peripheral blood mononuclear cells and IP-10 by an enzyme-linked immunosorbent assay in serum from 99 patients with seronegative occult HCV infection and 130 untreated patients with chronic hepatitis C. IL-28B genotypes were also determined in 54 healthy volunteers. Prevalence of the IL-28B CC genotype was significantly higher in seronegative occult HCV infection (52/99; 52.5%) than in chronic hepatitis C (32/130; 24.6%, P < 0.0001) or healthy controls (19/54: 32.5%, P = 0.039). Among patients with seronegative occult HCV infection, HCV-RNA load in liver was significantly lower in those with the IL-28B CC genotype than in those with CT + TT genotypes (2.8 × 10(5)  ± 5.8 × 10(4) vs. 4.1 × 10(5)  ± 5.9 × 10(4)  copies/μg of total RNA respectively; P = 0.023). Mean serum IP-10 levels were significantly lower in patients with seronegative occult HCV infection than in patients with chronic hepatitis C (160.8 ± 17.9 vs. 288.7 ± 13.3 pg/ml respectively; P < 0.0001). These findings suggest that the host immune response plays an important role in seronegative occult HCV infection in comparison with chronic hepatitis C. © 2015 Wiley Periodicals, Inc.

  10. [Efficacy and safety of heptral, vitamin B6 and folic acid during toxic hepatitis induced by CCL4].

    PubMed

    Antelava, N A; Gogoluari, M I; Gogoluari, L I; Pirtskhalaĭshvili, N N; Okudzhava, M V

    2007-09-01

    The aim of this work was to evaluate of efficacy and safety of complex Heptral, Vitamin B6 and Folic Acid in experimental hepatitis therapy compared with monotherapy. Experiments were carried out on pubertal rats. Eperimental hepatitis models were induced by Tetrachlormethane. The tetrachlormethane intoxication was reproduced by subcutaneous injection of CCL(4) 1ml/kg dissolved in 1ml of olive oil. Cytochrome P450, cytochrome b5, reduced glutation,activity of glutationetranspherase and content of ATP in hepatocytes were measured by the spectrophotometric techniques,but content of homocysteine by chromophtography techniques. Under CCL(4) intoxication disturbance of liver detoxication function, energy deficit and surplus of homocysteine were observed. Treatment of the toxic hepatitis with heptral increased the level of cytochrome P450, cytochrome b5, glutation activity of glutationetranspherase glutathione and reduced content of homocysteine. Complex therapy with Heptral and B6 and folic acid reveal more expressive hepatoprotective effect and safety than monotherapy with Heptral. Complex therapy improves not only the parameters of biotransformation (metabolic and conjugation phase), but also normalizes the level of ATP and homocystein. Vitamins B6 and folic acid increases the efficacy and safety of Heptral. This complex was recomended for treatment of hepatitis.

  11. Protective Effect of Baccharis trimera Extract on Acute Hepatic Injury in a Model of Inflammation Induced by Acetaminophen

    PubMed Central

    Pádua, Bruno da Cruz; Rossoni Júnior, Joamyr Victor; de Brito Magalhães, Cíntia Lopes; Chaves, Míriam Martins; Silva, Marcelo Eustáquio; Pedrosa, Maria Lucia; de Souza, Gustavo Henrique Bianco; Brandão, Geraldo Célio; Rodrigues, Ivanildes Vasconcelos; Lima, Wanderson Geraldo; Costa, Daniela Caldeira

    2014-01-01

    Background. Acetaminophen (APAP) is a commonly used analgesic and antipyretic. When administered in high doses, APAP is a clinical problem in the US and Europe, often resulting in severe liver injury and potentially acute liver failure. Studies have demonstrated that antioxidants and anti-inflammatory agents effectively protect against the acute hepatotoxicity induced by APAP overdose. Methods. The present study attempted to investigate the protective effect of B. trimera against APAP-induced hepatic damage in rats. The liver-function markers ALT and AST, biomarkers of oxidative stress, antioxidant parameters, and histopathological changes were examined. Results. The pretreatment with B. trimera attenuated serum activities of ALT and AST that were enhanced by administration of APAP. Furthermore, pretreatment with the extract decreases the activity of the enzyme SOD and increases the activity of catalase and the concentration of total glutathione. Histopathological analysis confirmed the alleviation of liver damage and reduced lesions caused by APAP. Conclusions. The hepatoprotective action of B. trimera extract may rely on its effect on reducing the oxidative stress caused by APAP-induced hepatic damage in a rat model. General Significance. These results make the extract of B. trimera a potential candidate drug capable of protecting the liver against damage caused by APAP overdose. PMID:25435714

  12. Insulin protects against hepatic damage postburn.

    PubMed

    Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

    2011-01-01

    Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes.

  13. Insulin Protects against Hepatic Damage Postburn

    PubMed Central

    Jeschke, Marc G; Kraft, Robert; Song, Juquan; Gauglitz, Gerd G; Cox, Robert A; Brooks, Natasha C; Finnerty, Celeste C; Kulp, Gabriela A; Herndon, David N; Boehning, Darren

    2011-01-01

    Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway, leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes. PMID:21267509

  14. Fuzheng Huayu recipe alleviates hepatic fibrosis via inhibiting TNF-α induced hepatocyte apoptosis.

    PubMed

    Tao, Yan-yan; Yan, Xiu-chuan; Zhou, Tao; Shen, Li; Liu, Zu-long; Liu, Cheng-hai

    2014-11-18

    What was the relationship of Fuzheng Huayu recipe (FZHY) inhibiting hepatocyte apoptosis and HSC activation at different stage of liver fibrosis? In order to answer this question, the study was carried out to dynamically observe FZHY's effect on hepatocyte apoptosis and HSC activation and further explored underling mechanism of FZHY against hepatocyte apoptosis. Mice were randomly divided into four groups: normal, model, FZHY, and N-acetylcystein (NAC) groups. Acute hepatic injury and liver fibrosis in mice were induced by CCl4. Three days before the first CCl4 injection, treatment with FZHY powder or NAC respectively was started. In vitro, primary hepatocytes were pretreated with FZHY medicated serum or Z-VAD-FMK and then incubated with ActD and TNF-α. Primary HSCs were treated with DNA from apoptotic hepatocytes incubated by Act D/TNF-α or FZHY medicated. Liver sections were analyzed for HE staining and immunohistochemical evaluation of apoptosis. Serum ALT and AST, Alb content and TNF-α expression in liver tissue were detected. Hyp content was assayed and collagen deposition was visualized. Expressions of α-SMA and type I collagen were analyzed by immunofluorescence and immunoblotting. Flow cytometry, immunofluorescence, and DNA ladder for hepatocyte apoptosis and immunoblotting for TNF-R1, Bcl-2 and Bax were also analyzed. Mice showed characteristic features of massive hepatocytes apoptosis in early stage of liver injury and developed severe hepatic fibrosis in later phase. FZHY treatment significantly alleviated acute liver injury and hepatocyte apoptosis, and inhibited liver fibrosis by decreasing α-SMA expression and hepatic Hyp content. In vitro, primary hepatocytes were induced by TNF-α and Act D. The anti-apoptotic effect of FZHY was generated by reducing TNFR1 expression and balancing the expressions of Bcl-2 and Bax. Meanwhile, the nuclear DNA from apoptotic hepatocytes stimulated HSC activation in a dose dependent manner, and the DNA from

  15. Gut microbiota and hepatitis-B-virus-induced chronic liver disease: implications for faecal microbiota transplantation therapy.

    PubMed

    Kang, Y; Cai, Y

    2017-08-01

    Hepatitis B is one of the most common infectious diseases globally. It has been estimated that there are 350 million chronic hepatitis B virus (HBV) carriers worldwide. The liver is connected to the small intestine by the bile duct, which carries bile formed in the liver to the intestine. Nearly all of the blood that leaves the stomach and intestines must pass through the liver. Human intestines contain a wide diversity of microbes, collectively termed the 'gut microbiota'. Gut microbiota play a significant role in host metabolic processes and host immune modulation, and influence host development and physiology (organ development). Altered gut microbiota is a common complication in liver disease. Changes in intestinal microbiota seem to play an important role in induction and promotion of HBV-induced chronic liver disease progression, and specific species among the intestinal commensal bacteria may play either a pathogenic or a protective role in the development of HBV-induced chronic liver disease. Thus, the gut microbiome may represent fertile targets for prevention or management of HBV-induced chronic liver disease. Faecal microbiota transplantation (FMT) may be a useful therapy for HBV-related disease in the future. However, the data available in this field remain limited, and relevant scientific work has only just commenced. New technologies have enabled systematic studies of gut microbiota, and provided more realistic information about its composition and pathological variance. This review summarizes the cutting edge of research into the relationship between gut microbiota and HBV-induced chronic liver disease, and the future prospects of FMT therapy. Copyright © 2017 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

  16. Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases.

    PubMed

    Bessone, Fernando; Lucena, M I; Roma, Marcelo G; Stephens, Camilla; Medina-Cáliz, Inmaculada; Frider, Bernardo; Tsariktsian, Guillermo; Hernández, Nelia; Bruguera, Miquel; Gualano, Gisela; Fassio, Eduardo; Montero, Joaquín; Reggiardo, María V; Ferretti, Sebastián; Colombato, Luis; Tanno, Federico; Ferrer, Jaime; Zeno, Lelio; Tanno, Hugo; Andrade, Raúl J

    2016-02-01

    Cyproterone acetate (CPA), an anti-androgenic drug for prostate cancer, has been associated with drug-induced liver injury (DILI). We aim to expand the knowledge on the spectrum of phenotypes and outcomes of CPA-induced DILI. Twenty-two males (70 ± 8 years; range 54-83) developing liver damage as a result of CPA therapy (dose: 150 ± 50 mg/day; range 50-200) were included. Severity index and causality by RUCAM were assessed. From 1993 to 2013, 22 patients were retrieved. Latency was 163 ± 97 days. Most patients were symptomatic, showing hepatocellular injury (91%) and jaundice. Liver tests at onset were: ALT 18 ± 13 × ULN, ALP 0.7 ± 0.7 × ULN and total serum bilirubin 14 ± 10 mg/dl. International normalized ratio values higher than 1.5 were observed in 14 (66%) patients. Severity was mild in 1 case (4%), moderate in 7 (32%), severe in 11 (50%) and fatal in 3 (14%). Five patients developed ascitis, and four encephalopathy. One patient had a liver injury that resembled autoimmune hepatitis. Eleven (50%) were hospitalized. Nineteen patients recovered after CPA withdrawal, although three required steroid therapy (two of them had high ANA titres). Liver biopsy was performed in seven patients (two hepatocellular collapse, one submassive necrosis, two cholestatic hepatitis, one cirrhosis with iron overload and one autoimmune hepatitis). RUCAM category was 'highly probable' in 19 (86%), 'probable' in 1 (4%), and 'possible' in 2 (9%). CPA-induced liver injury is severe and can be fatal, and may occasionally resemble autoimmune DILI. The benefit/risk ratio of this drug should be thoroughly assessed in each patient. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Apitherapy products enhance the recovery of CCL4-induced hepatic damages in rats.

    PubMed

    Saral, Özlem; Yildiz, Oktay; Aliyazicioğlu, Rezzan; Yuluğ, Esin; Canpolat, Sinan; Öztürk, Ferhat; Kolayli, Sevgi

    2016-01-05

    Our objective was to identify the antioxidant properties of honeybee products from Turkey, chestnut honey, pollen, propolis, and royal jelly, and their hepatoprotective activity against CCl4-induced hepatic damage in rats. Animals were fed with honeybee products for 7 days following CCl4 injection. Development of liver damage and oxidative stress were monitored by measuring the activities of the enzymes alanine transaminase, aspartate transaminase, malondialdehyde, superoxide dismutase, and catalase. Antioxidant capacities of the bee products were identified using FRAP and DPPH assays, as well as by measuring total phenolic and flavonoid contents. The antioxidant activities of the honeybee products were highest in propolis, followed, in order, by pollen, honey, and royal jelly. Despite their different levels of antioxidant capacity, their roles in the prevention of liver damage induced by CCl4 were very similar, which can be explained through their bioavailability to the treated animals. Our results suggest that honey, propolis, pollen, and royal jelly significantly enhanced the healing of CCl4-induced liver damage, partially due to their antioxidant properties and bioavailability.

  18. Autoimmune-like hepatitis during masitinib therapy in an amyotrophic lateral sclerosis patient

    PubMed Central

    Salvado, Maria; Vargas, Victor; Vidal, Marta; Simon-Talero, Macarena; Camacho, Jessica; Gamez, Josep

    2015-01-01

    We report a case of acute severe hepatitis resulting from masitinib in a young amyotrophic lateral sclerosis patient. Hepatotoxicity induced by masitinib, a tyrosine kinase inhibitor, is usually transient with mild elevation of transaminases, although acute hepatitis has been not reported to date. The hepatitis was resolved after masitinib was discontinued and a combination of prednisone and azathioprine was started. The transaminases returned to baseline normal values five months later. This is the first case in the hepatitis literature associated with masitinib. The autoimmune role of this drug-induced liver injury is discussed. Physicians should be aware of this potential complication. PMID:26420975

  19. Lack of chemoprevention of dietary Agaricus blazei against rat colonic aberrant crypt foci.

    PubMed

    Ziliotto, L; Barbisan, L F; Rodrigues, M A M

    2008-06-01

    The mushroom Agaricus blazei (Ab) has been widely used in folk medicine to treat various diseases including cancer. No information is available on its possible protective effects on the development of colon cancer. The potential blocking effect of Ab intake on the initiation stage of colon carcinogenesis was investigated in a short-term (4-week) bioassay using aberrant crypt foci (ACF) as biomarker. Male Wistar rats were given four subcutaneous injections of the carcinogen 1,2-dimethylhydrazine (DMH, 40 mg/kg bw, twice a week), during 2 weeks to induce ACF. The diet containing Ab at 5% was given 2 weeks before and during carcinogen treatment to investigate the potential beneficial effects of this edible mushroom on DMH-induced ACF. All groups were killed at the end of the fourth week. The colons were analyzed for ACF formation in 1% methylene blue whole-mount preparations and for cell proliferation in histological sections immunohistochemically stained for the proliferating cell nuclear antigen (PCNA). All DMH-treated rats developed ACF mainly in the middle and distal colon. Agaricus blazei intake at 5% did not alter the number of ACF induced by DMH or the PCNA indices in the colonic mucosa. Thus, the results of the present study did not confirm a chemopreventive activity of Ab on the initiation stage of rat colon carcinogenesis.

  20. C/EBPα-dependent preneoplastic tumor foci are the origin of hepatocellular carcinoma and aggressive pediatric liver cancer.

    PubMed

    Cast, Ashley; Valanejad, Leila; Wright, Mary; Nguyen, Phuong; Gupta, Anita; Zhu, Liqin; Shin, Soona; Timchenko, Nikolai

    2018-05-01

    Recent publications show that classic hepatoblastoma (HBL) is the result of failure of hepatic stem cells to differentiate into hepatocytes, while hepatocellular carcinoma (HCC) is caused by the dedifferentiation of hepatocytes into cancer stem cells. However, the mechanisms of aggressive HBL and the mechanisms that cause dedifferentiation of hepatocytes into cancer stem cells are unknown. We found that, similar to HCC but opposite to classic HBL, aggressive HBL is the result of dedifferentiation of hepatocytes into cancer stem cells. In both cases of liver cancer, the dephosphorylation of tumor suppressor protein CCAAT/enhancer binding protein α (C/EBPα) at Ser193 (Ser190 in human protein) or mutation of Ser193 to Ala results in a modified protein with oncogenic activities. We have investigated liver cancer in a mouse model C/EBPα-S193A, in a large cohort of human HBL samples, and in Pten/p53 double knockout mice and found that these cancers are characterized by elevation of C/EBPα that is dephosphorylated at Ser190/193. We found that dephosphorylated C/EBPα creates preneoplastic foci with cancer stem cells that give rise to HCC and aggressive HBL. C/EBPα-dependent dedifferentiation of hepatocytes into cancer stem cells includes increased proliferation of hepatocytes, followed by generation of multinucleated hepatocytes and subsequent appearance of hepatocytes with delta-like 1 homolog-positive intranuclear inclusions. We further isolated C/EBPα-dependent multinucleated hepatocytes and found that they possess characteristics of tumor-initiating cells, including elevation of stem cell markers. C/EBPα-dependent cancer stem cells are observed in patients with aggressive HBL and in patients with a predisposition for liver cancer. The earliest steps of adult HCC and aggressive pediatric liver cancer have identical features that include conversion of the tumor suppressor C/EBPα into an oncogenic isoform, which further creates preneoplastic foci where

  1. Metformin ameliorates IL-6-induced hepatic insulin resistance via induction of orphan nuclear receptor small heterodimer partner (SHP) in mouse models.

    PubMed

    Kim, Y D; Kim, Y H; Cho, Y M; Kim, D K; Ahn, S W; Lee, J M; Chanda, D; Shong, M; Lee, C H; Choi, H S

    2012-05-01

    IL-6 is a proinflammatory cytokine associated with the pathogenesis of hepatic diseases. Metformin is an anti-diabetic drug used for the treatment of type 2 diabetes, and orphan nuclear receptor small heterodimer partner (SHP, also known as NR0B2), a transcriptional co-repressor, plays an important role in maintaining metabolic homeostasis. Here, we demonstrate that metformin-mediated activation of AMP-activated protein kinase (AMPK) increases SHP protein production and regulates IL-6-induced hepatic insulin resistance. We investigated metformin-mediated SHP production improved insulin resistance through the regulation of an IL-6-dependent pathway (involving signal transducer and activator of transcription 3 [STAT3] and suppressor of cytokine signalling 3 [SOCS3]) in both Shp knockdown and Shp null mice. IL-6-induced STAT3 transactivation and SOCS3 production were significantly repressed by metformin, adenoviral constitutively active AMPK (Ad-CA-AMPK), and adenoviral SHP (Ad-SHP), but not in Shp knockdown, or with the adenoviral dominant negative form of AMPK (Ad-DN-AMPK). Chromatin immunoprecipitation (ChIP), co-immunoprecipitation (Co-IP) and protein localisation studies showed that SHP inhibits DNA binding of STAT3 on the Socs3 gene promoter via interaction and colocalisation within the nucleus. Upregulation of inflammatory genes and downregulation of hepatic insulin signalling by acute IL-6 treatment were observed in wild-type mice but not in Shp null mice. Finally, chronic IL-6 exposure caused hepatic insulin resistance, leading to impaired insulin tolerance and elevated gluconeogenesis, and these phenomena were aggravated in Shp null mice. Our results demonstrate that SHP upregulation by metformin may prevent hepatic disorders by regulating the IL-6-dependent pathway, and that this pathway can help to ameliorate the pathogenesis of cytokine-mediated metabolic dysfunction.

  2. Fluoride-induced iron overload contributes to hepatic oxidative damage in mouse and the protective role of Grape seed proanthocyanidin extract.

    PubMed

    Niu, Qiang; He, Ping; Xu, Shangzhi; Ma, Ruling; Ding, Yusong; Mu, Lati; Li, Shugang

    2018-01-01

    Emerging evidence has demonstrated that iron overload plays an important role in oxidative stress in the liver. This study aimed to explore whether fluoride-induced hepatic oxidative stress is associated with iron overload and whether grape seed proanthocyanidin extract (GSPE) alleviates oxidative stress by reducing iron overload. Forty Kunming male mice were randomly divided into 4 groups and treated for 5 weeks with distilled water (control), sodium fluoride (NaF) (100 mg/L), GSPE (400 mg/kg bw), or NaF (100 mg/L) + GSPE (400 mg/kg bw). Mice exposed to NaF showed typical poisoning changes of morphology, increased aspartate aminotransferase and alanine aminotransferase activities in the liver. NaF treatment also increased MDA accumulation, decreased GSH-Px, SOD and T-AOC levels in liver, indicative of oxidative stress. Intriguingly, all these detrimental effects were alleviated by GSPE. Further study revealed that NaF induced disorders of iron metabolism, as manifested by elevated iron level with increased hepcidin but decreased ferroportin expression, which contributed to hepatic oxidative stress. Importantly, the iron dysregulation induced by NaF could be normalized by GSPE. Collectively, these data provide a novel insight into mechanisms underlying fluorosis and highlight the potential of GSPE as a naturally occurring prophylactic treatment for fluoride-induced hepatotoxicity associated with iron overload.

  3. An unusual cause of febrile hepatitis

    PubMed Central

    Stelzer, Teresa; Kohler, Sibylle; Marques Maggio, Ewerton; Heuss, Ludwig Theodor

    2015-01-01

    We describe the case of a 51-year-old man with recently diagnosed ulcerative colitis who developed fever and elevated liver enzymes as well as cholestasis a few weeks after starting treatment with mesalazine. As no obvious cause was found and fever persisted, liver biopsy was performed and revealed granulomatous hepatitis. The patient recovered completely after cessation of mesalazine, so that a drug-induced granulomatous hepatitis after exclusion of other differential diagnoses in an extensive work up was assumed. The present case demonstrates that even though drug-induced liver injury due to mesalazine is rare, it should be considered in unclear cases and lead to prompt discontinuation of mesalazine. PMID:26113581

  4. 18F-FAC PET selectively images hepatic infiltrating CD4 and CD8 T cells in a mouse model of autoimmune hepatitis.

    PubMed

    Salas, Jessica R; Chen, Bao Ying; Wong, Alicia; Cheng, Donghui; Van Arnam, John S; Witte, Owen N; Clark, Peter M

    2018-04-26

    Immune cell-mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation ( 18 F-FDG and 18 F-FAC) and hepatocyte biology ( 18 F-DFA) can visualize and quantify hepatic infiltrating immune cells and hepatocyte inflammation, respectively, in a preclinical model of autoimmune hepatitis. Methods: Mice treated with Concanavalin A (ConA) to induce a model of autoimmune hepatitis or vehicle were imaged with 18 F-FDG, 18 F-FAC, and 18 F-DFA PET. Immunohistochemistry, digital autoradiography, and ex vivo accumulation assays were used to localize areas of altered radiotracer accumulation in the liver. For comparison, mice treated with an adenovirus to induce a viral hepatitis or vehicle were imaged with 18 F-FDG, 18 F-FAC, and 18 F-DFA PET. 18 F-FAC PET was performed on mice treated with ConA, and vehicle or dexamethasone. Biopsy samples of patients suffering from autoimmune hepatitis were immunostained for deoxycytidine kinase (dCK). Results: Hepatic accumulation of 18 F-FDG and 18 F-FAC was 173% and 61% higher, respectively, and hepatic accumulation of 18 F-DFA was 41% lower in a mouse model of autoimmune hepatitis compared to control mice. Increased hepatic 18 F-FDG accumulation was localized to infiltrating leukocytes and inflamed sinusoidal endothelial cells, increased hepatic 18 F-FAC accumulation was concentrated in infiltrating CD4 and CD8 cells, and decreased hepatic 18 F-DFA accumulation was apparent in hepatocytes throughout the liver. In contrast, viral hepatitis increased hepatic 18 F-FDG accumulation by 109% and decreased hepatic 18 F-DFA accumulation by 20% but had no effect on hepatic 18 F-FAC accumulation (non-significant 2% decrease). 18 F-FAC PET provided a non-invasive biomarker of the efficacy of

  5. [Experimental study of active ingredients group in liver protection from erzhi wan on acute hepatic injury induced by CCl4 in mice].

    PubMed

    Yan, Bing; Cai, Xiujiang; Yao, Weifeng; Zhang, Li; Huang, Meiyan; Ding, Anwei

    2012-05-01

    To study the active ingredients in liver protection from Erzhi Wan (AIEP) on acute hepatic injury induced by carbon tetrachloride (CCl4) in mice. Sixty Kunming mice were randomly divided into six groups: the normal group, the model group, bifendate group (150 mg x kg(-1)), high AIEP group (19.8 g x kg(-1)), middle AIEP group (13.2 g x kg(-1)) and low AIEP group (6.6 g x kg(-1)). The treatment groups were orally administered once per day for 7 d separately, whereas the normal and model groups were orally administered with saline. Except normal rats, all the other rats were injected intraperitoneally CCl4 20 mL x kg(-1) once. The rats were sacrificed 16 h after CCl4 administration. Serum and liver samples were collected for analysis. The acute hepatic injury model was prepared by CCl4 injected intraperitoneally. Then, the therapeutic effects of AIEP on the model were evaluated by the activity determination of serum alanine aminotransferase and aspirate aminotransferase (ALT and AST), superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in liver,and the hepatic pathohistological changes following the treatment. The activities of ALT and AST and the MDA content in liver was significantly increased and the activity of SOD was largely inhibited in the animals of modeling group. Following the treatment with AIEP, ALT and AST activities and MDA content were significantly reduced and SOD activity was obviously increased in the mice of treatment group. Furthermore, AIEP could ameliorate the hepatic pathological changes. AIEP have protective effects on acute hepatic injury induced by CCL4 in mice, and are the effect of the liver protecting active sites.

  6. Mouse Hepatitis Virus Infection Induces a Toll-Like Receptor 2-Dependent Activation of Inflammatory Functions in Liver Sinusoidal Endothelial Cells during Acute Hepatitis

    PubMed Central

    Bleau, Christian; Filliol, Aveline; Samson, Michel

    2016-01-01

    ABSTRACT Under physiological conditions, the liver sinusoidal endothelial cells (LSECs) mediate hepatic immune tolerance toward self or foreign antigens through constitutive expression of anti-inflammatory mediators. However, upon viral infection or Toll-like receptor 2 (TLR2) activation, LSECs can achieve proinflammatory functions, but their role in hepatic inflammation during acute viral hepatitis is unknown. Using the highly virulent mouse hepatitis virus type 3 (MHV3) and the attenuated variants 51.6-MHV3 and YAC-MHV3, exhibiting lower tropism for LSECs, we investigated in vivo and in vitro the consequence of LSEC infection on their proinflammatory profiles and the aggravation of acute hepatitis process. In vivo infection with virulent MHV3, in comparison to attenuated strains, resulted in fulminant hepatitis associated with higher hepatic viral load, tissue necrosis, and levels of inflammatory mediators and earlier recruitment of inflammatory cells. Such hepatic inflammatory disorders correlated with disturbed production of interleukin-10 (IL-10) and vascular factors by LSECs. We next showed in vitro that infection of LSECs by the virulent MHV3 strain altered their production of anti-inflammatory cytokines and promoted higher release of proinflammatory and procoagulant factors and earlier cell damage than infection by attenuated strains. This higher replication and proinflammatory activation in LSECs by the virulent MHV3 strain was associated with a specific activation of TLR2 signaling by the virus. We provide evidence that TLR2 activation of LSCEs by MHV3 is an aggravating factor of hepatic inflammation and correlates with the severity of hepatitis. Taken together, these results indicate that preservation of the immunotolerant properties of LSECs during acute viral hepatitis is imperative in order to limit hepatic inflammation and damage. IMPORTANCE Viral hepatitis B and C infections are serious health problems affecting over 350 million and 170 million

  7. Mouse Hepatitis Virus Infection Induces a Toll-Like Receptor 2-Dependent Activation of Inflammatory Functions in Liver Sinusoidal Endothelial Cells during Acute Hepatitis.

    PubMed

    Bleau, Christian; Filliol, Aveline; Samson, Michel; Lamontagne, Lucie

    2016-10-15

    Under physiological conditions, the liver sinusoidal endothelial cells (LSECs) mediate hepatic immune tolerance toward self or foreign antigens through constitutive expression of anti-inflammatory mediators. However, upon viral infection or Toll-like receptor 2 (TLR2) activation, LSECs can achieve proinflammatory functions, but their role in hepatic inflammation during acute viral hepatitis is unknown. Using the highly virulent mouse hepatitis virus type 3 (MHV3) and the attenuated variants 51.6-MHV3 and YAC-MHV3, exhibiting lower tropism for LSECs, we investigated in vivo and in vitro the consequence of LSEC infection on their proinflammatory profiles and the aggravation of acute hepatitis process. In vivo infection with virulent MHV3, in comparison to attenuated strains, resulted in fulminant hepatitis associated with higher hepatic viral load, tissue necrosis, and levels of inflammatory mediators and earlier recruitment of inflammatory cells. Such hepatic inflammatory disorders correlated with disturbed production of interleukin-10 (IL-10) and vascular factors by LSECs. We next showed in vitro that infection of LSECs by the virulent MHV3 strain altered their production of anti-inflammatory cytokines and promoted higher release of proinflammatory and procoagulant factors and earlier cell damage than infection by attenuated strains. This higher replication and proinflammatory activation in LSECs by the virulent MHV3 strain was associated with a specific activation of TLR2 signaling by the virus. We provide evidence that TLR2 activation of LSCEs by MHV3 is an aggravating factor of hepatic inflammation and correlates with the severity of hepatitis. Taken together, these results indicate that preservation of the immunotolerant properties of LSECs during acute viral hepatitis is imperative in order to limit hepatic inflammation and damage. Viral hepatitis B and C infections are serious health problems affecting over 350 million and 170 million people worldwide

  8. Complementary Effects of Interleukin-15 and Alpha Interferon Induce Immunity in Hepatitis B Virus Transgenic Mice.

    PubMed

    Di Scala, Marianna; Otano, Itziar; Gil-Fariña, Irene; Vanrell, Lucia; Hommel, Mirja; Olagüe, Cristina; Vales, Africa; Galarraga, Miguel; Guembe, Laura; Ortiz de Solorzano, Carlos; Ghosh, Indrajit; Maini, Mala K; Prieto, Jesús; González-Aseguinolaza, Gloria

    2016-10-01

    In chronic hepatitis B (CHB), failure to control hepatitis B virus (HBV) is associated with T cell dysfunction. HBV transgenic mice mirror many features of the human disease, including T cell unresponsiveness, and thus represent an appropriate model in which to test novel therapeutic strategies. To date, the tolerant state of CD8(+) T cells in these animals could be altered only by strong immunogens or by immunization with HBV antigen-pulsed dendritic cells; however, the effectors induced were unable to suppress viral gene expression or replication. Because of the known stimulatory properties of alpha interferon (IFN-α) and interleukin-15 (IL-15), this study explored the therapeutic potential of liver-directed gene transfer of these cytokines in a murine model of CHB using adeno-associated virus (AAV) delivery. This combination not only resulted in a reduction in the viral load in the liver and the induction of an antibody response but also gave rise to functional and specific CD8(+) immunity. Furthermore, when splenic and intrahepatic lymphocytes from IFN-α- and IL-15-treated animals were transferred to new HBV carriers, partial antiviral immunity was achieved. In contrast to previous observations made using either cytokine alone, markedly attenuated PD-L1 induction in hepatic tissue was observed upon coadministration. An initial study with CHB patient samples also gave promising results. Hence, we demonstrated synergy between two stimulating cytokines, IL-15 and IFN-α, which, given together, constitute a potent approach to significantly enhance the CD8(+) T cell response in a state of immune hyporesponsiveness. Such an approach may be useful for treating chronic viral infections and neoplastic conditions. With 350 million people affected worldwide and 600,000 annual deaths due to HBV-induced liver cirrhosis and/or hepatocellular carcinoma, chronic hepatitis B (CHB) is a major health problem. However, current treatment options are costly and not very effective

  9. Inhibitory effect of natural coumarin compounds, esculetin and esculin, on oxidative DNA damage and formation of aberrant crypt foci and tumors induced by 1,2-dimethylhydrazine in rat colons.

    PubMed

    Kaneko, Takao; Tahara, Shoichi; Takabayashi, Fumiyo

    2007-11-01

    The effects of esculetin (6,7-dihydroxycoumarin) and its 6-glycoside, esculin, on 8-oxo-2'-deoxyguanosine (8-oxodG) formation and carcinogenesis induced by a chemical carcinogen, 1,2-dimethylhydrazine (DMH), were examined in the colons of male Fischer 344 rats. Animals were given water containing esculetin or esculin for 7 d before subcutaneous injection of DMH (20 mg/kg body wt), killed 24 h after DMH treatment, and the levels of thiobarbituric acid reactive substances (TBARS) and 8-oxodG in the colons were determined. Both esculetin and esculin suppressed significantly the DMH-induced increases in 8-oxodG and TBARS in rat colon mucosa. We further investigated the modifying effect of esculin intake on the development of DMH-induced colonic aberrant crypt foci (ACF). Animals were given DMH once a week for 4 weeks to induce ACF. They then received water containing esculin ad libitum for 5 weeks (initiation phase) or 11 weeks after DMH treatment (post-initiation phase). Animals in the positive control group received tap water throughout the experiment. At the end of the experiment (16 weeks), the ingestion of esculin during the initiation phase significantly reduced the incidence of gross tumors, the number of ACF per rat and the mean number of AC per focus, while the esculin treatment during the post-initiation phase significantly decreased only the number of ACF per rat. These results suggest that esculin intake has an inhibitory effect on DMH-induced oxidative DNA damage and carcinogenesis in rat colons.

  10. Primary Seronegative but Molecularly Evident Hepadnaviral Infection Engages Liver and Induces Hepatocarcinoma in the Woodchuck Model of Hepatitis B

    PubMed Central

    Mulrooney-Cousins, Patricia M.; Chauhan, Ranjit; Churchill, Norma D.; Michalak, Tomasz I.

    2014-01-01

    Hepadnavirus at very low doses establishes in woodchucks asymptomatic, serologically undetectable but molecularly evident persistent infection. This primary occult infection (POI) preferentially engages the immune system and initiates virus-specific T cell response in the absence of antiviral antibody induction. The current study aimed to determine whether POI with time may culminate in serologically identifiable infection and hepatitis, and what are, if any, its pathological consequences. Juvenile woodchucks were intravenously injected with inocula containing 10 or 100 virions of woodchuck hepatitis virus (WHV) to induce POI and followed for life or up to 5.5 years thereafter. All 10 animals established molecularly detectable infection with virus DNA in serum (<100–200 copies/mL) and in circulating lymphoid cells, but serum WHV surface antigen and antibodies to WHV core antigen remained undetectable for life. By approximately 2.5–3.5 years post-infection, circulating virus transiently increased to 103 copies/mL and virus replication became detectable in the livers, but serological markers of infection and biochemical or histological evidence of hepatitis remained undetectable. Nonetheless, typical hepatocellular carcinoma (HCC) developed in 2/10 animals. WHV DNA integration into hepatic and lymphatic system genomes was identified in 9/10 animals. Virus recovered from the liver virus-negative or virus-positive phases of POI displayed the wild-type sequence and transmitted infection to healthy woodchucks causing hepatitis and HCC. In summary, for the first time, our data demonstrate that an asymptomatic hepadnaviral persistence initiated by very small amounts of otherwise pathogenic virus, advancing in the absence of traditional serological markers of infection and hepatitis, coincides with virus DNA integration into the host's hepatic and immune system genomes, retains liver pro-oncogenic potency and is capable of transmitting liver pathogenic infection. This

  11. Evidence supporting pre-radiation elimination of oral foci of infection in head and neck cancer patients to prevent oral sequelae. A systematic review.

    PubMed

    Schuurhuis, Jennifer M; Stokman, Monique A; Witjes, Max J H; Dijkstra, Pieter U; Vissink, Arjan; Spijkervet, Frederik K L

    2015-03-01

    Pre-radiation dental screening of head-neck cancer patients aims to identify and eliminate oral foci of infection to prevent post-radiation oral problems. The evidence for the efficacy of dental screening is unclear. In this systematic review, we analyzed available evidence on the efficacy of pre-radiation elimination of oral foci of infection in preventing oral sequelae. A search was conducted (MEDLINE/EMBASE) for papers published up to May 2014. Papers on head-neck cancer patients subjected to pre-radiation dental screening, (chemo)radiation and oral follow-up were included. Of the 1770 identified papers, 20 studies fulfilled the inclusion criteria of which 17 were retrospective. A great heterogeneity in patient groups, dental screening techniques, definitions of oral foci of infection and techniques for eliminating foci was found. Most papers lacked essential details on how dental screening was performed and a clear definition of an oral focus of infection. The evidence for efficacy of elimination of oral foci of infection to prevent post-radiotherapy oral sequelae was inconclusive. Consequently, the efficacy of pre-radiation elimination of oral foci of infection remains unclear. No conclusions can be drawn about a definition of an oral focus of infection and whether pre-radiation elimination of these foci should be mandatory. We therefore suggest prospective studies with well-defined criteria for oral foci of infection, a clear description of which foci were eliminated and how, a detailed description of pre-radiation dental screening, clearly described patient and tumor characteristics, and a detailed dental history and dental status. Subsequently, oral problems that occur post-radiation should be systematically recorded. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Capsaicin affects brain function in a model of hepatic encephalopathy associated with fulminant hepatic failure in mice

    PubMed Central

    Avraham, Y; Grigoriadis, NC; Magen, I; Poutahidis, T; Vorobiav, L; Zolotarev, O; Ilan, Y; Mechoulam, R; Berry, EM

    2009-01-01

    Background and purpose: Hepatic encephalopathy is a neuropsychiatric syndrome caused by liver failure. In view of the effects of cannabinoids in a thioacetamide-induced model of hepatic encephalopathy and liver disease and the beneficial effect of capsaicin (a TRPV1 agonist) in liver disease, we assumed that capsaicin may also affect hepatic encephalopathy. Experimental approach: Fulminant hepatic failure was induced in mice by thioacetamide and 24 h later, the animals were injected with one of the following compound(s): 2-arachidonoylglycerol (CB1, CB2 and TRPV1 receptor agonist); HU308 (CB2 receptor agonist), SR141716A (CB1 receptor antagonist); SR141716A+2-arachidonoylglycerol; SR144528 (CB2 receptor antagonist); capsaicin; and capsazepine (TRPV1 receptor agonist and antagonist respectively). Their neurological effects were evaluated on the basis of activity in the open field, cognitive function in an eight-arm maze and a neurological severity score. The mice were killed 3 or 14 days after thioacetamide administration. 2-arachidonoylglycerol and 5-hydroxytryptamine (5-HT) levels were determined by gas chromatography-mass spectrometry and high-performance liquid chromatography with electrochemical detection, respectively. Results: Capsaicin had a neuroprotective effect in this animal model as shown by the neurological score, activity and cognitive function. The effect of capsaicin was blocked by capsazepine. Thioacetamide induced astrogliosis in the hippocampus and the cerebellum and raised brain 5-hydroxytryptamine levels, which were decreased by capsaicin, SR141716A and HU-308. Thioacetamide lowered brain 2-arachidonoylglycerol levels, an effect reversed by capsaicin. Conclusions: Capsaicin improved both liver and brain dysfunction caused by thioacetamide, suggesting that both the endocannabinoid and the vanilloid systems play important roles in hepatic encephalopathy. Modulation of these systems may have therapeutic value. PMID:19764982

  13. Hexanucleotide Repeats in ALS/FTD Form Length-Dependent RNA Foci, Sequester RNA Binding Proteins, and Are Neurotoxic

    PubMed Central

    Lee, Youn-Bok; Chen, Han-Jou; Peres, João N.; Gomez-Deza, Jorge; Attig, Jan; Štalekar, Maja; Troakes, Claire; Nishimura, Agnes L.; Scotter, Emma L.; Vance, Caroline; Adachi, Yoshitsugu; Sardone, Valentina; Miller, Jack W.; Smith, Bradley N.; Gallo, Jean-Marc; Ule, Jernej; Hirth, Frank; Rogelj, Boris; Houart, Corinne; Shaw, Christopher E.

    2013-01-01

    Summary The GGGGCC (G4C2) intronic repeat expansion within C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Intranuclear neuronal RNA foci have been observed in ALS and FTD tissues, suggesting that G4C2 RNA may be toxic. Here, we demonstrate that the expression of 38× and 72× G4C2 repeats form intranuclear RNA foci that initiate apoptotic cell death in neuronal cell lines and zebrafish embryos. The foci colocalize with a subset of RNA binding proteins, including SF2, SC35, and hnRNP-H in transfected cells. Only hnRNP-H binds directly to G4C2 repeats following RNA immunoprecipitation, and only hnRNP-H colocalizes with 70% of G4C2 RNA foci detected in C9ORF72 mutant ALS and FTD brain tissues. We show that expanded G4C2 repeats are potently neurotoxic and bind hnRNP-H and other RNA binding proteins. We propose that RNA toxicity and protein sequestration may disrupt RNA processing and contribute to neurodegeneration. PMID:24290757

  14. The Heteroaryldihydropyrimidine Bay 38-7690 Induces Hepatitis B Virus Core Protein Aggregates Associated with Promyelocytic Leukemia Nuclear Bodies in Infected Cells.

    PubMed

    Huber, Andrew D; Wolf, Jennifer J; Liu, Dandan; Gres, Anna T; Tang, Jing; Boschert, Kelsey N; Puray-Chavez, Maritza N; Pineda, Dallas L; Laughlin, Thomas G; Coonrod, Emily M; Yang, Qiongying; Ji, Juan; Kirby, Karen A; Wang, Zhengqiang; Sarafianos, Stefan G

    2018-04-25

    Heteroaryldihydropyrimidines (HAPs) are compounds that inhibit hepatitis B virus (HBV) replication by modulating viral capsid assembly. While their biophysical effects on capsid assembly in vitro have been previously studied, the effect of HAP treatment on capsid protein (Cp) in individual HBV-infected cells remains unknown. We report here that the HAP Bay 38-7690 promotes aggregation of recombinant Cp in vitro and causes a time- and dose-dependent decrease of Cp in infected cells, consistent with previously studied HAPs. Interestingly, immunofluorescence analysis showed Cp aggregating in nuclear foci of Bay 38-7690-treated infected cells in a time- and dose-dependent manner. We found these foci to be associated with promyelocytic leukemia (PML) nuclear bodies (NBs), which are structures that affect many cellular functions, including DNA damage response, transcription, apoptosis, and antiviral responses. Cp aggregation is not an artifact of the cell system used, as it is observed in HBV-expressing HepAD38 cells, in HepG2 cells transfected with an HBV-expressing plasmid, and in HepG2-NTCP cells infected with HBV. Use of a Cp overexpression vector without HBV sequences shows that aggregation is independent of viral replication, and use of an HBV-expressing plasmid harboring a HAP resistance mutation in Cp abrogated the aggregation, demonstrating that the effect is due to direct compound-Cp interactions. These studies provide novel insight into the effects of HAP-based treatment at a single-cell level. IMPORTANCE Despite the availability of effective vaccines and treatments, HBV remains a significant global health concern, with more than 240 million individuals chronically infected. Current treatments are highly effective at controlling viral replication and disease progression but rarely cure infections. Therefore, much emphasis is being placed on finding therapeutics with new drug targets, such as viral gene expression, covalently closed circular DNA formation and

  15. Fasting-Induced Changes in Hepatic P450 Mediated Drug Metabolism Are Largely Independent of the Constitutive Androstane Receptor CAR.

    PubMed

    de Vries, E M; Lammers, L A; Achterbergh, R; Klümpen, H-J; Mathot, R A A; Boelen, A; Romijn, J A

    2016-01-01

    Hepatic drug metabolism by cytochrome P450 enzymes is altered by the nutritional status of patients. The expression of P450 enzymes is partly regulated by the constitutive androstane receptor (CAR). Fasting regulates the expression of both P450 enzymes and CAR and affects hepatic drug clearance. We hypothesized that the fasting-induced alterations in P450 mediated drug clearance are mediated by CAR. To investigate this we used a drug cocktail validated in humans consisting of five widely prescribed drugs as probes for specific P450 enzymes: caffeine (CYP1A2), metoprolol (CYP2D6), omeprazole (CYP2C19), midazolam (CYP3A4) and s-warfarin (CYP2C9). This cocktail was administered to wild type (WT, C57Bl/6) mice or mice deficient for CAR (CAR-/-) that were either fed ad libitum or fasted for 24 hours. Blood was sampled at predefined intervals and drug concentrations were measured as well as hepatic mRNA expression of homologous/orthologous P450 enzymes (Cyp1a2, Cyp2d22, Cyp3a11, Cyp2c37, Cyp2c38 and Cyp2c65). Fasting decreased Cyp1a2 and Cyp2d22 expression and increased Cyp3a11 and Cyp2c38 expression in both WT and CAR-/- mice. The decrease in Cyp1a2 was diminished in CAR-/- in comparison with WT mice. Basal Cyp2c37 expression was lower in CAR-/- compared to WT mice. Fasting decreased the clearance of all drugs tested in both WT and CAR-/- mice. The absence of CAR was associated with an decrease in the clearance of omeprazole, metoprolol and midazolam in fed mice. The fasting-induced reduction in clearance of s-warfarin was greater in WT than in CAR-/-. The changes in drug clearance correlated with the expression pattern of the specific P450 enzymes in case of Cyp1a2-caffeine and Cyp2c37-omeprazole. We conclude that CAR is important for hepatic clearance of several widely prescribed drugs metabolized by P450 enzymes. However the fasting-induced alterations in P450 mediated drug clearance are largely independent of CAR.

  16. PKCλ in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity

    PubMed Central

    Matsumoto, Michihiro; Ogawa, Wataru; Akimoto, Kazunori; Inoue, Hiroshi; Miyake, Kazuaki; Furukawa, Kensuke; Hayashi, Yoshitake; Iguchi, Haruhisa; Matsuki, Yasushi; Hiramatsu, Ryuji; Shimano, Hitoshi; Yamada, Nobuhiro; Ohno, Shigeo; Kasuga, Masato; Noda, Tetsuo

    2003-01-01

    PKCλ is implicated as a downstream effector of PI3K in insulin action. We show here that mice that lack PKCλ specifically in the liver (L-λKO mice), produced with the use of the Cre-loxP system, exhibit increased insulin sensitivity as well as a decreased triglyceride content and reduced expression of the sterol regulatory element–binding protein-1c (SREBP-1c) gene in the liver. Induction of the hepatic expression of Srebp1c and of its target genes involved in fatty acid/triglyceride synthesis by fasting and refeeding or by hepatic expression of an active form of PI3K was inhibited in L-λKO mice compared with that in control animals. Expression of Srebp1c induced by insulin or by active PI3K in primary cultured rat hepatocytes was inhibited by a dominant-negative form of PKCλ and was mimicked by overexpression of WT PKCλ. Restoration of PKCλ expression in the liver of L-λKO mice with the use of adenovirus-mediated gene transfer corrected the metabolic abnormalities of these animals. Hepatic PKCλ is thus a determinant of hepatic lipid content and whole-body insulin sensitivity. PMID:12975478

  17. Plum polyphenols inhibit colorectal aberrant crypt foci formation in rats: potential role of the miR-143/protein kinase B/mammalian target of rapamycin axis.

    PubMed

    Banerjee, Nivedita; Kim, Hyemee; Talcott, Stephen T; Turner, Nancy D; Byrne, David H; Mertens-Talcott, Susanne U

    2016-10-01

    The nutritional prevention of aberrant crypt foci by polyphenols may be a crucial step to dietary cancer prevention. The objective of this study was to determine the underlying mechanisms that contribute to the anti-inflammatory and antitumorigenic properties of plum (Prunus salicina L.) polyphenols, including chlorogenic acid and neochlorogenic acid, in azoxymethane (AOM)-treated rats. The hypothesis was that plum polyphenolics suppress AOM-induced aberrant crypt foci formation through alterations in the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and relative micro-RNA expressions. Sprague-Dawley rats (n=10/group) received plum beverage (1346mg gallic acid equivalents/L) or a control beverage ad libitum for 10 weeks with subcutaneous injections of AOM (15mg/kg) at weeks 2 and 3. Results show that the consumption of the plum beverage decreased the number of dysplastic aberrant crypt foci by 48% (P<.05) and lowered proliferation of mucosal cells by 24% (P<.05). The plum beverage decreased the activity of glutathione peroxidase, superoxide dismutase, and catalase in mucosal scrapings, as well as the superoxide dismutase activity in serum. The results were accompanied by a down-regulation of proinflammatory enzymes nuclear factor κB, nitric oxide synthase, cyclooxygenase-2, and vascular cell adhesion molecule 1 messenger RNA. Plum inhibited the expression of AKT and mTOR messenger RNA, phosphorylated AKT, mTOR, and hypoxia-inducible factor-1α protein levels, and the ratio of the phosphorylated/total protein expression of mTOR. Also, the plum beverage increased the expression of miR-143, which is involved in the regulation of AKT. These results suggest that plum polyphenols may exhibit a chemopreventive potential against colon carcinogenesis by impacting the AKT/mTOR pathway and miR-143. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Ascorbic acid deficiency decreases hepatic cytochrome P-450, especially CYP2B1/2B2, and simultaneously induces heme oxygenase-1 gene expression in scurvy-prone ODS rats.

    PubMed

    Kobayashi, Misato; Hoshinaga, Yukiko; Miura, Natsuko; Tokuda, Yuki; Shigeoka, Shigeru; Murai, Atsushi; Horio, Fumihiko

    2014-01-01

    The mechanisms underlying the decrease in hepatic cytochrome P-450 (CYP) content in ascorbic acid deficiency was investigated in scurvy-prone ODS rats. First, male ODS rats were fed a diet containing sufficient ascorbic acid (control) or a diet without ascorbic acid (deficient) for 18 days, with or without the intraperitoneal injection of phenobarbital. Ascorbic acid deficiency decreased hepatic microsomal total CYP content, CYP2B1/2B2 protein, and mitochondrial cytochrome oxidase (COX) complex IV subunit I protein, and simultaneously increased heme oxygenase-1 protein in microsomes and mitochondria. Next, heme oxygenase-1 inducers, that is lipopolysaccharide and hemin, were administered to phenobaribital-treated ODS rats fed sufficient ascorbic acid. The administration of these inducers decreased hepatic microsomal total CYP content, CYP2B1/2B2 protein, and mitochondrial COX complex IV subunit I protein. These results suggested that the stimulation of hepatic heme oxygenase-1 expression by ascorbic acid deficiency caused the decrease in CYP content in liver.

  19. High-Fat Diet Increased Renal and Hepatic Oxidative Stress Induced by Vanadium of Wistar Rat.

    PubMed

    Wang, J P; Cui, R Y; Zhang, K Y; Ding, X M; Luo, Y H; Bai, S P; Zeng, Q F; Xuan, Y; Su, Z W

    2016-04-01

    The study was conducted to assess the effect of vanadium (V) in high-fat diet on the liver and kidney of rats in a 5-week trial. Seventy-two female Wistar rats (BW = 95 ± 5 g) were randomly allotted into eight groups. Groups I, II, III, and IV obtained low-fat diet containing 0, 3, 15, and 30 mg/kg V, and V, VI, VII, and VIII groups received the respective vanadium doses with high-fat diet, respectively. There were lesions in the liver and kidney of V, VI, VII, and VIII groups, granular degeneration and vacuolar degeneration were observed in the renal tubular and glomerulus epithelial cells, and hepatocytes showed granular degeneration and vacuolar degeneration. Supplemented high-fat diet with vanadium was shown to decrease (P < 0.05) activities of superoxide dismutase, total antioxidant capacity, glutathione-S transferase, and NAD(P)H/quinone oxidoreductase 1 (NQO1) and increase malondialdehyde content in the liver and kidney. The relative expression of hepatic nuclear factor erythroid 2-related factor 2 (Nrf-2) and NQO1 mRNA was downregulated by V addition and high-fat diet, and the effect of V was more pronounced in high-fat diet (interaction, P < 0.05), with VIII group having the lowest mRNA expression of Nrf-2 and NQO1 in the liver and kidney. In conclusion, it suggested that dietary vanadium ranging from 15 to 30 mg/kg could lead to oxidative damage and vanadium accumulation in the liver and kidney, which caused renal and hepatic toxicity. The high-fat diet enhanced vanadium-induced hepatic and renal damage, and the mechanism was related to the modulation of the hepatic and renal mRNA expression of Nrf-2 and NQO1.

  20. Nicotine induces fibrogenic changes in human liver via nicotinic acetylcholine receptors expressed on hepatic stellate cells

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Soeda, Junpei; Morgan, Maelle; McKee, Chad

    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 inmore » 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

  1. Protective effects of a natural herbal compound quercetin against snake venom-induced hepatic and renal toxicities in rats.

    PubMed

    Al-Asmari, Abdulrahman K; Khan, Haseeb A; Manthiri, Rajamohamed A; Al-Khlaiwi, Ahmad A; Al-Asmari, Bayan A; Ibrahim, Khalid E

    2018-05-08

    Echis pyramidum is a highly poisonous viper snake. Previous studies have shown acute phase hepatic and renal toxicities of Echis pyramidum venom (EPV) in rats. This study reports the protective effects of a natural herbal compound quercetin (QRC) on EPV-induced hepatic and renal toxicities in rats. A singly injection of EPV (4.76 mg/kg) caused significant increase in serum biomarkers of liver and kidney function. Pre-treatment of QRC (10 mg/kg) significantly reduced the toxic effects of EPV on functional impairment in liver and kidneys of rats. Administration of QRC also reversed EPV-induced increase in lipid peroxidation and decrease in total thiols. The histopathology of liver showed fat accumulation, focal degeneration and cytoplasmic vacuolation of hepatocytes in EPV treated rats. EPV also caused renal tubular dilation and focal atrophy of glomerular tufts in rat kidneys. Administration of QRC prevented EPV-induced structural tissue damage in liver and kidneys of rats. In conclusion, QRC significantly inhibited the acute phase toxic effects of EPV on liver and kidneys of rats by preventing the oxidative stress in these organs. QRC is also known for its anti-inflammatory, anti-edema, anti-hemorrhagic and PLA2-inhibitory properties and therefore may be regarded as a multi-action antidote against snake venom toxicity. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.

    PubMed

    Zhang, Fuyang; Zhao, Shihao; Yan, Wenjun; Xia, Yunlong; Chen, Xiyao; Wang, Wei; Zhang, Jinglong; Gao, Chao; Peng, Cheng; Yan, Feng; Zhao, Huishou; Lian, Kun; Lee, Yan; Zhang, Ling; Lau, Wayne Bond; Ma, Xinliang; Tao, Ling

    2016-11-01

    The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD+BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD+BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte. Copyright © 2016. Published by Elsevier

  3. HPMC supplementation reduces fatty liver, intestinal permeability, and insulin resistance with altered hepatic gene expression in diet-induced obese mice

    USDA-ARS?s Scientific Manuscript database

    The effects of hydroxypropyl methylcellulose (HPMC), a highly viscous nonfermentable soluble dietary fiber, were evaluated on global hepatic gene profiles, steatosis and insulin resistance in high-fat (HF) diet-induced obese (DIO) mice. DIO C57BL/6J mice were fed a HF diet supplemented with either ...

  4. UV-induced replication arrest in the xeroderma pigmentosum variant leads to DNA double-strand breaks, γ-H2AX formation, and Mre11 relocalization

    PubMed Central

    Limoli, Charles L.; Giedzinski, Erich; Bonner, William M.; Cleaver, James E.

    2002-01-01

    UV-induced replication arrest in the xeroderma pigmentosum variant (XPV) but not in normal cells leads to an accumulation of the Mre11/Rad50/Nbs1 complex and phosphorylated histone H2AX (γ-H2AX) in large nuclear foci at sites of stalled replication forks. These complexes have been shown to signal the presence of DNA damage, in particular, double-strand breaks (DSBs). This finding suggests that UV damage leads to the formation of DSBs during the course of replication arrest. After UV irradiation, XPV cells showed a fluence-dependent increase in the yield of γ-H2AX foci that paralleled the production of Mre11 foci. The percentage of foci-positive cells increased rapidly (10–15%) up to fluences of 10 J⋅m−2 before saturating at higher fluences. Frequencies of γ-H2AX and Mre11 foci both reached maxima at 4 h after UV irradiation. This pattern contrasts sharply to the situation observed after x-irradiation, where peak levels of γ-H2AX foci were found to precede the formation of Mre11 foci by several hours. The nuclear distributions of γ-H2AX and Mre11 were found to colocalize spatially after UV- but not x-irradiation. UV-irradiated XPV cells showed a one-to-one correspondence between Mre11 and γ-H2AX foci-positive cells. These results show that XPV cells develop DNA DSBs during the course of UV-induced replication arrest. These UV-induced foci occur in cells that are unable to carry out efficient bypass replication of UV damage and may contribute to further genetic variation. PMID:11756691

  5. The hepatocurative effects of Cynara scolymus L. leaf extract on carbon tetrachloride-induced oxidative stress and hepatic injury in rats.

    PubMed

    Colak, Emine; Ustuner, Mehmet Cengiz; Tekin, Neslihan; Colak, Ertugrul; Burukoglu, Dilek; Degirmenci, Irfan; Gunes, Hasan Veysi

    2016-01-01

    Cynara scolymus is a pharmacologically important medicinal plant containing phenolic acids and flavonoids. Experimental studies indicate antioxidant and hepatoprotective effects of C. scolymus but there have been no studies about therapeutic effects of liver diseases yet. In the present study, hepatocurative effects of C. scolymus leaf extract on carbon tetrachloride (CCl4)-induced oxidative stress and hepatic injury in rats were investigated by serum hepatic enzyme levels, oxidative stress indicator (malondialdehyde-MDA), endogenous antioxidants, DNA fragmentation, p53, caspase 3 and histopathology. Animals were divided into six groups: control, olive oil, CCl4, C. scolymus leaf extract, recovery and curative. CCl4 was administered at a dose of 0.2 mL/kg twice daily on CCl4, recovery and curative groups. Cynara scolymus extract was given orally for 2 weeks at a dose of 1.5 g/kg after CCl4 application on the curative group. Significant decrease of serum alanine-aminotransferase (ALT) and aspartate-aminotransferase (AST) levels were determined in the curative group. MDA levels were significantly lower in the curative group. Significant increase of superoxide dismutase (SOD) and catalase (CAT) activity in the curative group was determined. In the curative group, C. scolymus leaf extract application caused the DNA % fragmentation, p53 and caspase 3 levels of liver tissues towards the normal range. Our results indicated that C. scolymus leaf extract has hepatocurative effects of on CCl4-induced oxidative stress and hepatic injury by reducing lipid peroxidation, providing affected antioxidant systems towards the normal range. It also had positive effects on the pathway of the regulatory mechanism allowing repair of DNA damage on CCl4-induced hepatotoxicity.

  6. Intestinal and Hepatic Expression of Cytochrome P450s and mdr1a in Rats with Indomethacin-Induced Small Intestinal Ulcers

    PubMed Central

    Kawauchi, Shoji; Nakamura, Tsutomu; Yasui, Hiroyuki; Nishikawa, Chikako; Miki, Ikuya; Inoue, Jun; Horibe, Sayo; Hamaguchi, Tsuneo; Tanahashi, Toshihito; Mizuno, Shigeto

    2014-01-01

    Background: Non-steroidal anti-inflammatory drugs induce the serious side effect of small intestinal ulcerations (SIUs), but little information is available regarding the consequences to drug metabolism and absorption. Aim: We examined the existence of secondary hepatic inflammation in rats with indomethacin (INM)-induced SIUs and assessed its relationship to the cytochrome P450 (CYP) and P-glycoprotein (mdr1a), the major drug-metabolizing factors in the small intestine and the liver. Methods: Gene expression of the CYP family of enzymes and mdr1a was measured with quantitative real-time polymerase chain reaction (qPCR). Vancomycin (VCM), a poorly absorbed drug, was administered intraduodenally to rats with SIUs. Results: INM induced SIUs predominantly in the lower region of the small intestine with high expression of inflammatory markers. Liver dysfunction was also observed, which suggested a secondary inflammatory response in rats with SIUs. In the liver of rats with SIUs, the expression of CYP2C11, CYP2E1, and CYP3A1 was significantly decreased, and loss of CYP3A protein was observed. Although previous studies have shown a direct effect of INM on CYP3A activity, we could not confirm any change in hepatic CY3A4 expression (major isoform of human CYP3A) in vitro. The plasma VCM concentration was increased in rats with SIUs due to partial absorption from the mucosal injury, but not in normal mucosa. Conclusions: INM-induced SIUs had a subtle effect on intestinal CYP expression, but had an apparent action on hepatic CYP, which was influenced, at least in part, by the secondary inflammation. Furthermore, drug absorption was increased in rats with SIUs. PMID:25317066

  7. A Case of Solitary Well-Differentiated Papillary Mesothelioma with Invasive Foci in the Pleura.

    PubMed

    Shimizu, Shigeki; Yoon, Hyung-Eun; Ito, Norimasa; Tsuji, Taisuke; Funakoshi, Yasunobu; Utsumi, Tomoki; Sakaguchi, Masahiro; Tsujimura, Toru; Kasai, Takahiko; Hiroshima, Kenzo; Matsumura, Akihide

    2017-01-01

    Well-differentiated papillary mesothelioma (WDPM) is a rare, distinct tumor consisting of mesothelial cells with a papillary architecture, bland cytological features, and a tendency toward superficial spread without invasion. Rare cases with superficial invasion are termed WDPM with invasive foci. We report a case of solitary WDPM with invasive foci in the pleura. A 61-year-old woman presented with a lung adenocarcinoma. A small papillary lesion measuring 29 × 10 × 8 mm was incidentally found in the parietal pleura during a lobectomy for the lung adenocarcinoma. The fibrovascular core of the small papillary lesion was surrounded by a single layer of cuboidal cells with mild to moderate atypia and large nucleoli. Atypical mesothelial cells focally invaded the submesothelial layer. The cells of the papillary lesion were positive for cytokeratins and mesothelial markers. The Ki67 index was <1 %. The lesion did not show p16 loss on fluorescence in situ hybridization. We could not detect atypical mesothelial cells in the specimen from an extrapleural pneumonectomy. WDPM with invasive foci is prone to multifocality; however, our case represents a solitary case in the pleura. © 2016 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.

  8. Gut-derived lipopolysaccharide promotes T-cell-mediated hepatitis in mice through Toll-like receptor 4.

    PubMed

    Lin, Yan; Yu, Le-Xing; Yan, He-Xin; Yang, Wen; Tang, Liang; Zhang, Hui-Lu; Liu, Qiong; Zou, Shan-Shan; He, Ya-Qin; Wang, Chao; Wu, Meng-Chao; Wang, Hong-Yang

    2012-09-01

    Robust clinical and epidemiologic data support the role of inflammation as a key player in hepatocellular carcinoma (HCC) development. Our previous data showed that gut-derived lipopolysaccharide (LPS) promote HCC development by activating Toll-like receptor 4 (TLR4) expressed on myeloid-derived cells. However, the effects of gut-derived LPS on other types of liver injury models are yet to be studied. The purpose of this study was to determine the importance of gut-derived LPS and TLR4 signaling in a T-cell-mediated hepatitis-Con A-induced hepatitis model, which mimic the viral hepatitis. Reduction of endotoxin using antibiotics regimen or genetic ablation of TLR4 in mice significantly alleviate Con A-induced liver injury by inhibiting the infiltration of T lymphocytes into the liver and the activation of CD4(+) T lymphocytes as well as the production of T helper 1 cytokines; in contrast, exogenous LPS can promote Con A-induced hepatitis and CD4(+) T cells activation in vivo and in vitro. Reconstitution of TLR4-expressing myeloid cells in TLR4-deficient mice restored Con A-induced liver injury and inflammation, indicating the major cell target of LPS. In addition, TLR4 may positively regulate the target hepatocellular apoptosis via the perforin/granzyme B pathway. These data suggest that gut-derived LPS and TLR4 play important positive roles in Con A-induced hepatitis and modulation of the gut microbiotia may represent a new avenue for therapeutic intervention to treat acute hepatitis induced by hepatitis virus infection, thus to prevent hepatocellular carcinoma.

  9. Dynamic of Immune Response induced in Hepatitis B Surface Antigen-transgenic Mice Immunized with a Novel Therapeutic Formulation

    PubMed Central

    Almeida, Freya M Freyre; Blanco, Aracelys; Trujillo, Heidy; Hernández, Dunia; García, Daymir; Alba, José S; Abad, Matilde López; Merino, Nelson; Lobaina, Yadira

    2016-01-01

    ABSTRACT The development of therapeutic vaccines against chronic hepatitis B requires the capacity of the formulation to subvert a tolerated immune response as well as the evaluation of histopathological damage resulting from the treatment. In the present study, the dynamicity of induced immune response to hepatitis B surface antigen (HBsAg) was evaluated in transgenic mice that constitutively express the HBsAg gene (HBsAg-tg mice). After immunization with a vaccine candidate containing both surface (HBsAg) and core (HBcAg) antigens of hepatitis B virus (HBV), the effect of vaccination on clearance of circulating HBsAg and the potential histological alterations were examined. Transgenic (tg) and non-transgenic (Ntg) mice were immunized by intranasal (IN) and subcutaneous (SC) routes simultaneously. A control group received phosphate-buffered saline (PBS) by IN route and aluminum by SC route. Positive responses, at both humoral and cellular levels, were obtained after five immunizations in HBsAg-tg mice. Such responses were delayed and of lower intensity in tg mice, compared to vaccinated Ntg mice. Serum IgG response was characterized by a similar IgG subclass pattern. Even when HBsAg-specific CD8+ T cell responses were clearly detectable by gamma-interferon ELISPOT assay, histopathological alterations were not detected in any organ, including the liver and kidneys. Our study demonstrated, that it is possible to subvert the immune tolerance against HBsAg in tg mice, opening a window for new studies to optimize the schedule, dose, and formulation to improve the immune response to the therapeutic vaccine candidate. These results can be considered a safety proof to support clinical developments for the formulation under study. How to cite this article Freyre FM, Blanco A, Trujillo H, Hernández D, García D, Alba JS, Lopez M, Merino N, Lobaina Y, Aguilar JC. Dynamic of Immune Response induced in Hepatitis B Surface Antigen-transgenic Mice Immunized with a Novel

  10. Piscine orthoreovirus (PRV) in red and melanised foci in white muscle of Atlantic salmon (Salmo salar).

    PubMed

    Bjørgen, Håvard; Wessel, Øystein; Fjelldal, Per Gunnar; Hansen, Tom; Sveier, Harald; Sæbø, Håkon Rydland; Enger, Katrine Bones; Monsen, Eirik; Kvellestad, Agnar; Rimstad, Espen; Koppang, Erling Olaf

    2015-09-08

    Melanised focal changes (black spots) are common findings in the white skeletal muscle of seawater-farmed Atlantic salmon (Salmo salar). Fillets with melanised focal changes are considered as lower quality and cause large economic losses. It has been suggested that red focal changes (red spots) precede the melanised focal changes. In the present work, we examined different populations of captive and wild salmon for the occurrence of both types of changes, which were investigated for the presence of different viruses by immunohistochemistry and RT-qPCR. The occurrence of red or melanised foci varied significantly between the populations, from none in wild fish control group, low prevalence of small foci in fish kept in in-house tanks, to high prevalence of large foci in farm-raised salmon. Large amounts of Piscine orthoreovirus (PRV) antigen were detected in all foci. No other viruses were detected. Red focal changes contained significantly higher levels of PRV RNA than apparently non-affected areas in white muscle of the same individuals. Some changes displayed a transient form between a red and melanised pathotype, indicating a progression from an acute to a chronic manifestation. We conclude that PRV is associated with the focal pathological changes in the white muscle of farmed Atlantic salmon and is a premise for the development of focal melanised changes.

  11. Regulation of hepatic glucose metabolism in health and disease

    PubMed Central

    Petersen, Max C.; Vatner, Daniel F.; Shulman, Gerald I.

    2017-01-01

    The liver is crucial for the maintenance of normal glucose homeostasis — it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis. PMID:28731034

  12. Ameliorative effect of nanoencapsulated flavonoid against chlorpyrifos-induced hepatic oxidative damage and immunotoxicity in Wistar rats.

    PubMed

    Suke, Sanvidhan G; Sherekar, Prasad; Kahale, Vivek; Patil, Shaktipal; Mundhada, Dharmendra; Nanoti, Vivek M

    2018-04-18

    The theme of the present work is to evaluate the protective effect of nanoencapsulated quercetin (NEQ) against chlorpyrifos (CPF)-induced hepatic damage and immune alterations in animals. Nanoparticles (NP) drug encapsulation was prepared. Forty male Wistar rats were divided into eight groups. Two groups served as control and CPF (13.5 mg/kg) treatment for 28 days. Other three groups were free quercetin (QC), NP and NEQ treated with 3 mg/kg respectively for 15 days; whereas remaining three groups received treatment of CPF and QC, NP, NEQ, respectively, for 15 days. The results show that significantly altered oxidative stress in the liver tissue and liver enzyme parameters in blood and immune responses in CPF-treated rats compared to controls. Administration of NEQ attenuated biochemical and immunological parameters. The liver histopathological analysis confirmed pathological improvement. Hence, use of NEQ appeared to be beneficial to a great extent in attenuating and restoring hepatic oxidative damage and immune alteration sustained by pesticide exposure. © 2018 Wiley Periodicals, Inc.

  13. Vaccination with dendritic cells pulsed with hepatitis C pseudo particles induces specific immune responses in mice

    PubMed Central

    Weigand, Kilian; Voigt, Franziska; Encke, Jens; Hoyler, Birgit; Stremmel, Wolfgang; Eisenbach, Christoph

    2012-01-01

    AIM: To explore dendritic cells (DCs) multiple functions in immune modulation. METHODS: We used bone-marrow derived dendritic cells from BALB/c mice pulsed with pseudo particles from the hepatitis C virus to vaccinate naive BALB/c mice. Hepatitis C virus (HCV) pseudo particles consist of the genotype 1b derived envelope proteins E1 and E2, covering a non-HCV core structure. Thus, not a single epitope, but the whole “viral surface” induces immunogenicity. For vaccination, mature and activated DC were injected subcutaneously twice. RESULTS: Humoral and cellular immune responses measured by enzyme-linked immunosorbent assay and interferon-gamma enzyme-linked immunosorbent spot test showed antibody production as well as T-cells directed against HCV. Furthermore, T-cell responses confirmed two highly immunogenic regions in E1 and E2 outside the hypervariable region 1. CONCLUSION: Our results indicate dendritic cells as a promising vaccination model for HCV infection that should be evaluated further. PMID:22371638

  14. Relationship between increasing concentrations of two carcinogens and statistical image descriptors of foci morphology in the cell transformation assay.

    PubMed

    Callegaro, Giulia; Corvi, Raffaella; Salovaara, Susan; Urani, Chiara; Stefanini, Federico M

    2017-06-01

    Cell Transformation Assays (CTAs) have long been proposed for the identification of chemical carcinogenicity potential. The endpoint of these in vitro assays is represented by the phenotypic alterations in cultured cells, which are characterized by the change from the non-transformed to the transformed phenotype. Despite the wide fields of application and the numerous advantages of CTAs, their use in regulatory toxicology has been limited in part due to concerns about the subjective nature of visual scoring, i.e. the step in which transformed colonies or foci are evaluated through morphological features. An objective evaluation of morphological features has been previously obtained through automated digital processing of foci images to extract the value of three statistical image descriptors. In this study a further potential of the CTA using BALB/c 3T3 cells is addressed by analysing the effect of increasing concentrations of two known carcinogens, benzo[a]pyrene and NiCl 2 , with different modes of action on foci morphology. The main result of our quantitative evaluation shows that the concentration of the considered carcinogens has an effect on foci morphology that is statistically significant for the mean of two among the three selected descriptors. Statistical significance also corresponds to visual relevance. The statistical analysis of variations in foci morphology due to concentration allowed to quantify morphological changes that can be visually appreciated but not precisely determined. Therefore, it has the potential of providing new quantitative parameters in CTAs, and of exploiting all the information encoded in foci. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  15. Vasopressin-induced changes in splanchnic blood flow and hepatic and portal venous pressures in liver resection.

    PubMed

    Bown, L Sand; Ricksten, S-E; Houltz, E; Einarsson, H; Söndergaard, S; Rizell, M; Lundin, S

    2016-05-01

    To minimize blood loss during hepatic surgery, various methods are used to reduce pressure and flow within the hepato-splanchnic circulation. In this study, the effect of low- to moderate doses of vasopressin, a potent splanchnic vasoconstrictor, on changes in portal and hepatic venous pressures and splanchnic and hepato-splanchnic blood flows were assessed in elective liver resection surgery. Twelve patients were studied. Cardiac output (CO), stroke volume (SV), mean arterial (MAP), central venous (CVP), portal venous (PVP) and hepatic venous pressures (HVP) were measured, intraoperatively, at baseline and during vasopressin infusion at two infusion rates (2.4 and 4.8 U/h). From arterial and venous blood gases, the portal (splanchnic) and hepato-splanchnic blood flow changes were calculated, using Fick's equation. CO, SV, MAP and CVP increased slightly, but significantly, while systemic vascular resistance and heart rate remained unchanged at the highest infusion rate of vasopressin. PVP was not affected by vasopressin, while HVP increased slightly. Vasopressin infusion at 2.4 and 4.8 U/h reduced portal blood flow (-26% and -37%, respectively) and to a lesser extent hepato-splanchnic blood flow (-9% and -14%, respectively). The arterial-portal vein lactate gradient was not significantly affected by vasopressin. Postoperative serum creatinine was not affected by vasopressin. Short-term low to moderate infusion rates of vasopressin induced a splanchnic vasoconstriction without metabolic signs of splanchnic hypoperfusion or subsequent renal impairment. Vasopressin caused a centralization of blood volume and increased cardiac output. Vasopressin does not lower portal or hepatic venous pressures in this clinical setting. © 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  16. Clinical associations of hepatic stellate cell (HSC) hyperplasia.

    PubMed

    Mounajjed, Taofic; Graham, Rondell P; Sanderson, Schuyler O; Smyrk, Thomas C

    2014-07-01

    Hepatic stellate cell (HSC) hyperplasia has been principally attributed to hypervitaminosis A. There are sporadic reports of HSC hyperplasia in other conditions such as chronic biliary disease and hepatitis C, but clinical associations of this entity have not been studied in detail. We aimed to investigate the clinical associations of HSC hyperplasia aside from hypervitaminosis A. We identified 34 patients whose liver histology showed HSC hyperplasia. We reviewed the liver samples; additional histologic findings in addition to HSC hyperplasia were consolidated into a histologic diagnosis. We collected clinical, laboratory, and radiologic data; the histologic diagnosis was combined with this data to reach an "overall diagnosis." Four patients had hypervitaminosis A (all native livers). In native livers (n = 24), HSC hyperplasia also occurred in association with drug-induced hepatitis [n = 6, niacin was the most common inducing agent (n = 3)], reactive hepatitis (n = 4), chronic hepatitis C (n = 4), autoimmune hepatitis (n = 3), steatohepatitis (n = 1), chronic biliary disease (n = 1), and portal venopathy (n = 1). In liver allografts (n = 10), HSC hyperplasia was seen in protocol biopsies without other significant abnormalities (n = 5), chronic biliary disease (n = 4), and acute cellular rejection (n = 1). All patients used medications (total of 99) and 82 % were on multiple medications. HSC hyperplasia is an uncommon and relatively nonspecific finding that most commonly occurs in multimedicated patients, often in the absence of hypervitaminosis A. Associated conditions include drug toxicity (such as niacin), post-liver transplant setting, reactive hepatitis (due to systemic illness or inflammatory disorders of the gastrointestinal tract), and chronic liver disease.

  17. High fat diet-induced oxidative stress blocks hepatocyte nuclear factor 4α and leads to hepatic steatosis in mice.

    PubMed

    Yu, Dongsheng; Chen, Gang; Pan, Minglin; Zhang, Jia; He, Wenping; Liu, Yang; Nian, Xue; Sheng, Liang; Xu, Bin

    2018-06-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease with manifestation of over-accumulation of fat in liver. Increasing evidences indicate that NAFLD may be in part caused by malfunction of very low density lipoprotein (VLDL) secretion. Hepatocyte nuclear factor 4α (HNF4α), a nuclear receptor protein, plays an important role in sustain hepatic lipid homeostasis via transcriptional regulation of genes involved in secretion of VLDL, such as apolipoprotein B (ApoB). However, the exact functional change of HNF4α in NAFLD remains to be elucidated. In the present study, we found that high fat diet (HFD) induced cytoplasmic retention of HNF4α in hepatocytes, which led to down-regulation of hepatic ApoB expression and its protein level in serum, as well as reduced secretion of VLDL. We further revealed that oxidative stress, elevated in fatty liver, was the key factor inducing the cytoplasmic retention of HNF4α in hepatocytes by activating protein kinase C (PKC)-mediated phosphorylation in HNF4α. Thus, our findings reveal a novel mechanism underlying HFD-induced fatty liver that oxidative stress impairs function of HNF4α on ApoB expression and VLDL secretion via PKC activation, eventually promoting fat accumulation in the liver. Therefore, oxidative stress/PKC/HNF4α pathway may be a novel target to treat diet-induced fatty liver. © 2017 Wiley Periodicals, Inc.

  18. Rituximab-based treatment, HCV replication, and hepatic flares.

    PubMed

    Sagnelli, Evangelista; Pisaturo, Mariantonietta; Sagnelli, Caterina; Coppola, Nicola

    2012-01-01

    Rituximab, a chimeric mouse-human monoclonal antibody directed to the CD20 antigen expressed on pre-B lymphocytes and mature lymphocytes, causes a profound B-cell depletion. Due to its peculiar characteristics, this drug has been used to treat oncohaematological diseases, B cell-related autoimmune diseases, rheumatoid arthritis, and, more recently, HCV-associated mixed cryoglobulinaemic vasculitis. Rituximab-based treatment, however, may induce an increased replication of several viruses such as hepatitis B virus, cytomegalovirus, varicella-zoster virus, echovirus, and parvovirus B19. Recent data suggest that rituximab-based chemotherapy induces an increase in HCV expression in hepatic cells, which may become a target for a cell-mediated immune reaction after the withdrawal of treatment and the restoration of the immune control. Only a few small studies have investigated the occurrence of HCV reactivation and an associated hepatic flare in patients with oncohaematological diseases receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). These studies suggest that the hepatic flares are frequently asymptomatic, but life-threatening liver failure occurs in nearly 10% of cases.

  19. Structural basis for host membrane remodeling induced by protein 2B of hepatitis A virus.

    PubMed

    Vives-Adrián, Laia; Garriga, Damià; Buxaderas, Mònica; Fraga, Joana; Pereira, Pedro José Barbosa; Macedo-Ribeiro, Sandra; Verdaguer, Núria

    2015-04-01

    The complexity of viral RNA synthesis and the numerous participating factors require a mechanism to topologically coordinate and concentrate these multiple viral and cellular components, ensuring a concerted function. Similarly to all other positive-strand RNA viruses, picornaviruses induce rearrangements of host intracellular membranes to create structures that act as functional scaffolds for genome replication. The membrane-targeting proteins 2B and 2C, their precursor 2BC, and protein 3A appear to be primarily involved in membrane remodeling. Little is known about the structure of these proteins and the mechanisms by which they induce massive membrane remodeling. Here we report the crystal structure of the soluble region of hepatitis A virus (HAV) protein 2B, consisting of two domains: a C-terminal helical bundle preceded by an N-terminally curved five-stranded antiparallel β-sheet that displays striking structural similarity to the β-barrel domain of enteroviral 2A proteins. Moreover, the helicoidal arrangement of the protein molecules in the crystal provides a model for 2B-induced host membrane remodeling during HAV infection. No structural information is currently available for the 2B protein of any picornavirus despite it being involved in a critical process in viral factory formation: the rearrangement of host intracellular membranes. Here we present the structure of the soluble domain of the 2B protein of hepatitis A virus (HAV). Its arrangement, both in crystals and in solution under physiological conditions, can help to understand its function and sheds some light on the membrane rearrangement process, a putative target of future antiviral drugs. Moreover, this first structure of a picornaviral 2B protein also unveils a closer evolutionary relationship between the hepatovirus and enterovirus genera within the Picornaviridae family. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  20. Structural Basis for Host Membrane Remodeling Induced by Protein 2B of Hepatitis A Virus

    PubMed Central

    Vives-Adrián, Laia; Garriga, Damià; Buxaderas, Mònica; Fraga, Joana; Pereira, Pedro José Barbosa

    2015-01-01

    ABSTRACT The complexity of viral RNA synthesis and the numerous participating factors require a mechanism to topologically coordinate and concentrate these multiple viral and cellular components, ensuring a concerted function. Similarly to all other positive-strand RNA viruses, picornaviruses induce rearrangements of host intracellular membranes to create structures that act as functional scaffolds for genome replication. The membrane-targeting proteins 2B and 2C, their precursor 2BC, and protein 3A appear to be primarily involved in membrane remodeling. Little is known about the structure of these proteins and the mechanisms by which they induce massive membrane remodeling. Here we report the crystal structure of the soluble region of hepatitis A virus (HAV) protein 2B, consisting of two domains: a C-terminal helical bundle preceded by an N-terminally curved five-stranded antiparallel β-sheet that displays striking structural similarity to the β-barrel domain of enteroviral 2A proteins. Moreover, the helicoidal arrangement of the protein molecules in the crystal provides a model for 2B-induced host membrane remodeling during HAV infection. IMPORTANCE No structural information is currently available for the 2B protein of any picornavirus despite it being involved in a critical process in viral factory formation: the rearrangement of host intracellular membranes. Here we present the structure of the soluble domain of the 2B protein of hepatitis A virus (HAV). Its arrangement, both in crystals and in solution under physiological conditions, can help to understand its function and sheds some light on the membrane rearrangement process, a putative target of future antiviral drugs. Moreover, this first structure of a picornaviral 2B protein also unveils a closer evolutionary relationship between the hepatovirus and enterovirus genera within the Picornaviridae family. PMID:25589659