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Sample records for hepatotoxic cyclic heptapeptides

  1. A cytotoxic cyclic heptapeptide from the seeds of Annona cherimola.

    PubMed

    Wélé, Alassane; Zhang, Yanjun; Ndoye, Idrissa; Brouard, Jean-Paul; Pousset, Jean-Louis; Bodo, Bernard

    2004-09-01

    From a methanol extract of the seeds of Annona cherimola, a new cyclic heptapeptide, cherimolacyclopeptide C, has been isolated. The structure was elucidated on the basis of the MS/MS fragmentation using a Q-TOF mass spectrometer equipped with an ESI source, extensive 2D NMR experiments, and chemical degradation. Cherimolacyclopeptide C exhibited significant in vitro cytotoxic activity against KB cells, with an IC(50) value of 0.072 microM.

  2. Structure-activity relationships of sialogogic heptapeptides analogous to physalaemin.

    PubMed

    Gao, C; Abe, K

    2000-05-01

    The rationale behind this study was to determine in detail which amino acids in physalaemin are crucial to its sialogogue activity, with a view of synthesizing new sialogogues which might be of use in the treatment of dry mouth. With the progressive elimination of amino acids, one by one, from the C- and N-terminal regions, 126 heptapeptides were newly synthesized by the multipin peptide method, for comparison with II naturally occurring tachykinins. The C-terminal amide in position II was essential for salivation, but not the pyrolidine group or the N-terminal amino acid residues in positions I to 4. In 18 heptapeptides in which M in position II (MII) was replaced by another amino acid, one by one, none caused salivation. In 18 heptapeptides, in which L10 or G9 was replaced, three peptides caused salivation but none had significantly increased secretory activities. In 18 heptapeptides in which Y8 was replaced, four caused salivation but only one (I) had significantly increased secretory activity. In 18 heptapeptides in which F7 was replaced, only Y caused salivation but with significantly reduced secretory activity. In contrast, in 18 heptapeptides in which K6 and N5 were replaced, most caused salivation and some of them had significantly increased secretory activities. It is concluded that the sequence FYGLM-NH2 conserved in the C-terminal region of physalaemin is optimal, that amides in position II and F7 are very important for salivation, but that K6 and N5 can be replaced by some other amino acids, resulting in increased secretory activities.

  3. A Biosurfactant-Inspired Heptapeptide with Improved Specificity to Kill MRSA.

    PubMed

    Liu, Yuan; Ding, Shuangyang; Dietrich, Richard; Märtlbauer, Erwin; Zhu, Kui

    2017-02-01

    The emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) poses a serious threat to public health. New antibiotics and strategies are urgently needed to combat S. aureus associated infections. Bacaucin, a novel cyclic lipopeptide from Bacillus subtilis CAU21, is reported. Bacaucin shows broad antibacterial activity against Gram-positive bacteria, but is also hemolytic and cytotoxic. However, bacaucin-1, a bacaucin-inspired ring-opened heptapeptide, shows specific antibacterial activity against MRSA by a membrane-disruptive mechanism without detectable toxicity to mammalian cells or induction of bacterial resistance. Bacaucin-1 was efficient in preventing infections in both in vitro and in vivo models and is a valuable prototype antibiotic with high potential against S. aureus infections. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. [Hepatotoxicity of the microcystin cyanotoxin].

    PubMed

    Leal, Andréa de Castro; Soares, Manoel do Carmo Pereira

    2004-01-01

    At public health, there is increasingly interest on evaluating the possibility of human intoxication by biotoxins from blue-green algae, mainly the hepatotoxins from the microcystin group. Microcystin, a monocyclic heptapeptide, is mainly produced by a cyanobacteria called Microcistis aeruginosa. It is characterized by a few variable amino acids, from which two of them have an unusual structure and play an important role in the hepatotoxicity of the microcystin. Although human illnesses include gastroenteritis, allergic or irritative reactions, and neurotoxicity, the main target of this toxin is the liver. Inside the hepatocytes, microcystins are carried by the transportation system of the bile acid, inhibiting the activity of the protein phosphatase in the cytoplasm. This inhibition causes a morphologic change in the plasmatic membrane because of the hyperphosphorylation of cytokeratins, and also the tumoral promotion by the hyperphosphorylated proteins. The techniques used in the detection and quantification of the microcystins in the environment include liquid chromatography, bioanalysis of mice, and immunoenzymatic tests using mono and polyclonal antibodies against those toxins. The latter has been remarked because of its practicality and its high sensibility.

  5. Inhibition of Insulin Amyloid Fibrillation by a Novel Amphipathic Heptapeptide

    PubMed Central

    Ratha, Bhisma N.; Ghosh, Anirban; Brender, Jeffrey R.; Gayen, Nilanjan; Ilyas, Humaira; Neeraja, Chilukoti; Das, Kali P.; Mandal, Atin K.; Bhunia, Anirban

    2016-01-01

    The aggregation of insulin into amyloid fibers has been a limiting factor in the development of fast acting insulin analogues, creating a demand for excipients that limit aggregation. Despite the potential demand, inhibitors specifically targeting insulin have been few in number. Here we report a non-toxic and serum stable-designed heptapeptide, KR7 (KPWWPRR-NH2), that differs significantly from the primarily hydrophobic sequences that have been previously used to interfere with insulin amyloid fibrillation. Thioflavin T fluorescence assays, circular dichroism spectroscopy, and one-dimensional proton NMR experiments suggest KR7 primarily targets the fiber elongation step with little effect on the early oligomerization steps in the lag time period. From confocal fluorescence and atomic force microscopy experiments, the net result appears to be the arrest of aggregation in an early, non-fibrillar aggregation stage. This mechanism is noticeably different from previous peptide-based inhibitors, which have primarily shifted the lag time with little effect on later stages of aggregation. As insulin is an important model system for understanding protein aggregation, the new peptide may be an important tool for understanding peptide-based inhibition of amyloid formation. PMID:27679488

  6. Hydrazine inhalation hepatotoxicity.

    PubMed

    Kao, Yung Hsiang; Chong, C H; Ng, W T; Lim, D

    2007-10-01

    Abstract Hydrazine is a hazardous chemical commonly used as a reactant in rocket and jet fuel cells. Animal studies have demonstrated hepatic changes after hydrazine inhalation. Human case reports of hydrazine inhalation hepatotoxicity are rare. We report a case of mild hepatotoxicity following brief hydrazine vapour inhalation in a healthy young man, which resolved completely on expectant management.

  7. Botanicals and Hepatotoxicity.

    PubMed

    Roytman, Marina M; Poerzgen, Peter; Navarro, Victor

    2018-06-19

    The use of botanicals, often in the form of multi-ingredient herbal dietary supplements (HDS), has grown tremendously in the past three decades despite their unproven efficacy. This is paralleled by an increase in dietary supplement-related health complications, notably hepatotoxicity. This article reviews the demographics and motivations of dietary supplement (DS) consumers and the regulatory framework for DS in the US and other developed countries. It examines in detail three groups of multi-ingredient HDS associated with hepatotoxicity: OxyElite Pro (two formulations), green tea extract-based DS, and "designer anabolic steroids." These examples illustrate the difficulties in identifying and adjudicating causality of suspect compound(s) of multi-ingredient HDS-associated liver injury in the clinical setting. The article outlines future directions for further study of HDS-associated hepatotoxicity as well as measures to safeguard the consumer against it. © 2018, The American Society for Clinical Pharmacology and Therapeutics.

  8. Tobramycin-induced hepatotoxicity.

    PubMed

    Nisly, Sarah A; Ray, Shaunta' M; Moye, Robert A

    2007-12-01

    To report a case of tobramycin-induced hepatotoxicity. A 20-year-old female was hospitalized for treatment of Pseudomonas aeruginosa bacteremia and osteomyelitis. Empiric intravenous antibiotic therapy with piperacillin/tazobactam, vancomycin, and ciprofloxacin was started, and based on the results of culture and sensitivity testing, was changed to intravenous ceftazidime and tobramycin 70 mg every 8 hours on hospital day 3. Liver enzyme levels then increased over days 3-6. Tests for hepatitis A, B, and C were all nonreactive, and HIV testing was negative. On day 8, therapy was changed from ceftazidime to piperacillin/tazobactam and the tobramycin dose was increased to 100 mg every 8 hours. Due to a continued increase in total bilirubin, aspartate aminotransferase, and alanine aminotransferase, piperacillin/tazobactam was discontinued and aztreonam was started on day 10. All antibiotics were stopped on day 12 and the elevated liver parameters began to decrease. Aztreonam and ciprofloxacin were restarted on day 16, and most laboratory test results returned to baseline levels by day 19; total bilirubin and alkaline phosphatase decreased to lower than baseline values. This case illustrates a possible occurrence of tobramycin-induced hepatotoxicity. Liver enzymes rose when tobramycin therapy was initiated, markedly increased when the tobramycin dose was increased, then resolved upon discontinuation of therapy. Other medication-related causes were ruled out by temporal relationship or rechallenge (aztreonam). Use of the Naranjo probability scale indicated a possible relationship between hepatotoxicity and tobramycin therapy. Other adverse reaction scales specific for evaluation of drug-induced liver disease were also used. Both the Council for International Organizations of Medical Sciences and Maria and Victorino scales indicated a probable likelihood of tobramycin-induced hepatotoxicity. This patient was not rechallenged with tobramycin due to the highly suggestive

  9. Adrenergic modulation of hepatotoxicity.

    PubMed

    Roberts, S M; DeMott, R P; James, R C

    1997-01-01

    Summaries of the interactions caused by altering adrenoreceptor activity in conjunction with the administration of selected hepatotoxicants are provided in Table 2 and Fig. 1. These hepatotoxicants can be divided into two groups, one whose toxicity is increased by adrenergic agonist drugs (group I) and the other whose toxicity is decreased by adrenergic antagonists (group II). Group I includes carbon tetrachloride, acetaminophen, and methylphenidate. Perhaps the most remarkable aspect these chemicals have in common is the striking potentiation that occurs with cotreatment with certain adrenergic agonist drugs. For each of these, cotreatment with the appropriate adrenergic agent can result in massive hepatocellular necrosis from an otherwise nontoxic dose. In terms of the specific adrenoreceptors involved and mechanisms of potentiation, however, they have little in common. Potentiation of carbon tetrachloride hepatotoxicity appears to be mediated by alpha(2)-adrenoceptor stimulation, acetaminophen is potentiated by alpha(1)-adrenoreceptor agonists, and methylphenidate responds to beta(2)-adrenoreceptor stimulation. Studies of the potentiation of carbon tetrachloride and acetaminophen agree that the timing of adrenergic stimulation relative to the hepatotoxicant dose is critically important to the interaction but markedly different for these two toxicants. Acetaminophen was potentiated only when the adrenergic drug was administered as a 3-h pretreatment. This is apparently a consequence of a mechanism of potentiation that involves adrenergic depression of hepatic glutathione content and a requirement that peak effects on glutathione of both the adrenergic agent and acetaminophen be coincident. The mechanism of potentiation of carbon tetrachloride hepatotoxicity is uncertain but clearly does not involve hepatic glutathione content. In contrast to acetaminophen, adrenergic effects must occur within a time window a few hours after the carbon tetrachloride dose for

  10. Molindone and hepatotoxicity.

    PubMed

    Bhatia, S C; Banta, L E; Ehrlich, D W

    1985-10-01

    An adolescent male with chronic schizophrenic disorder, paranoid type, was treated with molindone. He developed hepatotoxicity in the early treatment phase as evidenced by flu-like symptoms and laboratory abnormalities of liver functions. These symptoms and his hepatic functions improved on discontinuing molindone. Similar liver function trends were seen on reintroduction and subsequent withdrawal of the drug. Hepatic hypersensitivity has not been reported previously with the use of this drug. It is suggested that clinicians should be aware of this association and should assess hepatic functions in patients who develop a prodromal flu-like syndrome with this drug, especially in the early treatment phase.

  11. A single mutation in the hepta-peptide active site of Aspergillus niger PhyA phytase leads to myriad of biochemical changes

    The active site motif of proteins belonging to ‘Histidine Acid Phosphatase’ (HAP) contains a hepta-peptide region, RHGXRXP. A close comparison among fungal and yeast HAPs has revealed the fourth residue of the hepta-peptide to be E instead of A, which is the case with A. niger phyA phytase. However,...

  12. Neurotoxic and hepatotoxic cyanotoxins removal by nanofiltration.

    PubMed

    Teixeira, Margarida Ribau; Rosa, Maria João

    2006-08-01

    This study investigates the influence of chemical feed characteristics on nanofiltration performance for cyanotoxins removal, namely the neurotoxic anatoxin-a (alkaloid of 166 g/mol, positively charged) and the hepatotoxic microcystins (cyclic peptides of approximately 1,000 g/mol, negatively charged). Results indicate that NF membranes are an effective barrier against anatoxin-a and microcystins in drinking water. Anatoxin-a and especially microcystins were almost completely removed, regardless of the variations in feed water quality (natural organic matter and competitive toxin), the water recovery rate and the pH values. Anatoxin-a removal was governed by electrostatic interactions and steric hindrance, whereas for microcystins the latter was the main mechanism. In turn, fluxes were significantly impacted by background organics and, especially, inorganics (pH, calcium).

  13. Evidence for dimer formation by an amphiphilic heptapeptide that mediates chloride and carboxyfluorescein release from liposomes

    PubMed Central

    Pajewski, Robert; Ferdani, Riccardo; Pajewska, Jolanta; Djedovič, Natasha; Schlesinger, Paul H.; Gokel, George W.

    2008-01-01

    Heptapeptides having dioctadecyl, N-terminal hydrocarbon chains insert in phospholipid bilayer membranes and form pores through which at least chloride ions pass. Although amphiphilic, these compounds do not typically form vesicles themselves. They insert in the bilayers of phospholipid vesicles and mediate the release of carboxyfluorescein. Hill analysis indicates that at least two molecules of the amphiphile are involved in pore formation. In CD2Cl2, dimer formation is detected by NMR chemical shift changes. The anion release activity of individual anion transporters is increased by linking them covalently at the C-terminus or, even more, by linking them at the N-terminus. Evidence is presented that either linked molecule releases chloride from liposomes more effectively and rapidly than the individual transporter molecule at a comparable concentration. PMID:15703797

  14. Role of C-terminal heptapeptide in pore-forming activity of antimicrobial agent, gaegurin 4.

    PubMed

    Kim, H J; Kim, S S; Lee, M H; Lee, B J; Ryu, P D

    2004-10-01

    Gaegurin 4 (GGN4) is an antimicrobial peptide of 37 amino acids isolated from the skin of a frog, Rana rugosa. GGN4 has a disulfide bond between the residues 31 and 37, which is highly conserved among the antimicrobial peptides isolated from skin of the genus, Rana. However, the role of this C-terminal heptapeptide motif is not well understood. In this work, we compared the membrane effects of the full-length GGN4 (C37) and GGN4 1-30 (C30), which is devoid of the C-terminal seven amino acids to elucidate the function of the C-terminal motif. C37 induced significantly larger membrane conductance (>10x) in the model lipid bilayers formed with acidic and neutral phospholipids and larger K+ efflux from gram-positive (>30x) and gram-negative bacteria. However, the pores induced by C37 and C30 were not different in their permeability to K+ over Cl- (permeability ratio of K+ to Cl- = 4.8-7.1). In addition, the pore-forming effect of C37 or C30 in acidic membranes was not different from that in neutral membranes. Furthermore, C37-induced K+ efflux was not significantly decreased by the reducing agent, dithiothreitol. The results indicate that C-terminal heptapeptide sequence plays an important role in maintaining the high pore-forming activity of GGN4, but does not participate in forming GGN4-induced pore structure. The disulfide bond in this region does not appear critical for such high ionophoric activity of GGN4.

  15. Heptapeptide-loaded solid lipid nanoparticles for cosmetic anti-aging applications.

    PubMed

    Suter, Franz; Schmid, Daniel; Wandrey, Franziska; Zülli, Fred

    2016-11-01

    The cosmetic industry requires more and more expensive actives and ingredients such as retinol, coenzyme Q10, proteins, peptides and biotechnologically produced molecules. In this study, we demonstrate the development of a cost effective formulation of a nanostructured lipid carrier (NLC) or solid lipid nanoparticles (SLN) improving peptide delivery into skin. NLC or SLN are very suitable vehicles for the delivery of active ingredients into skin. The SLN, produced by using hot high pressure homogenization method combine advantages such as physical stability, protection of incorporated labile actives and controlled release. By the used method we dispersed the amorphous heptapeptide DEETGEF in shea butter and homogenized this pre-dispersion at 60°C together with the water phase using a Microfluidizer at 1000bar. The analysis of the obtained SLN-P7 showed a particle size of 173nm, incorporated peptide of 0.014%, entrapment efficiency of 90.8%, melting peak (DSC) of the core lipid of 27°C and a zeta potential of -54mV. By an ex vivo study with skin explants we could stimulate NQO1 (NAD(P)H quinone oxidoreductase), HMOX1 (Heme oxygenase-1) and PRDX1 (Peroxiredoxin-1) genes all of which are cell protecting enzymes. In a multicellular protection against UV induced stress study with skin explants we detected the formation of sun burn cells and the number and morphology of Langerhans cells. The application of our SLN-P7 formulation on skin explants led to a significant and dose dependent protection against UV irradiation. In the clinical suction blister study, irradiation with UVA light for two hours after final product application led to a statistically significant increase of the 8-OhdG (8-hydroxy-2'-deoxyguanosine) concentration in the human epidermis. The skin treated with our verum formulation showed a statistically significant 20% decrease in DNA damage compared to placebo. In conclusion, it was demonstrated that SLN technology enabled peptide delivery into skin

  16. Herbal hepatotoxicity and WHO global introspection method.

    PubMed

    Teschke, Rolf; Eickhoff, Axel; Wolff, Albrecht; Frenzel, Christian; Schulze, Johannes

    2013-01-01

    Herbal hepatotoxicity is a rare but highly disputed disease because numerous confounding variables may complicate accurate causality assessment. Case evaluation is even more difficult when the WHO global introspection method (WHO method) is applied as diagnostic algorithm. This method lacks liver specificity, hepatotoxicity validation, and quantitative items, basic qualifications required for a sound evaluation of hepatotoxicity cases. Consequently, there are no data available for reliability, sensitivity, specificity, positive and negative predictive value. Its scope is also limited by the fact that it cannot discriminate between a positive and a negative causality attribution, thereby stimulating case overdiagnosing and overreporting. The WHO method ignores uncertainties regarding daily dose, temporal association, start, duration, and end of herbal use, time to onset of the adverse reaction, and course of liver values after herb discontinuation. Insufficiently considered or ignored are comedications, preexisting liver diseases, alternative explanations upon clinical assessment, and exclusion of infections by hepatitis A-C, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus (HSV), and varicella zoster virus (VZV). We clearly prefer as alternative the scale of CIOMS (Council for International Organizations of Medical Sciences) which is structured, quantitative, liver specific, and validated for hepatotoxicity. In conclusion, causality of herbal hepatotoxicity is best assessed by the liver specific CIOMS scale validated for hepatotoxicity rather than the obsolete WHO method that is liver unspecific and not validated for hepatotoxicity. CIOMS based assessments will ensure the correct diagnosis and exclude alternative diagnosis that may require other specific therapies.

  17. Review article: herbal and dietary supplement hepatotoxicity.

    PubMed

    Bunchorntavakul, C; Reddy, K R

    2013-01-01

    Herbal and dietary supplements are commonly used throughout the World. There is a tendency for underreporting their ingestion by patients and the magnitude of their use is underrecognised by Physicians. Herbal hepatotoxicity is not uncommonly encountered, but the precise incidence and manifestations have not been well characterised. To review the epidemiology, presentation and diagnosis of herbal hepatotoxicity. This review will mainly discuss single ingredients and complex mixtures of herbs marketed under a single label. A Medline search was undertaken to identify relevant literature using search terms including 'herbal', 'herbs', 'dietary supplement', 'liver injury', 'hepatitis' and 'hepatotoxicity'. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches. The incidence rates of herbal hepatotoxicity are largely unknown. The clinical presentation and severity can be highly variable, ranging from mild hepatitis to acute hepatic failure requiring transplantation. Scoring systems for the causality assessment of drug-induced liver injury may be helpful, but have not been validated for herbal hepatotoxicity. Hepatotoxicity features of commonly used herbal products, such as Ayurvedic and Chinese herbs, black cohosh, chaparral, germander, greater celandine, green tea, Herbalife, Hydroxycut, kava, pennyroyal, pyrrolizidine alkaloids, skullcap, and usnic acid, have been individually reviewed. Furthermore, clinically significant herb-drug interactions are also discussed. A number of herbal medicinal products are associated with a spectrum of hepatotoxicity events. Advances in the understanding of the pathogenesis and the risks involved are needed to improve herbal medicine safety. © 2012 Blackwell Publishing Ltd.

  18. Synthesis and contractile activity of the C-terminal heptapeptide of substance P with N5-dimethyl glutamine in the 6-position. Active site studies.

    PubMed

    Poulos, C P; Pinas, N; Theodoropoulos, D

    1980-09-15

    The synthesis and testing of [N5-dimethyl-Gln6]-SP5-11 showed 37 +/- 12% contractile activity relative to SP, and intrinsic efficacy 98 +/- 4%. This finding indicates that the carboxamide groups of the dual Gln5-Cln6 moiety are not equally related with the contractile response of the C-terminal heptapeptide of SP.

  19. [Hepatox: database on hepatotoxic drugs].

    PubMed

    Quinton, A; Latry, P; Biour, M

    1993-01-01

    Hepatox is a data base on the hepatotoxic drugs file published every year in Gastroentérologie Clinique et Biologique. The program was developed under Omnis 7 for Apple computers, and under Visual Basic Professional Toolkit and Code Base for IBM PC and compatibles computers. The data base includes forms of 866 drugs identified by their approved name and those of their 1,300 corresponding proprietary names in France; drugs are distributed among 104 pharmacological classes. It is possible to have instantaneously access to the card of a drug identified by its approved name. Acceding to a drug identified by its proprietary name gives a list of the approved name of its components; going from a name of this list to the correspondent card of hepatoxicity is immediate. It is easy to extract lists of drugs responsible of a type of hepatic injury, and a table of types of hepatic injuries induced by the drugs of a pharmacological class.

  20. Total synthesis of cyclomarins A, C and D, marine cyclic peptides with interesting anti-tuberculosis and anti-malaria activities.

    PubMed

    Barbie, Philipp; Kazmaier, Uli

    2016-07-07

    Cyclomarins are cyclic heptapeptides containing four unusual amino acids. New synthetic protocols toward their synthesis have been developed, leading to the synthesis and biological evaluation of three natural occurring cyclomarins. Interestingly, cyclomarins address two completely different targets: Clp C1, a subunit of the caseinolytic protease of Mycobacterium tuberculosis (MTB), as well as PfAp3Ase of Plasmodium falciparum. Therefore, cyclomarins are interesting lead structures for the development of drugs against tuberculosis and malaria.

  1. Herbal hepatotoxicity: a critical review

    PubMed Central

    Teschke, Rolf; Frenzel, Christian; Glass, Xaver; Schulze, Johannes; Eickhoff, Axel

    2013-01-01

    This review deals with herbal hepatotoxicity, identical to herb induced liver injury (HILI), and critically summarizes the pitfalls associated with the evaluation of assumed HILI cases. Analysis of the relevant publications reveals that several dozens of different herbs and herbal products have been implicated to cause toxic liver disease, but major quality issues limit the validity of causality attribution. In most of these reports, discussions around quality specifications regarding herbal products, case data presentations and causality assessment methods prevail. Though the production of herbal drugs is under regulatory surveillance and quality aspects are normally not a matter of concern, low quality of the less regulated herbal supplements may be a critical issue considering product batch variability, impurities, adulterants and herb misidentifications. Regarding case data presentation, essential diagnostic information is often lacking, as is the use of valid and liver specific causality assessment methods that also consider alternative diseases. At present, causality is best assessed by using the Council for International Organizations of Medical Sciences scale ( CIOMS) in its original or updated form, which should primarily be applied prospectively by the treating physician when evaluating a patient rather than retrospectively by regulatory agencies. To cope with these problems, a common quality approach by manufacturers, physicians and regulatory agencies should strive for the best quality. We propose steps for improvements with impact on future cases of liver injury by herbs, herbal drugs and herbal supplements. PMID:22831551

  2. Unguisin F, a new cyclic peptide from the endophytic fungus Mucor irregularis.

    PubMed

    Akone, Sergi H; Daletos, Georgios; Lin, Wenhan; Proksch, Peter

    2016-01-01

    The new cyclic heptapeptide unguisin F (1) and the known congener unguisin E (2), were obtained from the endophytic fungus Mucor irregularis, isolated from the medicinal plant Moringa stenopetala, collected in Cameroon. The structure of the new compound was unambiguously determined on the basis of one- and two-dimensional NMR spectroscopy as well as by high-resolution mass spectrometry. The absolute configuration of the amino acid residues of 1 and 2 was determined using Marfey's analysis. Compounds 1 and 2 were evaluated for their antibacterial and antifungal potential, but failed to display significant activities.

  3. Cyclic peptide unguisin A is an anion receptor with high affinity for phosphate and pyrophosphate.

    PubMed

    Daryl Ariawan, A; Webb, James E A; Howe, Ethan N W; Gale, Philip A; Thordarson, Pall; Hunter, Luke

    2017-04-05

    Unguisin A (1) is a marine-derived, GABA-containing cyclic heptapeptide. The biological function of this flexible macrocycle is obscure. Here we show that compound 1 lacks any detectable activity in antimicrobial growth inhibition assays, a result that runs contrary to a previous report. However, we find that 1 functions as a promiscuous host molecule in a variety of anion-binding interactions, with high affinity particularly for phosphate and pyrophosphate. We also show that a series of rigidified, backbone-fluorinated analogues of 1 displays altered affinity for chloride ions.

  4. Acylated heptapeptide binds albumin with high affinity and application as tag furnishes long-acting peptides

    NASA Astrophysics Data System (ADS)

    Zorzi, Alessandro; Middendorp, Simon J.; Wilbs, Jonas; Deyle, Kaycie; Heinis, Christian

    2017-07-01

    The rapid renal clearance of peptides in vivo limits this attractive platform for the treatment of a broad range of diseases that require prolonged drug half-lives. An intriguing approach for extending peptide circulation times works through a `piggy-back' strategy in which peptides bind via a ligand to the long-lived serum protein albumin. In accordance with this strategy, we developed an easily synthesized albumin-binding ligand based on a peptide-fatty acid chimera that has a high affinity for human albumin (Kd=39 nM). This ligand prolongs the elimination half-life of cyclic peptides in rats 25-fold to over seven hours. Conjugation to a peptide factor XII inhibitor developed for anti-thrombotic therapy extends the half-life from 13 minutes to over five hours, inhibiting coagulation for eight hours in rabbits. This high-affinity albumin ligand could potentially extend the half-life of peptides in human to several days, substantially broadening the application range of peptides as therapeutics.

  5. Membrane-associated precursor to poliovirus VPg identified by immunoprecipitation with antibodies directed against a synthetic heptapeptide

    SciT

    Semelr, B.L.; Anderson, C.W.; Hanecak, R.

    1982-02-01

    A synthetic heptapeptide corresponding to the C-terminal sequence of the poliovirus genome protein (VPg) has been linked to bovine serum albumin and used to raise antibodies in rabbits. These antibodies precipitate not only VPg but also at least two more virus-specific polypeptides. The smaller polypeptide, denoted P3-9 (12,000 daltons), has been mapped by Edman degradation and by fragmentation with cyanogen bromide and determined to be the N-terminal cleavage product of polypeptide P3-1b, a precursor to the RNA polymerase. P3-9 contains the sequence of the basic protein VPg (22 amino acids) at its C terminus. As predicted by the known RNAmore » sequence of poliovirus, P3-9 also contains a hydrophobic region of 22 amino acids preceding VPg, an observation suggesting that P3-9 may be membrane-associated. This was confirmed by fractionation of infected cells in the presence or absence of detergent. We speculate that P3-9 may be the donor of VPg to RNA chains in the membrane-bound RNA replication complex.« less

  6. Cyclic Voltammetry.

    ERIC Educational Resources Information Center

    Evans, Dennis H.; And Others

    1983-01-01

    Cyclic voltammetry is a simple experiment that has become popular in chemical research because it can provide useful information about redox reactions in a form which is easily obtained and interpreted. Discusses principles of the method and illustrates its use in the study of four electrode reactions. (Author/JN)

  7. Risk prediction of hepatotoxicity in paracetamol poisoning.

    PubMed

    Wong, Anselm; Graudins, Andis

    2017-09-01

    Paracetamol (acetaminophen) poisoning is the most common cause of acute liver failure in the developed world. A paracetamol treatment nomogram has been used for over four decades to help determine whether patients will develop hepatotoxicity without acetylcysteine treatment, and thus indicates those needing treatment. Despite this, a small proportion of patients still develop hepatotoxicity. More accurate risk predictors would be useful to increase the early detection of patients with the potential to develop hepatotoxicity despite acetylcysteine treatment. Similarly, there would be benefit in early identification of those with a low likelihood of developing hepatotoxicity, as this group may be safely treated with an abbreviated acetylcysteine regimen. To review the current literature related to risk prediction tools that can be used to identify patients at increased risk of hepatotoxicity. A systematic literature review was conducted using the search terms: "paracetamol" OR "acetaminophen" AND "overdose" OR "toxicity" OR "risk prediction rules" OR "hepatotoxicity" OR "psi parameter" OR "multiplication product" OR "half-life" OR "prothrombin time" OR "AST/ALT (aspartate transaminase/alanine transaminase)" OR "dose" OR "biomarkers" OR "nomogram". The search was limited to human studies without language restrictions, of Medline (1946 to May 2016), PubMed and EMBASE. Original articles pertaining to the theme were identified from January 1974 to May 2016. Of the 13,975 articles identified, 60 were relevant to the review. Paracetamol treatment nomograms: Paracetamol treatment nomograms have been used for decades to help decide the need for acetylcysteine, but rarely used to determine the risk of hepatotoxicity with treatment. Reported paracetamol dose and concentration: A dose ingestion >12 g or serum paracetamol concentration above the treatment thresholds on the paracetamol nomogram are associated with a greater risk of hepatotoxicity. Paracetamol elimination half

  8. Active uptake of substance P carboxy-terminal heptapeptide (5-11) into rat brain and rabbit spinal cord slices.

    PubMed

    Nakata, Y; Kusaka, Y; Yajima, H; Segawa, T

    1981-12-01

    We previously reported that nerve terminals and glial cells lack an active uptake system capable of terminating transmitter action of substance P (SP). In the present study, we demonstrated the existence of an active uptake system for SP carboxy-terminal heptapeptide, (5-11)SP. When the slices from either rat brain or rabbit spinal cord were incubated with [3H](5-11)SP, the uptake of (5-11)SP into slices was observed. The uptake system has the properties of an active transport mechanism: it is dependent on temperature and sensitive to hypoosmotic treatment and is inhibited by ouabain and dinitrophenol (DNP). In the brain, (5-11)SP was accumulated by means of a high-affinity and a low-affinity uptake system. The Km and the Vmax values for the high-affinity system were 4.20 x 10(-8) M and 7.59 fmol/10 mg wet weight/min, respectively, whereas these values for the low-affinity system were 1.00 x 10(-6) M and 100 fmol/10 mg wet weight/min, respectively. In the spinal cord, there was only one uptake system, with a Km value of 2.16 x 10(-7) M and Vmax value of 26.2 fmol/10 mg wet weight/min. These results suggest that when SP is released from nerve terminals, it is hydrolysed into (5-11)SP before or after acting as a neurotransmitter, which is in turn accumulated into nerve terminals. Therefore, the uptake system may represent a possible mechanism for the inactivation of SP.

  9. The C- and N-Terminal Residues of Synthetic Heptapeptide Ion Channels Influence Transport Efficacy Through Phospholipid Bilayers

    PubMed Central

    Djedovič, Natasha; Ferdani, Riccardo; Harder, Egan; Pajewska, Jolanta; Pajewski, Robert; Weber, Michelle E.; Schlesinger, Paul H.; Gokel, George W.

    2008-01-01

    The synthetic peptide, R2N-COCH2OCH2CO-Gly-Gly-Gly-Pro-Gly-Gly-Gly-OR’, was shown to be selective for Cl- over K+ when R is n-octadecyl and R’ is benzyl. Nineteen heptapeptides have now been prepared in which the N-terminal and C-terminal residues have been varied. All of the N-terminal residues are dialkyl but the C-terminal chains are esters, 2° amides, or 3° amides. The compounds having varied N-terminal anchors and C-terminal benzyl groups are as follows: 1, R = n-propyl; 2, R = n-hexyl; 3, R = n-octyl; 4, R = n-decyl; 5, R = n-dodecyl; 6, R = n-tetradecyl; 7, R = n-hexadecyl; 8, R = n-octadecyl. Compounds 9-19 have R = n-octadecyl and C-terminal residues as follows: 9, OR’ = OCH2CH3; 10, OR’ = OCH(CH3)2; 11, OR’ = O(CH2)6CH3; 12, OR’ = OCH2-c-C6H11; 13, OR’ = O(CH2)9CH3; 14, OR’ = O (CH2)17CH3; 15, NR’2 = N[(CH2)6CH3]2; 16, NHR’ = NH(CH2)9CH3; 17, NR’2 = N[(CH2)9CH3]2; 18, NHR’ = NH(CH2)17CH3; 19, NR’2 = N[(CH2)17CH3]2. The highest anion transport activities were observed as follows. For the benzyl esters whose N-terminal residues were varied, i.e. 1-8, compound 3 was most active. For the C18 anchored esters 10-14, n-heptyl ester 11 was most active. For the C18 anchored, C-terminal amides 15-19, di-n-decylamide 17 was most active. It was concluded that both the C- and N-terminal anchors were important for channel function in the bilayer but that activity was lost unless only one of the two anchoring groups was dominant. PMID:19633728

  10. Cyclic multiverses

    NASA Astrophysics Data System (ADS)

    Marosek, Konrad; Dąbrowski, Mariusz P.; Balcerzak, Adam

    2016-09-01

    Using the idea of regularization of singularities due to the variability of the fundamental constants in cosmology we study the cyclic universe models. We find two models of oscillating and non-singular mass density and pressure (`non-singular' bounce) regularized by varying gravitational constant G despite the scale factor evolution is oscillating and having sharp turning points (`singular' bounce). Both violating (big-bang) and non-violating (phantom) null energy condition models appear. Then, we extend this idea on to the multiverse containing cyclic individual universes with either growing or decreasing entropy though leaving the net entropy constant. In order to get an insight into the key idea, we consider the doubleverse with the same geometrical evolution of the two `parallel' universes with their physical evolution [physical coupling constants c(t) and G(t)] being different. An interesting point is that there is a possibility to exchange the universes at the point of maximum expansion - the fact which was already noticed in quantum cosmology. Similar scenario is also possible within the framework of Brans-Dicke theory where varying G(t) is replaced by the dynamical Brans-Dicke field φ(t) though these theories are slightly different.

  11. [Hepatotoxicity associated with the use of Herbalife].

    PubMed

    Jóhannsson, Magnús; Ormarsdóttir, Sif; Olafsson, Sigurdur

    2010-03-01

    Many herbal products are known to be hepatotoxic. In a recent survey in Iceland concerning adverse reactions related to herbal medicines, Herbalife products were implicated in the majority of the reported cases of hepatotoxicity. The clinical presentations of five cases of Herbalife related liver injury during the period of 1999-2008 are analysed. Causality was assessed by using the WHO-UMC system for causality assessment and the RUCAM method. Of the five cases there were four females and one male; median age was 46 years (range 29-78). Herbalife had been used for 1 to 7 months prior to presentation. Four patients presented with a hepatocellular and one with a cholestatic reaction. Median values were for bilirubin 190 micromol/L (range: 26-311; ref. < 20 micromol/L), ALP 407 U/L (range: 149-712; ref. 35-105 U/L) and ALT 24 87 U/L (range: 456-2637; ref. 70 and 45 U/L for males and females, respectively). Liver biopsy was performed in 2 patients and was consistent with toxic hepatitis in both cases. Other causes of hepatitis were excluded by appropriate serological testing and ultrasound. Causality assessment according to RUCAM was probable in three cases and possible in two. Using the WHO-UMC criteria causality was certain in one case, probable in two and possible in two cases. Hepatotoxicity is probably associated with the use of Herbalife products. Hepatotoxicity due to herbal remedies is an important differential diagnosis in the diagnostic work-up of liver injury.

  12. Paracetamol poisoning in children and hepatotoxicity.

    PubMed Central

    Penna, A; Buchanan, N

    1991-01-01

    1. Paracetamol is one of the most common drugs that children accidentally ingest. Unlike the situation in adults, death and hepatotoxicity in children from paracetamol poisoning are exceedingly uncommon events. A review of the literature has revealed only seven deaths and fourteen cases of hepatotoxicity in children, with most of the cases resulting from chronic poisoning and not acute poisoning. 2. Children may be less prone to paracetamol hepatotoxicity because of developmental differences in the drug's metabolism and its pathways of detoxification. In the therapeutic setting of treatment of fever and pain in children, paracetamol is regarded as a drug with a higher therapeutic index, and as such, there seems to be little concern with strict adherence to dosage regimes. 3. Scrutiny of the above paediatric cases associated with chronic paracetamol poisoning suggests that the margin of safety of frequent therapeutic doses of paracetamol in infants and young children to be a lot lower than previously appreciated. This review highlights the need to re-evaluate the safety of paracetamol in the context of chronic therapy in infants and young children. PMID:1931463

  13. A case of lacosamide-induced hepatotoxicity.

    PubMed

    Sunwoo, Jun-Sang; Byun, Jung-Ick; Lee, Sang Kun

    2015-06-01

    Lacosamide is a novel antiepileptic drug that acts mainly via the selective enhancement of slow inactivation of voltage-gated sodium channels. It has been reported that lacosamide is effective and generally tolerable as an adjuvant treatment in patients with partial seizures. There are few reports regarding liver damage caused by lacosamide. We describe a case of a patient with drug-resistant epilepsy who developed symptomatic hepatotoxicity after lacosamide administration. A 22-year-old female with a 2-year history of temporal lobe epilepsy was admitted to our hospital because of nausea, dizziness, and abnormal liver function tests. Lacosamide was added for further seizure control 9 days before the current presentation. Her liver enzymes were markedly increased: aspartate aminotransferase, 635 U/L; alanine aminotransferase, 697 U/L. Lacosamide was ceased immediately, whereas other medications (zonisamide, clobazam, and tianeptine) were not withdrawn. The level of liver enzymes improved significantly within a few days, and a diagnosis of lacosamide-induced hepatitis was made based on the obvious temporal relationship. This case report demonstrates that hepatotoxicity may develop in association with lacosamide therapy. Liver function tests should be prompted in patients with symptoms suggestive of adverse effects after the initiation of lacosamide. Further research is required to identify predisposing factors of lacosamideinduced hepatotoxicity.

  14. Hepatotoxicity associated with choline magnesium trisalicylate: case report and review of salicylate-induced hepatotoxicity.

    PubMed

    Cersosimo, R J; Matthews, S J

    1987-01-01

    A case of a 21-year-old woman who had developed mild hepatotoxicity while receiving choline magnesium trisalicylate therapy is described. She presented with fever and mild hepatic enzyme elevations before salicylate therapy was instituted. Liver function tests (LFT) returned to normal within five days of hospitalization but she continued to develop daily fevers. Blood, urine, and throat cultures were negative. An acute viral illness or reactivation of systemic lupus erythematosus were the suspected diagnoses. Choline magnesium trisalicylate was then administered in an effort to control her fever, and was successful. After three days of salicylate therapy her LFT values began to rise. They continued to rise for five more days before salicylate hepatotoxicity was suspected. Choline magnesium trisalicylate was discontinued after eight days and the patient's LFT quickly returned to normal. The source of fever was never identified, although infection with cytomegalovirus was considered the most likely cause. Salicylate-induced hepatotoxicity is reviewed.

  15. Structure-activity relationship of C-terminal hexa- and heptapeptide substance P antagonists as studied in the guinea-pig ileum.

    PubMed

    Hörig, J; Schultheiss, H

    1984-10-01

    The 14 C-terminal heptapeptide analogues and one hexapeptide analogue of substance P (SP) were synthesized on the basis of the SP antagonist [D-Pro2,D-Trp7,9]SP-(1-11). They were tested in the guinea-pig ileum preparation for spasmogenic and antagonistic activities. All analogues except two had antagonistic activity. Spasmogenic activity was observed in three heptapeptide SP antagonists: [Arg5,D-Trp7,D-pCl-Phe9]SP-(5-11), [Arg5,D-Trp7,9,p-Cl-Phe8]SP-(5-11) and [Arg5,D-Trp7,9,Nle11]SP-(5-11). However, this effect became greatly reduced upon successive applications in almost all ileum preparations. For antagonistic potency D-Trp turned out to be of greater importance in position 9 than in position 7 of the SP molecule. The presence of a free amino group at the N-terminal of the peptide was also of significant importance for antagonistic potency. Exchange of Met11 for Nle resulted in a considerable increase of antagonistic potency, while other substitutions in this position were ineffective or slightly reduced the antagonistic effect in the ileum preparation.

  16. Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity[S

    PubMed Central

    Shi, Xiaolei; Yao, Dan; Gosnell, Blake A.; Chen, Chi

    2012-01-01

    During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury. PMID:22904346

  17. [Constitutional syndrome associated to metformin induced hepatotoxicity].

    PubMed

    de la Poza Gómez, Gema; Rivero Fernández, Miguel; Vázquez Romero, Manuel; Angueira Lapeña, Teresa; Arranz de la Mata, Gemma; Boixeda de Miquel, Daniel

    2008-12-01

    Metformin is an oral antidiabetic agent frequently used to manage type II diabetes. This drug produces nonspecific gastrointestinal symptoms in 5-20% of patients and, more rarely, has also been associated with severe adverse effects such as lactic acidosis. Only a few isolated cases of hepatotoxicity due to this drug have been documented. We report the case of an 83-year-old man with constitutional syndrome and hepatic biochemical alterations, which were attributed to metformin after ruling out an oncologic etiology and observing complete clinical and biochemical resolution after withdrawal of the drug.

  18. Levofloxacin-induced hepatotoxicity and death.

    PubMed

    Gulen, Muge; Ay, Mehmet Oguzhan; Avci, Akkan; Acikalin, Ayca; Icme, Ferhat

    2015-01-01

    Drug-induced hepatotoxicity is a major cause of hepatocellular injury in patients admitting to emergency services with acute liver failure. Hepatic necrosis may be at varying degrees from mild elevations in transaminases to fulminant hepatitis, and even death. The case of a 53-year-old female patient with toxic hepatitis due to levofloxacin and multiple organ failure secondary to toxic hepatitis is presented. Patient suffered itching, redness, and rash after receiving a single dose of 750 mg of levofloxacin tablets for pulmonary infection 10 days ago. Skin lesions had regressed within 3 days, but desquamation formed all over the body. After the fifth day of drug intake, complaints of abdominal pain, vomiting, and yellowing in skin color had started. The patient was referred to our emergency department with these complaints 10 days after drug intake. Patient was thought as a candidate for liver transplant, but cardiopulmonary arrest occurred, and the patient died before she could be referred to a transplant center. This case is important because hepatotoxicity and death due to levofloxacin is uncommon in the literature.

  19. Hepatotoxicity of illegal home-made alcohols.

    PubMed

    Gökce, Hasan; Akcan, Ramazan; Celikel, Adnan; Zeren, Cem; Ortanca, Ibrahim; Demirkiran, Sumeyra

    2016-10-01

    Alcohol-related hepatotoxicity is not only caused by excessive alcohol consumption but also caused and even accelerated by hepatotoxic ingredients other than ethanol. Concentrations of hepatotoxic substances might be significantly high, particularly in illegally produced home-made alcohols. In this study we aim to analyze the hepatotoxic effects of a home-made alcohol traditionally called "bogma raki" in Turkey. Fifty Wistar albino male rats were used. Five groups were randomly formed with ten animals in each. Besides laboratory diets, groups were fed as follows: Group 1 (control group) distilled water; Group 2 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day); Group 3 bogma raki with distilled water (%44 (v/v), 9.2 ml/kg/day)+walnut (10 g/kg/day); Group 4 whisky with distilled water (%40 (v/v), 9.2 ml/kg/day); Group 5 distilled water + walnut (10 g/kg/day), for 28 days. The toxicological analysis of The spirits were analyzed using Hewlett-Packard (Palo Alto, CA) GC/MS system with HP 6890 gas chromatograph, an HP 5972 mass selective detector (MSD) and an HP 6890 automatic liquid sampler GC/MS; the pressure of the carrier gas helium was 6.0 bar and the split value with a ratio of 1:100. The injection unit temperature set to 250 °C and MS quadrupole temperature set to 280 °C. The MS quadrupole detector ionization energy set to 70 eV. The initial column temperature was 60 °C (for 4 min) programmed by 6 °C/min to final temperature 160 °C and kept for 8 min at 160 °C. Utilized whisky and bogma raki samples were analyzed for the amounts of trans-anethole, ethanol, methanol, 1-propanolol, butanol, 2-butanol, 2-methyl-1-propanolol (isobutanol) and 3-methylbutanol (isoamyl alcohol). Histopathological changes in liver tissues were graded as follows; normal = 0 (<10%), mild = 1 (10%-40%), moderate = 2 (40%-70%), severe = 3 (above 70%). Chemical composition of illegally produced raki sample (%v/v) was as follows: trans-anethole %1

  20. In vitro transcriptomic prediction of hepatotoxicity for early drug discovery

    PubMed Central

    Cheng, Feng; Theodorescu, Dan; Schulman, Ira G.; Lee, Jae K.

    2012-01-01

    Liver toxicity (hepatotoxicity) is a critical issue in drug discovery and development. Standard preclinical evaluation of drug hepatotoxicity is generally performed using in vivo animal systems. However, only a small number of preselected compounds can be examined in vivo due to high experimental costs. A more efficient yet accurate screening technique which can identify potentially hepatotoxic compounds in the early stages of drug development would thus be valuable. Here, we develop and apply a novel genomic prediction technique for screening hepatotoxic compounds based on in vitro human liver cell tests. Using a training set of in vivo rodent experiments for drug hepatotoxicity evaluation, we discovered common biomarkers of drug-induced liver toxicity among six heterogeneous compounds. This gene set was further triaged to a subset of 32 genes that can be used as a multi-gene expression signature to predict hepatotoxicity. This multi-gene predictor was independently validated and showed consistently high prediction performance on five test sets of in vitro human liver cell and in vivo animal toxicity experiments. The predictor also demonstrated utility in evaluating different degrees of toxicity in response to drug concentrations which may be useful not only for discerning a compound’s general hepatotoxicity but also for determining its toxic concentration. PMID:21884709

  1. Hepatotoxicity of nucleoside reverse transcriptase inhibitors.

    PubMed

    Montessori, Valentina; Harris, Marianne; Montaner, Julio S G

    2003-05-01

    Hepatotoxicity is an adverse effect of all available classes of antiretrovirals, including nucleoside reverse transcriptase inhibitors (NRTI). A syndrome of hepatic steatosis and lactic acidosis has been recognized as a rare, potentially fatal complication since the advent of NRTI monotherapy in the early 1990s. Today, NRTI remain the backbone of antiretroviral combination regimens, and, with the success of current treatment strategies, exposure to two or more of these agents may occur over a number of years. Hepatic steatosis and lactic acidosis are accordingly being observed more frequently, along with a more recently recognized syndrome of chronic hyperlactatemia. These as well as other adverse effects of NRTI are mediated by inhibition of human DNA polymerase gamma, resulting in mitochondrial dysfunction in the liver and other tissues. Early recognition and intervention are essential to avert serious outcomes.

  2. ANTAGONISM OF CHLOROBENZENE-INDUCED HEPATOTOXICITY BY LINDANE

    EPA Science Inventory

    In a 2x2 factorial designed experiment involving chlorobenzene and gamma-hexachlorocyclohexane (lindane), the hepatotoxicity induced by a challenge dose of chlorobenzene was altered by the pretreatments due to selective changes in various metabolic pathways. These changes resulte...

  3. Herbal hepatotoxicity: a tabular compilation of reported cases.

    PubMed

    Teschke, Rolf; Wolff, Albrecht; Frenzel, Christian; Schulze, Johannes; Eickhoff, Axel

    2012-11-01

    Herbal hepatotoxicity is a field that has rapidly grown over the last few years along with increased use of herbal products worldwide. To summarize the various facets of this disease, we undertook a literature search for herbs, herbal drugs and herbal supplements with reported cases of herbal hepatotoxicity. A selective literature search was performed to identify published case reports, spontaneous case reports, case series and review articles regarding herbal hepatotoxicity. A total of 185 publications were identified and the results compiled. They show 60 different herbs, herbal drugs and herbal supplements with reported potential hepatotoxicity, additional information including synonyms of individual herbs, botanical names and cross references are provided. If known, details are presented for specific ingredients and chemicals in herbal products, and for references with authors that can be matched to each herbal product and to its effect on the liver. Based on stringent causality assessment methods and/or positive re-exposure tests, causality was highly probable or probable for Ayurvedic herbs, Chaparral, Chinese herbal mixture, Germander, Greater Celandine, green tea, few Herbalife products, Jin Bu Huan, Kava, Ma Huang, Mistletoe, Senna, Syo Saiko To and Venencapsan(®). In many other publications, however, causality was not properly evaluated by a liver-specific and for hepatotoxicity-validated causality assessment method such as the scale of CIOMS (Council for International Organizations of Medical Sciences). This compilation presents details of herbal hepatotoxicity, assisting thereby clinical assessment of involved physicians in the future. © 2012 John Wiley & Sons A/S.

  4. Stabilization of Angiotensin-(1-7) by key substitution with a cyclic non-natural amino acid.

    PubMed

    Wester, Anita; Devocelle, Marc; Tallant, E Ann; Chappell, Mark C; Gallagher, Patricia E; Paradisi, Francesca

    2017-10-01

    Angiotensin-(1-7) [Ang-(1-7)], a heptapeptide hormone of the renin-angiotensin-aldosterone system, is a promising candidate as a treatment for cancer that reflects its anti-proliferative and anti-angiogenic properties. However, the peptide's therapeutic potential is limited by the short half-life and low bioavailability resulting from rapid enzymatic metabolism by peptidases including angiotensin-converting enzyme (ACE) and dipeptidyl peptidase 3 (DPP 3). We report the facile assembly of three novel Ang-(1-7) analogues by solid-phase peptide synthesis which incorporates the cyclic non-natural δ-amino acid ACCA. The analogues containing the ACCA substitution at the site of ACE cleavage exhibit complete resistance to human ACE, while substitution at the DDP 3 cleavage site provided stability against DPP 3 hydrolysis. Furthermore, the analogues retain the anti-proliferative properties of Ang-(1-7) against the 4T1 and HT-1080 cancer cell lines. These results suggest that ACCA-substituted Ang-(1-7) analogues which show resistance against proteolytic degradation by peptidases known to hydrolyze the native heptapeptide may be novel therapeutics in the treatment of cancer.

  5. Silymarin nanoparticle prevents paracetamol-induced hepatotoxicity

    PubMed Central

    Das, Suvadra; Roy, Partha; Auddy, Runa Ghosh; Mukherjee, Arup

    2011-01-01

    Silymarin (Sm) is a polyphenolic component extracted from Silybum marianum. It is an antioxidant, traditionally used as an immunostimulant, hepatoprotectant, and dietary supplement. Relatively recently, Sm has proved to be a valuable chemopreventive and a useful antineoplastic agent. Medical success for Sm is, however, constrained by very low aqueous solubility and associated biopharmaceutical limitations. Sm flavonolignans are also susceptible to ion-catalyzed degradation in the gut. Proven antihepatotoxic activity of Sm cannot therefore be fully exploited in acute chemical poisoning conditions like that in paracetamol overdose. Moreover, a synchronous delivery that is required for hepatic regeneration is difficult to achieve by itself. This work is meant to circumvent the inherent limitations of Sm through the use of nanotechnology. Sm nanoparticles (Smnps) were prepared by nanoprecipitation in polyvinyl alcohol stabilized Eudragit RS100® polymer (Rohm Pharma GmbH, Darmstadt, Germany). Process parameter optimization provided 67.39% entrapment efficiency and a Gaussian particle distribution of average size 120.37 nm. Sm release from the nanoparticles was considerably sustained for all formulations. Smnps were strongly protective against hepatic damage when tested in a paracetamol overdose hepatotoxicity model. Nanoparticles recorded no animal death even when administered after an established paracetamol-induced hepatic necrosis. Preventing progress of paracetamol hepatic damage was traced for an efficient glutathione regeneration to a level of 11.3 μmol/g in hepatic tissue due to Smnps. PMID:21753880

  6. Active uptake system for substance P carboxy-terminal heptapeptide (5-11) into a fraction from rabbit enriched in glial cells.

    PubMed

    Inoue, A; Nakata, Y; Yajima, H; Segawa, T

    1984-10-01

    In the present study, we demonstrated the existence of an active uptake system for substance P carboxy-terminal heptapeptide, (5-11)SP. When a fraction from rabbit brain enriched in glial cells was incubated with [3H] (5-11)SP, an uptake of [3H](5-11)SP was observed. The uptake system has the properties of an active transport mechanism. Kinetic analysis indicated two components of [3H](5-11)SP uptake, one representing a high and the other a low affinity transport system. After unilateral ablation of the striatum, approximately 30% of the high affinity [3H](5-11)SP uptake capacity of substantia nigra slices disappeared. The subcellular distribution of the high affinity uptake indicated that [3H] 5-hydroxytryptamine was taken up mostly into the P2B fraction (synaptosomal fraction), whereas [3H](5-11)SP was taken up into the P2A fraction (myelin fraction) to the same extent as into the P2B fraction. These results suggest that when SP is released from nerve terminals, it is hydrolysed into (5-11)SP, which is in turn accumulated into glial cells as well as nerve terminals and that this high affinity uptake mechanism may play an important role in terminating the synaptic action of SP.

  7. Research Advances on Hepatotoxicity of Herbal Medicines in China.

    PubMed

    Liu, Changxiao; Fan, Huirong; Li, Yazhuo; Xiao, Xiaohe

    2016-01-01

    In general, herbal medicines have been considered as safe by the general public, since they are naturally occurring and have been applied in treatment for over thousands of years. As the use of herbal medicine is rapidly increasing globally, the potential toxicity of herbal drugs, in particular drug-induced liver injury (DILI), has now become a serious medical issue. According to the literature, the authors analyzed and discussed the hepatotoxicity problem of Chinese herbal medicines (CHM), including global overview on herbal-induced liver injury (HILI), current research progress on toxic CHM, diagnosis and treatment of HILI, and modern approaches and technologies of study of hepatotoxicity. As to promote the recognition of HILI and tackle the issue, a guideline for the diagnosis and treatment of HILI has recently been drafted by Chinese scientists. As suggested by the guideline, the hepatotoxicity issue of CHM, as a matter of fact, is overestimated. Up to date, the investigation of hepatotoxicity of CHM is now booming with worldwide application of CHM. This review therefore provides useful information for investigating hepatotoxicity of herbal medicine and characterizing DILI caused by CHM. In addition, authors describe in which way further efforts should be made to study the rationale of CHM and liver injury.

  8. Research Advances on Hepatotoxicity of Herbal Medicines in China

    PubMed Central

    Fan, Huirong; Li, Yazhuo; Xiao, Xiaohe

    2016-01-01

    In general, herbal medicines have been considered as safe by the general public, since they are naturally occurring and have been applied in treatment for over thousands of years. As the use of herbal medicine is rapidly increasing globally, the potential toxicity of herbal drugs, in particular drug-induced liver injury (DILI), has now become a serious medical issue. According to the literature, the authors analyzed and discussed the hepatotoxicity problem of Chinese herbal medicines (CHM), including global overview on herbal-induced liver injury (HILI), current research progress on toxic CHM, diagnosis and treatment of HILI, and modern approaches and technologies of study of hepatotoxicity. As to promote the recognition of HILI and tackle the issue, a guideline for the diagnosis and treatment of HILI has recently been drafted by Chinese scientists. As suggested by the guideline, the hepatotoxicity issue of CHM, as a matter of fact, is overestimated. Up to date, the investigation of hepatotoxicity of CHM is now booming with worldwide application of CHM. This review therefore provides useful information for investigating hepatotoxicity of herbal medicine and characterizing DILI caused by CHM. In addition, authors describe in which way further efforts should be made to study the rationale of CHM and liver injury. PMID:28078299

  9. Herbal Hepatotoxicity: Clinical Characteristics and Listing Compilation

    PubMed Central

    Frenzel, Christian; Teschke, Rolf

    2016-01-01

    Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance. PMID:27128912

  10. Early Endosomal Escape of a Cyclic Cell-Penetrating Peptide Allows Effective Cytosolic Cargo Delivery

    PubMed Central

    2015-01-01

    Cyclic heptapeptide cyclo(FΦRRRRQ) (cFΦR4, where Φ is l-2-naphthylalanine) was recently found to be efficiently internalized by mammalian cells. In this study, its mechanism of internalization was investigated by perturbing various endocytic events through the introduction of pharmacologic agents and genetic mutations. The results show that cFΦR4 binds directly to membrane phospholipids, is internalized into human cancer cells through endocytosis, and escapes from early endosomes into the cytoplasm. Its cargo capacity was examined with a wide variety of molecules, including small-molecule dyes, linear and cyclic peptides of various charged states, and proteins. Depending on the nature of the cargos, they may be delivered by endocyclic (insertion of cargo into the cFΦR4 ring), exocyclic (attachment of cargo to the Gln side chain), or bicyclic approaches (fusion of cFΦR4 and cyclic cargo rings). The overall delivery efficiency (i.e., delivery of cargo into the cytoplasm and nucleus) of cFΦR4 was 4–12-fold higher than those of nonaarginine, HIV Tat-derived peptide, or penetratin. The higher delivery efficiency, coupled with superior serum stability, minimal toxicity, and synthetic accessibility, renders cFΦR4 a useful transporter for intracellular cargo delivery and a suitable system for investigating the mechanism of endosomal escape. PMID:24896852

  11. Hepatotoxic constituents and toxicological mechanism of Xanthium strumarium L. fruits.

    PubMed

    Xue, Li-Ming; Zhang, Qiao-Yan; Han, Ping; Jiang, Yi-Ping; Yan, Rong-Di; Wang, Yang; Rahman, Khalid; Jia, Min; Han, Ting; Qin, Lu-Ping

    2014-03-14

    In the recent years, the international community has attached increasing importance to possible toxicity associated with Traditional Chinese Medicine (TCM). And hepatotoxicity is one of the major concerns, a fundamental pathological process induced by toxicant. This paper is in an attempt to identify the hepatotoxic components in Xanthium strumarium L. fruits (XSF) and interpret the toxicological mechanism induced by XSF. XSF extract was prepared and seven characteristic components were isolated and identified in XSF water extracts. We evaluated their hepatotoxicity effect on cell proliferation and lactate dehydrogenase (LDH) activity in L-02 and BRL liver cell line. An integrated metabonomics study using high-resolution (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy combined with multivariate statistical analysis was undertake to elucidate the hepatotoxicity mechanism induced in rats by XSF. The urine and serum metabolites were measured after treatment of rats with XSF (7.5, 15.0 and 30.0 g/kg/day) for 5 days. The results showed that atractyloside, carboxyatractyloside, 4'-desulphate-atractyloside and XSF induced significant cytotoxic effects in both L-02 and BRL liver cell lines, indicating that atractyloside, carboxyatractyloside, and 4'-desulphate-atractyloside were the toxic components of XSF. When rats were treated with XSF at 30.0 g/kg the hepatotoxicity was reflected in the changes observed in serum biochemical profiles and by the histopathological examination of the liver. The levels of VLDL/LDL, 3-HB, lactate, acetate, acetone and glutamate in serum were increased in this group, while d-glucose, choline and valine were decreased. The elevation in the levels of succinate, citrate, 2-oxo-glutamate, glycine, 3-HB, acetate, lactate, hippurate, dimethylglycine, methylamine, dimethylamine, phenylalanine and tryptophan was observed in urine, in contrast a reduction in the intensities of taurine, d-glucose, N-acetyl-glucoprotein and trimethylamine

  12. Heat Shock Protein 27-Targeted Heptapeptide of the PKC{Delta} Catalytic V5 Region Sensitizes Tumors With Radio- and Chemoresistance

    SciT

    Lee, Hae-June; Kim, Eun-Ho; School of Life Sciences and Biotechnology, Korea University, Seoul

    Purpose: Previous data suggest that the PKC{delta} catalytic V5 (PKC{delta}-V5) heptapeptide (HEPT) (FEQFLDI) binds HSP27 and blocks HSP27-mediated radio- or chemoresistance. Here we investigated further the in vivo function of the PKC{delta}-V5 HEPT. Methods and Materials: Labeling of HEPT with Cy5.5 or fluorescein isothiocyanate was performed to evaluate in vitro or in vivo distribution of HEPT. A clonogenic survival assay, flow cytometry, and Western blotting of cleaved caspase-3 were performed to determine in vitro sensitization effects of HEPT plus ionizing radiation (IR) versus IR alone or those of HEPT plus cisplatin(Cis) versus Cis alone. A nude mouse xenografting system wasmore » also applied to detect in vivo sensitizing effects of HEPT. Results: HEPT efficiently bound to HSP27 and showed sensitization after combined treatment with IR versus treatment with Cis alone in NCI-H1299 lung carcinoma cells, with higher HSP27 expression, which was similar to that of combined treatment with IR or with Cis alone in NCI-H460 lung carcinoma cells with lower HSP27 expression. In vivo image analysis using Cy5.5-labeled HEPT showed that HEPT was retained in HSP27-overexpressing cancer cells after xenografting to nude mice. Combined treatment of HEPT with IR versus that with Cis alone in xenografted mice showed that HEPT increased radio- or chemosensitization in NCI-H1299 cells compared to that in mice xenografted with NCI-H460 cells. Conclusions: The novel PKC{delta}-V5 HEPT may help overcome HSP27-mediated radio- or chemoresistance.« less

  13. Distribution in Rats Internal Organs of Intraperitoneally Given 125I-Labeled Heptapeptide [2-8]-Leucopyrokinin ([2-8]-LPK), a Truncated Analog of Insect Neuropeptide Leucopyrokinin.

    PubMed

    Ryszka, Florian; Dolińska, Barbara; Suszka-Świtek, Aleksandra; Rykaczewska-Czerwińska, Monika; Konopińska, Danuta; Kuczer, Mariola; Plech, Andrzej

    2015-01-01

    It was previously found that synthetic, insect-derived octapeptide leucopyrokinin (LPK) applied directly into the lateral brain ventricle induced a significant antinociceptive effect in rats. Its synthetic truncated analog heptapeptide [2-8]-leucopyrokinin displayed a stronger antinociceptive effect in comparison to native LPK. Moreover it was previously found a high accumulation of these both 125I-labeled peptides in adrenals, as well as in hypothalamus and in hippocampus of rats brain. The aim of the present study was to assess the distribution of 125I-labeled [2-8]-leucopyrokinin in rats' internal organs an in several parts of the brain after peripheral - intraperitoneal (i.p.) administration. The study was performed on male Wistar rats. A synthetic [2-8]-leucopyrokinin ([2-8]-LPK) was iodinated with Na125I. On the day of experiment a solution of 125I-[2-8]-LPK was i.p. injected and the next after 1 and 24 h animals were sacrificed by decapitation. Radioactivity levels in samples of parts of the brain and of internal organs were determined by counter Gamma Auto Count. A uniform, low accumulation 125I-[2-8]-LPK was found in evaluated samples of the brain and in internal organs. The results of the present study indicate a weak penetration into the brain and internal organs of intraperitoneally applied 125I-[2-8]-LPK in rats and correspond with previously determined weak biological effects of i.p. injected LPK and [2-8]-LPK.

  14. Are Math Grades Cyclical?

    ERIC Educational Resources Information Center

    Adams, Gerald J.; Dial, Micah

    1998-01-01

    The cyclical nature of mathematics grades was studied for a cohort of elementary school students from a large metropolitan school district in Texas over six years (average cohort size of 8495). The study used an autoregressive integrated moving average (ARIMA) model. Results indicate that grades do exhibit a significant cyclical pattern. (SLD)

  15. Affordable Cyclic Voltammetry

    ERIC Educational Resources Information Center

    Stewart, Greg; Kuntzleman, Thomas S.; Amend, John R.; Collins, Michael J.

    2009-01-01

    Cyclic voltammetry is an important component of the undergraduate chemical curriculum. Unfortunately, undergraduate students rarely have the opportunity to conduct experiments in cyclic voltammetry owing to the high cost of potentiostats, which are required to control these experiments. By using MicroLab data acquisition interfaces in conjunction…

  16. Hepatotoxicity of Microcystin-LR in Fed and Fasted Rats

    DTIC Science & Technology

    1990-04-20

    a free radical scavenger, silymarin , prot’cted mice against MCYST-LR (MEREISH et al., 1989). One of the more dramatic changes in liver after exposure...Microcystin-LR hepatotoxicity by silymarin in mice and rats. The FASEB J. 3, A1190. MERILUOTO, J. A. 0., SANDSTROM, A., ERIKSSON, J. E., REMAUD, G

  17. Side Effects of HIV Medicines: HIV and Hepatotoxicity

    MedlinePlus

    ... provider tells you to. How is hepatotoxicity detected? Liver function tests (LFTs) are a group of blood tests ... Laboratory Testing From the Department of Veterans Affairs: Primary Care of Veterans with HIV: Liver Disease and Cirrhosis From the National Institutes of ...

  18. Role of metabolism in drug-induced idiosyncratic hepatotoxicity.

    PubMed

    Walgren, Jennie L; Mitchell, Michael D; Thompson, David C

    2005-01-01

    Rare adverse reactions to drugs that are of unknown etiology, or idiosyncratic reactions, can produce severe medical complications or even death in patients. Current hypotheses suggest that metabolic activation of a drug to a reactive intermediate is a necessary, yet insufficient, step in the generation of an idiosyncratic reaction. We review evidence for this hypothesis with drugs that are associated with hepatotoxicity, one of the most common types of idiosyncratic reactions in humans. We identified 21 drugs that have either been withdrawn from the U.S. market due to hepatotoxicity or have a black box warning for hepatotoxicity. Evidence for the formation of reactive metabolites was found for 5 out of 6 drugs that were withdrawn, and 8 out of 15 drugs that have black box warnings. For the other drugs, either evidence was not available or suitable studies have not been carried out. We also review evidence for reactive intermediate formation from a number of additional drugs that have been associated with idiosyncratic hepatotoxicity but do not have black box warnings. Finally, we consider the potential role that high dosages may play in these adverse reactions.

  19. Genetics Home Reference: cyclic neutropenia

    MedlinePlus

    ... Facebook Twitter Home Health Conditions Cyclic neutropenia Cyclic neutropenia Printable PDF Open All Close All Enable Javascript to view the expand/collapse boxes. Description Cyclic neutropenia is a disorder that causes frequent infections and ...

  20. Cyclic control stick

    DOEpatents

    Whitaker, Charles N.; Zimmermann, Richard E.

    1989-01-01

    A cyclic control stick of the type used in helicopters for reducing the safety hazards associated with such a mechanism in the event of a crewman being thrown violently into contact with the cyclic control stick resulting from a crash or the like. The cyclic control stick is configured to break away upon the exertion of an impact force which exceeds a predetermined value and/or is exerted for more than a momentary time duration. The cyclic control stick is also configured to be adjustable so as to locate the grip thereof as far away from the crewman as possible for safety reasons without comprising the comfort of the crewman or the use of the control stick, and a crushable pad is provided on the top of the grip for impact energy absorbing purposes.

  1. Hepatotoxic microcystin removal using pumice embedded monolithic composite cryogel as an alternative water treatment method.

    PubMed

    Gurbuz, Fatma; Ceylan, Şeyda; Odabaşı, Mehmet; Codd, Geoffrey A

    2016-03-01

    Microcystins are the most commonly encountered water-borne cyanotoxins which present short- and long-term risks to human health. Guidelines at international and national level, and legislation in some countries, have been introduced for the effective health risk management of these potent hepatotoxic, tumour-promoters. The stable cyclic structure of microcystins and their common production by cyanobacteria in waterbodies at times of high total dissolved organic carbon content presents challenges to drinking water treatment facilities, with conventional, advanced and novel strategies under evaluation. Here, we have studied the removal of microcystins using three different forms of pumice particles (PPs), which are embedded into macroporous cryogel columns. Macroporous composite cryogel columns (MCCs) are a new generation of separation media designed to face this challenging task. Three different MCCs were prepared by adding plain PPs, Cu(2+)-attached PPs and Fe(3+)-attached PPs to reaction media before the cryogelation step. Column studies showed that MCCs could be successfully used as an alternative water treatment method for successful microcystin removal. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Hepatotoxicity by Drugs: The Most Common Implicated Agents

    PubMed Central

    Björnsson, Einar S.

    2016-01-01

    Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab. PMID:26861310

  3. Rofecoxib-induced hepatotoxicity: A forgotten complication of the coxibs

    PubMed Central

    Yan, Brian; Leung, Yvette; Urbanski, Stefan J; Myers, Robert P

    2006-01-01

    Rofecoxib is a member of the coxib family of nonsteroidal anti-inflammatory drugs that selectively inhibit cyclooxygenase-2. Although the coxibs are generally well-tolerated, rofecoxib was recently withdrawn from the market due to concerns regarding cardiovascular safety. Rare cases of hepatic injury attributable to the coxibs have been reported. In the present study, two additional cases of severe hepatotoxicity are described in patients with cholestatic symptoms and abnormal liver biochemistry, shortly following the initiation of rofecoxib for arthritic complaints. In both cases, liver histology was compatible with drug-induced hepatotoxicity, and rapid clinical and biochemical improvements were observed following rofecoxib discontinuation. With new coxibs and expanding indications on the horizon, physicians in all areas of practice must be aware of this disorder and consider it in any patient who develops hepatic dysfunction after taking a coxib. PMID:16691302

  4. Hepatotoxicity Induced by “the 3Ks”: Kava, Kratom and Khat

    PubMed Central

    Pantano, Flaminia; Tittarelli, Roberta; Mannocchi, Giulio; Zaami, Simona; Ricci, Serafino; Giorgetti, Raffaele; Terranova, Daniela; Busardò, Francesco P.; Marinelli, Enrico

    2016-01-01

    The 3Ks (kava, kratom and khat) are herbals that can potentially induce liver injuries. On the one hand, growing controversial data have been reported about the hepatotoxicity of kratom, while, on the other hand, even though kava and khat hepatotoxicity has been investigated, the hepatotoxic effects are still not clear. Chronic recreational use of kratom has been associated with rare instances of acute liver injury. Several studies and case reports have suggested that khat is hepatotoxic, leading to deranged liver enzymes and also histopathological evidence of acute hepatocellular degeneration. Numerous reports of severe hepatotoxicity potentially induced by kava have also been highlighted, both in the USA and Europe. The aim of this review is to focus on the different patterns and the mechanisms of hepatotoxicity induced by “the 3Ks”, while trying to clarify the numerous aspects that still need to be addressed. PMID:27092496

  5. Predicting Drug-induced Hepatotoxicity Using QSAR and Toxicogenomics Approaches

    PubMed Central

    Low, Yen; Uehara, Takeki; Minowa, Yohsuke; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro; Sedykh, Alexander; Muratov, Eugene; Fourches, Denis; Zhu, Hao; Rusyn, Ivan; Tropsha, Alexander

    2014-01-01

    Quantitative Structure-Activity Relationship (QSAR) modeling and toxicogenomics are used independently as predictive tools in toxicology. In this study, we evaluated the power of several statistical models for predicting drug hepatotoxicity in rats using different descriptors of drug molecules, namely their chemical descriptors and toxicogenomic profiles. The records were taken from the Toxicogenomics Project rat liver microarray database containing information on 127 drugs (http://toxico.nibio.go.jp/datalist.html). The model endpoint was hepatotoxicity in the rat following 28 days of exposure, established by liver histopathology and serum chemistry. First, we developed multiple conventional QSAR classification models using a comprehensive set of chemical descriptors and several classification methods (k nearest neighbor, support vector machines, random forests, and distance weighted discrimination). With chemical descriptors alone, external predictivity (Correct Classification Rate, CCR) from 5-fold external cross-validation was 61%. Next, the same classification methods were employed to build models using only toxicogenomic data (24h after a single exposure) treated as biological descriptors. The optimized models used only 85 selected toxicogenomic descriptors and had CCR as high as 76%. Finally, hybrid models combining both chemical descriptors and transcripts were developed; their CCRs were between 68 and 77%. Although the accuracy of hybrid models did not exceed that of the models based on toxicogenomic data alone, the use of both chemical and biological descriptors enriched the interpretation of the models. In addition to finding 85 transcripts that were predictive and highly relevant to the mechanisms of drug-induced liver injury, chemical structural alerts for hepatotoxicity were also identified. These results suggest that concurrent exploration of the chemical features and acute treatment-induced changes in transcript levels will both enrich the

  6. [Hepatotoxicity in healthy infants exposed to nevirapine during pregnancy].

    PubMed

    Iveli, Pablo; Noguera-Julian, Antoni; Soler-Palacín, Pere; Martín-Nalda, Andrea; Rovira-Girabal, Núria; Fortuny-Guasch, Clàudia; Figueras-Nadal, Concepció

    2016-01-01

    The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy. A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6weeks of age, was collected. Patients were allocated to 2groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS). This study included 160newborns from 159pregnancies (88exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95%CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95%CI: 0.0-6.1%) in the group exposed to nevirapine (P=.585). The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

  7. Exacerbation of Acetaminophen Hepatotoxicity by the Anthelmentic Drug Fenbendazole

    PubMed Central

    Gardner, Carol R.; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2012-01-01

    Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8–12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole. PMID

  8. Exacerbation of acetaminophen hepatotoxicity by the anthelmentic drug fenbendazole.

    PubMed

    Gardner, Carol R; Mishin, Vladimir; Laskin, Jeffrey D; Laskin, Debra L

    2012-02-01

    Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8-12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole.

  9. A Novel Resolvin-Based Strategy for Limiting Acetaminophen Hepatotoxicity

    PubMed Central

    Patel, Suraj J; Luther, Jay; Bohr, Stefan; Iracheta-Vellve, Arvin; Li, Matthew; King, Kevin R; Chung, Raymond T; Yarmush, Martin L

    2016-01-01

    Objectives: Acetaminophen (APAP)-induced hepatotoxicity is a major cause of morbidity and mortality. The current pharmacologic treatment for APAP hepatotoxicity, N-acetyl cysteine (NAC), targets the initial metabolite-driven injury but does not directly affect the host inflammatory response. Because of this, NAC is less effective if given at later stages in the disease course. Resolvins, a novel group of lipid mediators shown to attenuate host inflammation, may be a therapeutic intervention for APAP hepatotoxicity. Methods: The temporal patterns of liver injury and neutrophil activation were investigated in a murine model of APAP hepatotoxicity. In addition, the effect of neutrophil depletion and resolvin administration on the severity of liver injury induced by APAP was studied. In vitro studies to investigate the mechanism of resolvin effect on hepatocyte injury and neutrophil adhesion were performed. Results: We demonstrate that hepatic neutrophil activation occurs secondary to the initial liver injury induced directly by APAP. We also show that neutrophil depletion attenuates APAP-induced liver injury, and administration of resolvins hours after APAP challenge not only attenuates liver injury, but also extends the therapeutic window eightfold compared to NAC. Mechanistic in vitro analysis highlights resolvins' ability to inhibit neutrophil attachment to endothelial cells in the presence of the reactive metabolite of APAP. Conclusions: This study highlights the ability of resolvins to protect against APAP-induced liver injury and extend the therapeutic window compared to NAC. Although the mechanism for resolvin-mediated hepatoprotection is likely multifactorial, inhibition of neutrophil infiltration and activation appears to play an important role. PMID:26986653

  10. p-Aminophenol-induced hepatotoxicity in hamsters: role of glutathione.

    PubMed

    Fu, Xin; Chen, Theresa S; Ray, Mukunda B; Nagasawa, Herbert T; Williams, Walter M

    2004-01-01

    p-Aminophenol (PAP) is a widely used industrial chemical and a known nephrotoxin. Recently, it was found to also cause hepatotoxicity and glutathione (GSH) depletion in mice. The exact mechanism of liver toxicity is not known. The aims of this study were to determine whether PAP can cause acute hepatotoxicity in hamsters and to further investigate the role of GSH in PAP-induced toxicity. PAP was administered ip to hamsters in doses of 200-800 mg/kg. Liver damage at 24 h after PAP administration was assessed by elevations in plasma enzyme activities and histopathologic examination. GSH and cysteine (Cys) levels in liver at 4 h were determined by HPLC. PAP decreased hepatic GSH concentration to 8% and Cys to 30% of vehicle control values. It increased plasma glutamic pyruvic transaminase (GPT) activity by 47-fold and sorbitol dehydrogenase (SDH) activity by 113-fold. PAP also caused severe centrilobular hepatocellular necrosis. 2(RS)-n-Propylthiazolidine-4(R)-carboxylic acid (PTCA), a Cys precursor, attenuated the PAP-induced decreases in hepatic sulfhydryl levels; GSH and Cys were 39% and 78% of vehicle controls, respectively. PTCA also attenuated the PAP-induced elevations in plasma enzyme activities and hepatic necrosis. It was concluded that PAP hepatotoxicity is associated with depletion of hepatic GSH and can be prevented by PTCA. Copyright 2004 Wiley Periodicals, Inc.

  11. Predicting hepatotoxicity using ToxCast in vitro bioactivity and ...

    EPA Pesticide Factsheets

    Background: The U.S. EPA ToxCastTM program is screening thousands of environmental chemicals for bioactivity using hundreds of high-throughput in vitro assays to build predictive models of toxicity. We represented chemicals based on bioactivity and chemical structure descriptors then used supervised machine learning to predict their hepatotoxic effects.Results: A set of 677 chemicals were represented by 711 in vitro bioactivity descriptors (from ToxCast assays), 4,376 chemical structure descriptors (from QikProp, OpenBabel, PADEL, and PubChem), and three hepatotoxicity categories (from animal studies). Hepatotoxicants were defined by rat liver histopathology observed after chronic chemical testing and grouped into hypertrophy (161), injury (101) and proliferative lesions (99). Classifiers were built using six machine learning algorithms: linear discriminant analysis (LDA), Naïve Bayes (NB), support vector classification (SVM), classification and regression trees (CART), k-nearest neighbors (KNN) and an ensemble of classifiers (ENSMB). Classifiers of hepatotoxicity were built using chemical structure, ToxCast bioactivity, and a hybrid representation. Predictive performance was evaluated using 10-fold cross-validation testing and in-loop, filter-based, feature subset selection. Hybrid classifiers had the best balanced accuracy for predicting hypertrophy (0.78±0.08), injury (0.73±0.10) and proliferative lesions (0.72±0.09). Though chemical and bioactivity class

  12. Hepatotoxicity induced by methimazole in a previously healthy patient.

    PubMed

    Gallelli, Luca; Staltari, Orietta; Palleria, Caterina; De Sarro, Giovambattista; Ferraro, Maria

    2009-09-01

    We report a case of hepatotoxicity induced by methimazole treatment in a patient affected by hyperthyroidism. A 54-year-old man, presented to our observation for palpitations, excessive sweating, weakness, heat intolerance and weight loss. On physical examination, his blood pressure was 140/90 mmHg and heart beat was 100/min regular. He had mild tremors and left exophthalmos. Laboratory test revealed a significant increase in serum thyroid hormone levels with a decrease in thyroid stimulating hormone levels. A diagnosis of hyperthyroidism was made and he began treatment with methimazole (30 mg/day). Fourteen days later, he returned for the development of scleral icterus, followed by dark urine, and abdominal pain in the right upper quadrant. Laboratory examinations and liver biopsy performed a diagnosis of cholestatic hepatitis, secondary to methimazole usage. Methimazole was promptly withdrawn and cholestyramine, ursodeoxycholic acid, and chlorpheniramine were given. After five days, abdominal pain resolved and laboratory parameters returned to normal. Naranjo probability scale indicated a probable relationship between hepatotoxicity and methimazole therapy. In conclusion physicians should be aware the risk of hepatotoxicity related with methimazole.

  13. Experimental models of hepatotoxicity related to acute liver failure

    SciT

    Maes, Michaël; Vinken, Mathieu, E-mail: mvinken@vub.ac.be; Jaeschke, Hartmut

    Acute liver failure can be the consequence of various etiologies, with most cases arising from drug-induced hepatotoxicity in Western countries. Despite advances in this field, the management of acute liver failure continues to be one of the most challenging problems in clinical medicine. The availability of adequate experimental models is of crucial importance to provide a better understanding of this condition and to allow identification of novel drug targets, testing the efficacy of new therapeutic interventions and acting as models for assessing mechanisms of toxicity. Experimental models of hepatotoxicity related to acute liver failure rely on surgical procedures, chemical exposuremore » or viral infection. Each of these models has a number of strengths and weaknesses. This paper specifically reviews commonly used chemical in vivo and in vitro models of hepatotoxicity associated with acute liver failure. - Highlights: • The murine APAP model is very close to what is observed in patients. • The Gal/ET model is useful to study TNFα-mediated apoptotic signaling mechanisms. • Fas receptor activation is an effective model of apoptosis and secondary necrosis. • The ConA model is a relevant model of auto-immune hepatitis and viral hepatitis. • Multiple time point evaluation needed in experimental models of acute liver injury.« less

  14. Hepatotoxicity of NONI juice: Report of two cases

    PubMed Central

    Stadlbauer, Vanessa; Fickert, Peter; Lackner, Carolin; Schmerlaib, Jutta; Krisper, Peter; Trauner, Michael; Stauber, Rudolf E

    2005-01-01

    AIM: NONI juice (Morinda citrifolia) is an increasingly popular wellness drink claimed to be beneficial for many illnesses. No overt toxicity has been reported to date. We present two cases of novel hepatotoxicity of NONI juice. Causality of liver injury by NONI juice was asses-sed. Routine laboratory tests and transjugular or percutaneous liver biopsy were performed. The first patient underwent successful liver transplantation while the second patient recovered spontaneously after cessation of NONI juice. A 29-year-old man with previous toxic hepatitis associated with small doses of paracetamol developed sub-acute hepatic failure following consumption of 1.5 L NONI juice over 3 wk necessitating urgent liver transplantation. A 62-year-old woman without evidence of previous liver disease developed an episode of self-limited acute hepatitis following consumption of 2 L NONI juice for over 3 mo. The most likely hepatotoxic components of Morinda citrifolia were anthraquinones. Physicians should be aware of potential hepatotoxicity of NONI juice. PMID:16094725

  15. Rocuronium is more hepatotoxic than succinylcholine in vitro.

    PubMed

    Sauer, Martin; Piel, Ines; Haubner, Cristof; Richter, Georg; Mann, Miriam; Nöldge-Schomburg, Gabriele; Mencke, Thomas

    2017-09-01

    The development of liver failure is a major problem in critically ill patients. The hepatotoxicity of many drugs, as one important reason for liver failure, is poorly screened for in human models. Rocuronium and succinylcholine are neuromuscular blocking agents used for tracheal intubation and for rapid-sequence induction. We used an in-vitro test with a permanent cell line and compared rocuronium and succinylcholine for hepatotoxicity. In-vitro study. A basic science laboratory, University Hospital Rostock, Germany. The basic test compound is the permanent human liver cell line HepG2/C3A. In a standardised microtitre plate assay the toxicity of different concentrations of rocuronium, succinylcholine and plasma control was tested. After two incubation periods of 3 days, the viability of cells (XTT test, lactate dehydrogenase release and trypan blue staining), micro-albumin synthesis and the cytochrome 1A2 activity (metabolism of ethoxyresorufin) were measured. Differences between rocuronium and succinylcholine were assessed using the Kruskal-Wallis one-way test and two-tailed Mann-Whitney U test. Rocuronium, but not succinylcholine, led to a significant dose-dependent decrease of viability, albumin synthesis and cytochrome 1A2 activity of test cells. An in-vitro test with a cell line showed hepatotoxicity of rocuronium that was dose-dependent. Further studies are needed to investigate the underlying mechanisms of the effects of rocuronium on hepatic cellular integrity. Not suitable.

  16. Hepatotoxicity due to red bush tea consumption: a case report.

    PubMed

    Reddy, Shamantha; Mishra, Pragnyadipta; Qureshi, Sana; Nair, Singh; Straker, Tracey

    2016-12-01

    Many conventional drugs used today, including isoniazid, dapsone, and acetaminophen, are well recognized culprits of hepatotoxicity. With increasing use of complementary and alternative medical therapies, several herbal medicines, such as Ma-Huang, kava, and chaparral leaf, have been implicated as hepatotoxins. Hepatotoxicity may be the most frequent adverse reaction to these herbal remedies when taken in excessive quantities. A myriad of liver dysfunctions may occur including transient liver enzyme abnormalities due to acute and chronic hepatitis. These herbal products are often overlooked as the causal etiologic agent during the evaluation of a patient with elevated liver function tests. We describe a case of hepatotoxicity due to ingestion of red bush tea diagnosed during preoperative assessment of a patient scheduled for laparoscopic appendectomy. Elevated liver enzymes and thrombocytopenia detected in the patient's laboratory work up confounded the initial diagnosis of acute appendicitis and additional investigations were required to rule out cholecystitis and other causes of hepatitis. Open appendectomy was done uneventfully under spinal anesthesia without any further deterioration of hepatic function. Copyright © 2016. Published by Elsevier Inc.

  17. Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests.

    PubMed

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel

    2013-07-27

    To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) < 5 upper limit of normal (N) before reexposure, with N as the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n = 3). Confounding

  18. Herbalife hepatotoxicity: Evaluation of cases with positive reexposure tests

    PubMed Central

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel

    2013-01-01

    AIM: To analyze the validity of applied test criteria and causality assessment methods in assumed Herbalife hepatotoxicity with positive reexposure tests. METHODS: We searched the Medline database for suspected cases of Herbalife hepatotoxicity and retrieved 53 cases including eight cases with a positive unintentional reexposure and a high causality level for Herbalife. First, analysis of these eight cases focused on the data quality of the positive reexposure cases, requiring a baseline value of alanine aminotransferase (ALT) < 5 upper limit of normal (N) before reexposure, with N as the upper limit of normal, and a doubling of the ALT value at reexposure as compared to the ALT value at baseline prior to reexposure. Second, reported methods to assess causality in the eight cases were evaluated, and then the liver specific Council for International Organizations of Medical Sciences (CIOMS) scale validated for hepatotoxicity cases was used for quantitative causality reevaluation. This scale consists of various specific elements with scores provided through the respective case data, and the sum of the scores yields a causality grading for each individual case of initially suspected hepatotoxicity. RESULTS: Details of positive reexposure test conditions and their individual results were scattered in virtually all cases, since reexposures were unintentional and allowed only retrospective rather than prospective assessments. In 1/8 cases, criteria for a positive reexposure were fulfilled, whereas in the remaining cases the reexposure test was classified as negative (n = 1), or the data were considered as uninterpretable due to missing information to comply adequately with the criteria (n = 6). In virtually all assessed cases, liver unspecific causality assessment methods were applied rather than a liver specific method such as the CIOMS scale. Using this scale, causality gradings for Herbalife in these eight cases were probable (n = 1), unlikely (n = 4), and excluded (n

  19. Cyclic membrane separation process

    DOEpatents

    Nemser, Stuart M.

    2005-05-03

    A cyclic process for controlling environmental emissions of volatile organic compounds (VOC) from vapor recovery in storage and dispensing operations of liquids maintains a vacuum in the storage tank ullage. In the first part of a two-part cyclic process ullage vapor is discharged through a vapor recovery system in which VOC are stripped from vented gas with a selectively gas permeable membrane. In the second part, the membrane is inoperative while gas pressure rises in the ullage. In one aspect of this invention, a vacuum is drawn in the membrane separation unit thus reducing overall VOC emissions.

  20. Cyclic membrane separation process

    DOEpatents

    Bowser, John

    2004-04-13

    A cyclic process for controlling environmental emissions of volatile organic compounds (VOC) from vapor recovery in storage and dispensing operations of liquids maintains a vacuum in the storage tank ullage. In one of a two-part cyclic process ullage vapor is discharged through a vapor recovery system in which VOC are stripped from vented gas with a selectively gas permeable membrane. In the other part, the membrane is inoperative while gas pressure rises in the ullage. Ambient air is charged to the membrane separation unit during the latter part of the cycle.

  1. Hepatotoxicity Induced by Sophora flavescens and Hepatic Accumulation of Kurarinone, a Major Hepatotoxic Constituent of Sophora flavescens in Rats.

    PubMed

    Jiang, Peng; Zhang, Xiuwen; Huang, Yutong; Cheng, Nengneng; Ma, Yueming

    2017-10-25

    Our previous study showed that kurarinone was the main hepatotoxic ingredient of Sophora flavescens , accumulating in the liver. This study characterized the mechanism of Sophora flavescens extract (ESF) hepatotoxicity and hepatic accumulation of kurarinone. ESF impaired hepatic function and caused fat accumulation in the liver after oral administration (1.25 and 2.5 g/kg for 14 days in rats). Serum metabolomics evaluation based on high-resolution mass spectrometry was conducted and real-time PCR was used to determine the expression levels of CPT-1, CPT-2, PPAR-α, and LCAD genes. Effects of kurarinone on triglyceride levels were evaluated in HL-7702 cells. Tissue distribution of kurarinone and kurarinone glucuronides was analyzed in rats receiving ESF (2.5 g/kg). Active uptake of kurarinone and kurarinone glucuronides was studied in OAT2-, OATP1B1-, OATP2B1-, and OATP1B3-transfected HEK293 cells. Our results revealed that after oral administration of ESF in rats, kurarinone glucuronides were actively transported into hepatocytes by OATP1B3 and hydrolyzed into kurarinone, which inhibited fatty acid β-oxidation through the reduction of l-carnitine and the inhibition of PPAR-α pathway, ultimately leading to lipid accumulation and liver injury. These findings contribute to understanding hepatotoxicity of kurarinone after oral administration of ESF.

  2. Cyclic Voltammetry Experiment.

    ERIC Educational Resources Information Center

    Van Benschoten, James J.; And Others

    1983-01-01

    Describes a three-part experiment designed to introduce cyclic voltammetry to graduate/undergraduate students. Part 1 demonstrates formal reduction potential, redox electron transfer, diffusion coefficient, and electrochemical reversibility. Part 2 investigates electrochemical behavior of acetaminophen. Part 3 examines such experimental variables…

  3. Expansion and diversification of the MSDIN family of cyclic peptide genes in the poisonous agarics Amanita phalloides and A. bisporigera

    DOE PAGES

    Pulman, Jane A.; Childs, Kevin L.; Sgambelluri, R. Michael; ...

    2016-12-15

    Here, the cyclic peptide toxins of Amanita mushrooms, such as α-amanitin and phalloidin, are encoded by the “MSDIN” gene family and ribosomally biosynthesized. Based on partial genome sequence and PCR analysis, some members of the MSDIN family were previously identified in Amanita bisporigera, and several other members are known from other species of Amanita. However, the complete complement in any one species, and hence the genetic capacity for these fungi to make cyclic peptides, remains unknown. As a result, draft genome sequences of two cyclic peptide-producing mushrooms, the “Death Cap” A. phalloides and the “Destroying Angel” A. bisporigera, were obtained.more » Each species has ~30 MSDIN genes, most of which are predicted to encode unknown cyclic peptides. Some MSDIN genes were duplicated in one or the other species, but only three were common to both species. A gene encoding cycloamanide B, a previously described nontoxic cyclic heptapeptide, was also present in A. phalloides, but genes for antamanide and cycloamanides A, C, and D were not. In A. bisporigera, RNA expression was observed for 20 of the MSDIN family members. Based on their predicted sequences, novel cyclic peptides were searched for by LC/MS/MS in extracts of A. phalloides. The presence of two cyclic peptides, named cycloamanides E and F with structures cyclo(SFFFPVP) and cyclo(IVGILGLP), was thereby demonstrated. Of the MSDIN genes reported earlier from another specimen of A. bisporigera, 9 of 14 were not found in the current genome assembly. Differences between previous and current results for the complement of MSDIN genes and cyclic peptides in the two fungi probably represents natural variation among geographically dispersed isolates of A. phalloides and among the members of the poorly defined A. bisporigera species complex. Both A. phalloides and A. bisporigera contain two prolyl oligopeptidase genes, one of which (POPB) is probably dedicated to cyclic peptide biosynthesis

  4. Expansion and diversification of the MSDIN family of cyclic peptide genes in the poisonous agarics Amanita phalloides and A. bisporigera

    SciT

    Pulman, Jane A.; Childs, Kevin L.; Sgambelluri, R. Michael

    Here, the cyclic peptide toxins of Amanita mushrooms, such as α-amanitin and phalloidin, are encoded by the “MSDIN” gene family and ribosomally biosynthesized. Based on partial genome sequence and PCR analysis, some members of the MSDIN family were previously identified in Amanita bisporigera, and several other members are known from other species of Amanita. However, the complete complement in any one species, and hence the genetic capacity for these fungi to make cyclic peptides, remains unknown. As a result, draft genome sequences of two cyclic peptide-producing mushrooms, the “Death Cap” A. phalloides and the “Destroying Angel” A. bisporigera, were obtained.more » Each species has ~30 MSDIN genes, most of which are predicted to encode unknown cyclic peptides. Some MSDIN genes were duplicated in one or the other species, but only three were common to both species. A gene encoding cycloamanide B, a previously described nontoxic cyclic heptapeptide, was also present in A. phalloides, but genes for antamanide and cycloamanides A, C, and D were not. In A. bisporigera, RNA expression was observed for 20 of the MSDIN family members. Based on their predicted sequences, novel cyclic peptides were searched for by LC/MS/MS in extracts of A. phalloides. The presence of two cyclic peptides, named cycloamanides E and F with structures cyclo(SFFFPVP) and cyclo(IVGILGLP), was thereby demonstrated. Of the MSDIN genes reported earlier from another specimen of A. bisporigera, 9 of 14 were not found in the current genome assembly. Differences between previous and current results for the complement of MSDIN genes and cyclic peptides in the two fungi probably represents natural variation among geographically dispersed isolates of A. phalloides and among the members of the poorly defined A. bisporigera species complex. Both A. phalloides and A. bisporigera contain two prolyl oligopeptidase genes, one of which (POPB) is probably dedicated to cyclic peptide biosynthesis

  5. Hepatotoxicity during Treatment for Tuberculosis in People Living with HIV/AIDS.

    PubMed

    Araújo-Mariz, Carolline; Lopes, Edmundo Pessoa; Acioli-Santos, Bartolomeu; Maruza, Magda; Montarroyos, Ulisses Ramos; Ximenes, Ricardo Arraes de Alencar; Lacerda, Heloísa Ramos; Miranda-Filho, Demócrito de Barros; Albuquerque, Maria de Fátima P Militão de

    2016-01-01

    Hepatotoxicity is frequently reported as an adverse reaction during the treatment of tuberculosis. The aim of this study was to determine the incidence of hepatotoxicity and to identify predictive factors for developing hepatotoxicity after people living with HIV/AIDS (PLWHA) start treatment for tuberculosis. This was a prospective cohort study with PLWHA who were monitored during the first 60 days of tuberculosis treatment in Pernambuco, Brazil. Hepatotoxicity was considered increased levels of aminotransferase, namely those that rose to three times higher than the level before initiating tuberculosis treatment, these levels being associated with symptoms of hepatitis. We conducted a multivariate logistic regression analysis and the magnitude of the associations was expressed by the odds ratio with a confidence interval of 95%. Hepatotoxicity was observed in 53 (30.6%) of the 173 patients who started tuberculosis treatment. The final multivariate logistic regression model demonstrated that the use of fluconazole, malnutrition and the subject being classified as a phenotypically slow acetylator increased the risk of hepatotoxicity significantly. The incidence of hepatotoxicity during treatment for tuberculosis in PLWHA was high. Those classified as phenotypically slow acetylators and as malnourished should be targeted for specific care to reduce the risk of hepatotoxicity during treatment for tuberculosis. The use of fluconazole should be avoided during tuberculosis treatment in PLWHA.

  6. Drug induced hepatotoxicity: data from the Serbian pharmacovigilance database.

    PubMed

    Petronijevic, Marija; Ilic, Katarina; Suzuki, Ayako

    2011-04-01

    The main aim of this study was to determine the most frequently reported drugs to the Serbian Pharmacovigilance Database (SPD) with suspected induced hepatotoxicity. Additionally, reasons for the low reporting rate of adverse drug reactions (ADRs) in Serbia were identified. Retrospective observational study of spontaneously reported ADRs recorded in the SPD from January 1995 to December 2008 was performed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify cases of hepatobiliary disorders (HD). Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification. Medline and WHO-UMC databases were used to address specific queries suggested by our results. The questionnaire was used to investigate the health care professionals' knowledge and practice related to spontaneous reporting. Among the 1804 reports of ADRs recorded in the SPD between 1995 and 2008, 70 (3.9%) cases of HD were identified. Drugs most frequently associated with hepatotoxicity were anti-infectives for systemic use, drugs affecting the nervous system, herbal products, hypolipemics, and anticoagulant drugs (26.83, 24.39, 12.20, 9.76, and 8.54% cases, respectively). Four cases (5.71%) of liver injury resulted in death, which accounted for 10.26% of all ADR fatalities reported to the SPD. The main reasons for not reporting ADRs were lack of reporting knowledge (30.26%), well-known ADRs (29.89%), and insecurity about causality relationship (15.50%). Anti-infectives, nervous system drugs, and herbal products were the most common drug classes reported for hepatotoxicity in Serbia. There is a need for additional education about ADRs, and enhanced reporting by health care professionals. Copyright © 2011 John Wiley & Sons, Ltd.

  7. Herbal hepatotoxicity: suspected cases assessed for alternative causes.

    PubMed

    Teschke, Rolf; Schulze, Johannes; Schwarzenboeck, Alexander; Eickhoff, Axel; Frenzel, Christian

    2013-09-01

    Alternative explanations are common in suspected drug-induced liver injury (DILI) and account for up to 47.1% of analyzed cases. This raised the question of whether a similar frequency may prevail in cases of assumed herb-induced liver injury (HILI). We searched the Medline database for the following terms: herbs, herbal drugs, herbal dietary supplements, hepatotoxic herbs, herbal hepatotoxicity, and herb-induced liver injury. Additional terms specifically addressed single herbs and herbal products: black cohosh, Greater Celandine, green tea, Herbalife products, Hydroxycut, kava, and Pelargonium sidoides. We retrieved 23 published case series and regulatory assessments related to hepatotoxicity by herbs and herbal dietary supplements with alternative causes. The 23 publications comprised 573 cases of initially suspected HILI; alternative causes were evident in 278/573 cases (48.5%). Among them were hepatitis by various viruses (9.7%), autoimmune diseases (10.4%), nonalcoholic and alcoholic liver diseases (5.4%), liver injury by comedication (DILI and other HILI) (43.9%), and liver involvement in infectious diseases (4.7%). Biliary and pancreatic diseases were frequent alternative diagnoses (11.5%), raising therapeutic problems if specific treatment is withheld; pre-existing liver diseases including cirrhosis (9.7%) were additional confounding variables. Other diagnoses were rare, but possibly relevant for the individual patient. In 573 cases of initially assumed HILI, 48.5% showed alternative causes unrelated to the initially incriminated herb, herbal drug, or herbal dietary supplement, calling for thorough clinical evaluations and appropriate causality assessments in future cases of suspected HILI.

  8. Herbal hepatotoxicity: Challenges and pitfalls of causality assessment methods

    PubMed Central

    Teschke, Rolf; Frenzel, Christian; Schulze, Johannes; Eickhoff, Axel

    2013-01-01

    The diagnosis of herbal hepatotoxicity or herb induced liver injury (HILI) represents a particular clinical and regulatory challenge with major pitfalls for the causality evaluation. At the day HILI is suspected in a patient, physicians should start assessing the quality of the used herbal product, optimizing the clinical data for completeness, and applying the Council for International Organizations of Medical Sciences (CIOMS) scale for initial causality assessment. This scale is structured, quantitative, liver specific, and validated for hepatotoxicity cases. Its items provide individual scores, which together yield causality levels of highly probable, probable, possible, unlikely, and excluded. After completion by additional information including raw data, this scale with all items should be reported to regulatory agencies and manufacturers for further evaluation. The CIOMS scale is preferred as tool for assessing causality in hepatotoxicity cases, compared to numerous other causality assessment methods, which are inferior on various grounds. Among these disputed methods are the Maria and Victorino scale, an insufficiently qualified, shortened version of the CIOMS scale, as well as various liver unspecific methods such as the ad hoc causality approach, the Naranjo scale, the World Health Organization (WHO) method, and the Karch and Lasagna method. An expert panel is required for the Drug Induced Liver Injury Network method, the WHO method, and other approaches based on expert opinion, which provide retrospective analyses with a long delay and thereby prevent a timely assessment of the illness in question by the physician. In conclusion, HILI causality assessment is challenging and is best achieved by the liver specific CIOMS scale, avoiding pitfalls commonly observed with other approaches. PMID:23704820

  9. Potential protective effect of honey against paracetamol-induced hepatotoxicity.

    PubMed

    Galal, Reem M; Zaki, Hala F; Seif El-Nasr, Mona M; Agha, Azza M

    2012-11-01

    Paracetamol overdose causes severe hepatotoxicity that leads to liver failure in both humans and experimental animals. The present study investigates the protective effect of honey against paracetamol-induced hepatotoxicity in Wistar albino rats. We have used silymarin as a standard reference hepatoprotective drug. Hepatoprotective activity was assessed by measuring biochemical parameters such as the liver function enzymes, serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST). Equally, comparative effects of honey on oxidative stress biomarkers such as malondialdyhyde (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx) were also evaluated in the rat liver homogenates.  We estimated the effect of honey on serum levels and hepatic content of interleukin-1beta (IL-1β) because the initial event in paracetamol-induced hepatotoxicity has been shown to be a toxic-metabolic injury that leads to hepatocyte death, activation of the innate immune response and upregulation of inflammatory cytokines. Paracetamol caused marked liver damage as noted by significant increased activities of serum AST and ALT as well as the level of Il-1β. Paracetamol also resulted in a significant decrease in liver GSH content and GPx activity which paralleled an increase in Il-1β and MDA levels. Pretreatment with honey and silymarin prior to the administration of paracetamol significantly prevented the increase in the serum levels of hepatic enzyme markers, and reduced both oxidative stress and inflammatory cytokines. Histopathological evaluation of the livers also revealed that honey reduced the incidence of paracetamol-induced liver lesions. Honey can be used as an effective hepatoprotective agent against paracetamol-induced liver damage.

  10. Cyclically optimized electrochemical processes

    NASA Astrophysics Data System (ADS)

    Ruedisueli, Robert Louis

    It has been frequently observed in experiment and industry practice that electrochemical processes (deposition, dissolution, fuel cells) operated in an intermittent or cyclic (AC) mode show improvements in efficiency and/or quality and yield over their steady (DC) mode of operation. Whether rationally invoked by design or empirically tuned-in, the optimal operating frequency and duty cycle is dependent upon the dominant relaxation time constant for the process in question. The electrochemical relaxation time constant is a function of: double-layer and reaction intermediary pseudo-capacitances, ion (charge) transport via electrical migration (mobility), and diffusion across a concentration gradient to electrode surface reaction sites where charge transfer and species incorporation or elimination occurs. The rate determining step dominates the time constant for the reaction or process. Electrochemical impedance spectroscopy (EIS) and piezoelectric crystal electrode (PCE) response analysis have proven to be useful tools in the study and identification of reaction mechanisms. This work explains and demonstrates with the electro-deposition of copper the application of EIS and PCE measurement and analysis to the selection of an optimum cyclic operating schedule, an optimum driving frequency for efficient, sustained cyclic (pulsed) operation.

  11. Bee sting therapy-induced hepatotoxicity: A case report.

    PubMed

    Alqutub, Adel Nazmi; Masoodi, Ibrahim; Alsayari, Khalid; Alomair, Ahmed

    2011-10-27

    The use of bee venom as a therapeutic agent for the relief of joint pains dates back to Hippocrates, and references to the treatment can be found in ancient Egyptian and Greek medical writings as well. Also known as apitherapy, the technique is widely used in Eastern Europe, Asia, and South America. The beneficial effects of bee stings can be attributed to mellitinin, an anti-inflammatory agent, known to be hundred times stronger than cortisone. Unfortunately, certain substances in the bee venom trigger allergic reactions which can be life threatening in a sensitized individual. Multiple stings are known to cause hemolysis, kidney injury, hepatotoxicity and myocardial infarction. The toxicity can be immediate or can manifest itself only weeks after the exposure. We describe hepatotoxicity in a 35-year-old female, following bee sting therapy for multiple sclerosis. She presented to our clinic 3 wk after therapy with a history of progressive jaundice. The patient subsequently improved, and has been attending our clinic now for the last 9 mo.

  12. Hepatotoxicity and nephrotoxicity of 3-bromopyruvate in mice.

    PubMed

    Pan, Qiong; Sun, Yiming; Jin, Qili; Li, Qixiang; Wang, Qing; Liu, Hao; Zhao, Surong

    2016-11-01

    To investigate the hepatotoxicity and nephrotoxicity of 3-Bromopyruvate (3BP) in mice. Fifteen nude mice were grafted subcutaneously in the left flank with MDA-MB-231 cells, then all mice were divided into control group (PBS), 3BP group (8 mg/kg), positive group (DNR: 0.8 mg/kg) when tumor volume reached approximately 100 mm3. 28 days later, tumors, livers and kidneys were stored in 4 % formalin solution and stained with hematoxylin and eosin staining. The Kunming mice experiment included control group (PBS), 3BP group (4mg/kg; 8mg/kg; 16mg/kg), positive group (DNR: 0.8 mg/kg). 24 hours later, the blood were used for the determination of hepatic damage serum biomarkers. Livers were stored in 4 % formalin solution for the later detection. 3BP at the dose of 8mg/kg had a good effect on inhibiting tumor growth in nude mice and did not damage liver and kidney tissues. Kunming mice experiment showed 3BP at the dose of 16mg/kg did damage to liver tissues. 3-Bromopyruvate at the dose of suppressing tumor growth did not exhibit hepatotoxicity and nephrotoxicity in nude mice, and the effect on liver was confirmed in Kunming mice.

  13. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics

    PubMed Central

    García-Cortés, Miren; Robles-Díaz, Mercedes; Ortega-Alonso, Aida; Medina-Caliz, Inmaculada; Andrade, Raul J.

    2016-01-01

    Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs. PMID:27070596

  14. Hepatotoxicity by Dietary Supplements: A Tabular Listing and Clinical Characteristics.

    PubMed

    García-Cortés, Miren; Robles-Díaz, Mercedes; Ortega-Alonso, Aida; Medina-Caliz, Inmaculada; Andrade, Raul J

    2016-04-09

    Dietary supplements (DS) are extensively consumed worldwide despite unproven efficacy. The true incidence of DS-induced liver injury (DSILI) is unknown but is probably under-diagnosed due to the general belief of safety of these products. Reported cases of herbals and DS-induced liver injury are increasing worldwide. The aim of this manuscript is to report a tabular listing with a description of DS associated with hepatotoxicity as well as review the phenotype and severity of DSILI. Natural remedies related to hepatotoxicity can be divided into herbal product-induced liver injury and DS-induced liver injury. In this article, we describe different DS associated with liver injury, some of them manufactured DS containing several ingredients (Herbalife™ products, Hydroxycut™, LipoKinetix™, UCP-1 and OxyELITE™) while others have a single ingredient (green tea extract, linoleic acid, usnic acid, 1,3-Dimethylamylamine, vitamin A, Garcinia cambogia and ma huang). Additional DS containing some of the aforementioned ingredients implicated in liver injury are also covered. We have also included illicit androgenic anabolic steroids for bodybuilding in this work, as they are frequently sold under the denomination of DS despite being conventional drugs.

  15. In vivo investigation on the chronic hepatotoxicity induced by sertraline.

    PubMed

    Almansour, Mansour I; Jarrar, Yazun B; Jarrar, Bashir M

    2018-05-30

    Although sertraline is widely prescribed as relatively safe antidepressant drug, hepatic toxicity was reported in some patients with sertraline treatment. The present study was conducted to investigate the morphometric, hepatotoxicity, and change in gene expression of drug metabolizing enzymes. Male healthy adult rabbits (Oryctolagus cuniculus) ranging from 1050 to 1100 g were exposed to oral daily doses of sertraline (0, 1, 2, 4, 8 mg/kg) for 9 weeks. The animals were subjected to morphometric, hepatohistological, histochemical and quantitative real-time polymerase chain reaction analyses. Sertraline chronic exposure induced morphometric changes and provoked histological and histochemical alterations including: hepatocytes hydropic degeneration, necrosis, nuclear alteration, sinusoidal dilation, bile duct hyperplasia, inflammatory cells infiltration, portal vessel congestion, Kupffer cells hyperplasia, portal fibrosis and glycogen depletion. In addition, the gene expression of drug and arachidonic acid metabolizing enzymes were reduced significantly (p value <0.05). The most affected genes were cyp4a12, ephx2, cyp2d9 and cyp1a2, demonstrating 5 folds or more down-regulation. These findings suggest that chronic sertraline treatment induced toxic histological alterations in the hepatic tissues and reduced the gene expression of drug metabolizing enzymes. Patients on chronic sertraline treatment may be on risk of hepatotoxicity with reduced capacity to metabolize drugs and fatty acids. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Lipoic acid attenuates Aroclor 1260-induced hepatotoxicity in adult rats.

    PubMed

    Aly, Hamdy A A; Mansour, Ahmed M; Hassan, Memy H; Abd-Ellah, Mohamed F

    2016-08-01

    The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and reduced glutathione (GSH) content was significantly decreased in liver. Caspase-3 & -9 activities were significantly increased in liver. Lipoic acid pretreatment significantly reverted all these abnormalities toward their normal levels. In conclusion, Aroclor 1260 induced liver dysfunction, at least in part, by induction of oxidative stress. Apoptotic effect of hepatic cells is involved in Aroclor 1260-induced liver injury. Lipoic acid could protect rats against Aroclor 1260-induced hepatotoxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 913-922, 2016. © 2014 Wiley Periodicals, Inc.

  17. Hepatotoxicity and subchronic toxicity tests of Morinda citrifolia (noni) fruit.

    PubMed

    West, Brett J; Su, Chen X; Jensen, C Jarakae

    2009-10-01

    Morinda citrifolia (noni) fruit juice has been approved as a safe food in many nations. A few cases of hepatitis in people who had been drinking noni juice have been reported, even though no causal link could be established between the liver injury and ingestion of the juice. To more fully evaluate the hepatotoxic potential of noni fruit juice, in vitro hepatotoxicity tests were conducted in human liver cells, HepG2 cell line. A subchronic oral toxicity test of noni fruit was also performed in Sprague-Dawley (SD) rats to provide benchmark data for understanding the safety of noni juice, without the potential confounding variables associated with many commercial noni juice products. Freeze-dried filtered noni fruit puree did not decrease HepG2 cell viability or induce neutral lipid accumulation and phospholipidosis. There were no histopathological changes or evidence of dose-responses in hematological and clinical chemistry measurements, including liver function tests. The no-observed-adverse-effect level (NOAEL) for freeze-dried noni fruit puree is greater than 6.86 g/kg body weight, equivalent to approximately 90 ml of noni fruit juice/kg. These findings corroborate previous conclusions that consumption of noni fruit juice is unlikely to induce adverse liver effects.

  18. Bee sting therapy-induced hepatotoxicity: A case report

    PubMed Central

    Alqutub, Adel Nazmi; Masoodi, Ibrahim; Alsayari, Khalid; Alomair, Ahmed

    2011-01-01

    The use of bee venom as a therapeutic agent for the relief of joint pains dates back to Hippocrates, and references to the treatment can be found in ancient Egyptian and Greek medical writings as well. Also known as apitherapy, the technique is widely used in Eastern Europe, Asia, and South America. The beneficial effects of bee stings can be attributed to mellitinin, an anti-inflammatory agent, known to be hundred times stronger than cortisone. Unfortunately, certain substances in the bee venom trigger allergic reactions which can be life threatening in a sensitized individual. Multiple stings are known to cause hemolysis, kidney injury, hepatotoxicity and myocardial infarction. The toxicity can be immediate or can manifest itself only weeks after the exposure. We describe hepatotoxicity in a 35-year-old female, following bee sting therapy for multiple sclerosis. She presented to our clinic 3 wk after therapy with a history of progressive jaundice. The patient subsequently improved, and has been attending our clinic now for the last 9 mo. PMID:22059110

  19. Allopurinol Use During Maintenance Therapy for Acute Lymphoblastic Leukemia Avoids Mercaptopurine-related Hepatotoxicity.

    PubMed

    Giamanco, Nicole M; Cunningham, Bethany S; Klein, Laura S; Parekh, Dina S; Warwick, Anne B; Lieuw, Kenneth

    2016-03-01

    6-Mercaptopurine (6-MP) is the mainstay of treatment for acute lymphoblastic leukemia and lymphoblastic lymphoma. It is metabolized into the pharmacologically active, 6-thioguanine nucleotide (6-TGN), and 6-methyl mercaptopurine nucleotides (6-MMPN), which is associated with hepatotoxicity that jeopardizes antileukemic therapy. Allopurinol alters the metabolism of 6-MP to increase 6-TGN levels and decreases 6-methyl mercaptopurine nucleotides levels. We report 2 cases in which combination therapy of allopurinol with 6-MP was used successfully to avoid hepatotoxicity while delivering adequate 6-TGN levels. We suggest that this combination therapy can be used safely to change the metabolite production in patients who develop excessive hepatotoxicity.

  20. [Asthma and cyclic neutropenia].

    PubMed

    Salazar Cabrera, A N; Berrón Pérez, R; Ortega Martell, J A; Onuma Takane, E

    1996-01-01

    We report a male with history of recurrent infections (recurrent oral aphtous disease [ROAD], middle ear infections and pharyngo amigdalitis) every 3 weeks since he was 7 months old. At the age of 3 years cyclic neutropenia was diagnosed with cyclic fall in the total neutrophil count in blood smear every 21 days and prophylactic antimicrobial therapy was indicated. Episodic events every 3 weeks of acute asthma and allergic rhinitis were detected at the age of 6 years old and specific immunotherapy to Bermuda grass was given during 3 years with markedly improvement in his allergic condition but not in the ROAD. He came back until the age of 16 with episodic acute asthma and ROAD. The total neutrophil count failed to 0 every 21 days and surprisingly the total eosinophil count increased up to 2,000 at the same time, with elevation of serum IgE (412 Ul/mL). Specific immunotherapy to D.pt. and Aller.a. and therapy with timomodulin was indicated. After 3 months we observed clinical improvement in the asthmatic condition and the ROAD disappeared, but the total neutrophil count did not improve. We present this case as a rare association between 2 diseases with probably no etiological relationship but may be physiopatological that could help to understand more the pathogenesis of asthma.

  1. Acute hepatotoxicity induced by hepatotoxins in Suncus murinus

    SciT

    Lin, S.; Saito, H.; Yohro, T.

    A comparative study was conducted to contrast the hepatotoxicity of several chemicals in the musk shrew (Suncus murinus) versus other common laboratory species (mouse or rat), and the following results were obtained from serum enzymes (SGOT and SGPT) and histopathological findings of liver specimens. (1) The sensitivity of Suncus liver to CCl/sub 4/ was different from that of mouse liver. (2) The sensitivity of Suncus liver to ..beta..-D-galactosamine was weaker than that of rat liver. (3) The sensitivity of Suncus liver to ethanol was stronger than that of mouse liver. After a single oral administration of ethanol (99.5% v/v, 0.1more » ml/50 g body weight), the gallbladder of Suncus became enlarged and dark blue in color. (4) A striking fatty degeneration was seen 24 h after a single ip administration of amethopterin at 50 mg/kg in Suncus liver.« less

  2. Fructose diet alleviates acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Cho, Sungjoon; Tripathi, Ashutosh; Chlipala, George; Green, Stefan; Lee, Hyunwoo; Chang, Eugene B; Jeong, Hyunyoung

    2017-01-01

    Acetaminophen (APAP) is a commonly used analgesic and antipyretic that can cause hepatotoxicity due to production of toxic metabolites via cytochrome P450 (Cyp) 1a2 and Cyp2e1. Previous studies have shown conflicting effects of fructose (the major component in Western diet) on the susceptibility to APAP-induced hepatotoxicity. To evaluate the role of fructose-supplemented diet in modulating the extent of APAP-induced liver injury, male C57BL/6J mice were given 30% (w/v) fructose in water (or regular water) for 8 weeks, followed by oral administration of APAP. APAP-induced liver injury (determined by serum levels of liver enzymes) was decreased by two-fold in mice pretreated with fructose. Fructose-treated mice exhibited (~1.5 fold) higher basal glutathione levels and (~2 fold) lower basal (mRNA and activity) levels of Cyp1a2 and Cyp2e1, suggesting decreased bioactivation of APAP and increased detoxification of toxic metabolite in fructose-fed mice. Hepatic mRNA expression of heat shock protein 70 was also found increased in fructose-fed mice. Analysis of bacterial 16S rRNA gene amplicons from the cecal samples of vehicle groups showed that the fructose diet altered gut bacterial community, leading to increased α-diversity. The abundance of several bacterial taxa including the genus Anaerostipes was found to be significantly correlated with the levels of hepatic Cyp2e1, Cyp1a2 mRNA, and glutathione. Together, these results suggest that the fructose-supplemented diet decreases APAP-induced liver injury in mice, in part by reducing metabolic activation of APAP and inducing detoxification of toxic metabolites, potentially through altered composition of gut microbiota.

  3. Inhibition of pannexin1 channels alleviates acetaminophen-induced hepatotoxicity.

    PubMed

    Maes, Michaël; McGill, Mitchell R; da Silva, Tereza Cristina; Abels, Chloé; Lebofsky, Margitta; Weemhoff, James L; Tiburcio, Taynã; Veloso Alves Pereira, Isabel; Willebrords, Joost; Crespo Yanguas, Sara; Farhood, Anwar; Beschin, Alain; Van Ginderachter, Jo A; Penuela, Silvia; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu

    2017-05-01

    Pannexins constitute a relatively new family of transmembrane proteins that form channels linking the cytoplasmic compartment with the extracellular environment. The presence of pannexin1 in the liver has been documented previously, where it underlies inflammatory responses, such as those occurring upon ischemia-reperfusion injury. In the present study, we investigated whether pannexin1 plays a role in acute drug-induced liver toxicity. Hepatic expression of pannexin1 was characterized in a mouse model of acetaminophen-induced hepatotoxicity. Subsequently, mice were overdosed with acetaminophen followed by treatment with the pannexin1 channel inhibitor 10 Panx1. Sampling was performed 1, 3, 6, 24 and 48 h after acetaminophen administration. Evaluation of the effects of pannexin1 channel inhibition was based on a number of clinically relevant readouts, including protein adduct formation, measurement of aminotransferase activity and histopathological examination of liver tissue as well as on a series of markers of inflammation, oxidative stress and regeneration. Although no significant differences were found in histopathological analysis, pannexin1 channel inhibition reduced serum levels of alanine and aspartate aminotransferase. This was paralleled by a reduced amount of neutrophils recruited to the liver. Furthermore, alterations in the oxidized status were noticed with upregulation of glutathione levels upon suppression of pannexin1 channel opening. Concomitant promotion of regenerative activity was detected as judged on increased proliferating cell nuclear antigen protein quantities in 10 Panx1-treated mice. Pannexin1 channels are important actors in liver injury triggered by acetaminophen. Inhibition of pannexin1 channel opening could represent a novel approach for the treatment of drug-induced hepatotoxicity.

  4. Investigation of the Hepatotoxic and Immunotoxic Effects of the Peroxisome Proliferator Perfluorodecanoic Acid

    DTIC Science & Technology

    1991-04-30

    np. A #127 6Investigation of the Hepatotoxic and OHIO Immunotoxic Effects of the Peroxisome AJE Proliferator Perfluorodecanoic Acid Donald E. Frazier...Investigation of the Hepatotoxic and Immunotoxic Effects G-AFOSR 90-0371 of the Peroxisome Proliferator Perfluorodecanoic Acid TA - 2312/A5 L AUTMOS) Donald E...involved evaluation of the immunotoxic and toxic effects of perfluorodecanoic acid (PFDA). Eight day exposure to PFDA caused thymic atrophy with marked

  5. IL-1RN and IL-1β Polymorphism and ARV-Associated Hepatotoxicity

    PubMed Central

    Samani, Dharmesh; Nema, Vijay; Gangakhedkar, R. R.

    2018-01-01

    The severity of hepatic injury depends upon cytokines. Previous studies associated IL-1RN allele 2 with IL-1β production. Hence, we examined the association of IL-1 RN and IL-1β polymorphisms with ARV-associated hepatotoxicity. Genotyping of IL-1RN (VNTR), IL-1β (-511C/T) polymorphisms was done in 162 HIV-infected patients, 34 with ARV hepatotoxicity, 128 without hepatotoxicity, and 152 healthy controls using PCR and PCR-RFLP method. The haplotypes 1T and 2C enhanced the risk for severe hepatotoxicity (OR = 1.41, P = 0.25; OR = 1.67, P = 0.31). IL-1β-511TT genotype significantly represented among tobacco using HIV-infected individuals compared to nonusers (OR = 3.74, P = 0.05). IL-1β-511TT genotype among alcohol users increased the risk for hepatotoxicity (OR = 1.80, P = 0.90). IL-1β-511CT and -511TT genotypes overrepresented in alcohol using HIV-infected individuals (OR = 2.29, P = 0.27; OR = 2.64, P = 0.19). IL-RN 2/2 and 1/3 genotypes represented higher in nevirapine using hepatotoxicity patients (OR = 1.42, P = 0.64, OR = 8.79, P = 0.09). IL-1β-511CT and -511 TT genotypes among nevirapine users enhanced the risk for severe hepatotoxicity (OR = 4.29, P = 0.20; OR = 1.95, P = 0.56). IL-1β-511CT and -511TT genotypes were overrepresented in combined nevirapine and alcohol using HIV-infected individuals as compared to nevirapine users and alcohol nonusers (OR = 2.56, P = 0.26; OR = 2.84, P = 0.24). IL-1β-511TT genotype with tobacco, alcohol, and nevirapine usage revealed a trend of risk for the development of ARV-associated hepatotoxicity and its severity.

  6. Severe hepatotoxic reaction with progression to cirrhosis after use of a novel retinoid (acitretin).

    PubMed

    van Ditzhuijsen, T J; van Haelst, U J; van Dooren-Greebe, R J; van de Kerkhof, P C; Yap, S H

    1990-09-01

    We report the case of a 50-year-old female who suffered from severe palmar and plantar pustulosis. During treatment with acitretin, a novel oral retinoid, which is the main derivative of etretinate, the patient developed a severe hepatotoxic reaction. Subsequent histological studies strongly suggested the development of liver cirrhosis. Reversible elevation of serum aminotransferase values during treatment with acitretin has been reported. However, the present observation indicates that severe hepatotoxic injury may also follow treatment with this agent.

  7. Microbiota transplantation reveals beneficial impact of berberine on hepatotoxicity by improving gut homeostasis.

    PubMed

    Qin, Chenjie; Zhang, Huilu; Zhao, Linghao; Zeng, Min; Huang, Weijian; Fu, Gongbo; Zhou, Weiping; Wang, Hongyang; Yan, Hexin

    2017-11-29

    Berberine has been shown to reduce acute liver injury although the underlying mechanism is not fully understood. Because of the anatomic connection, the liver is constantly exposed to gut-derived bacterial products and metabolites. In this study, we showed that berberine has beneficial effects on both hepatotoxicity and intestinal damage in a rat model of chronic or acute liver injury. Microbiota transplantation from the rats with chronic hepatotoxicity could aggravate acute hepatotoxicity in mice treated with diethylnitrosamine (DEN). In rat models with gut homeostasis disruption induced by penicillin or dextran sulfate sodium (DSS), their fecal microbiota could also cause an enhanced hepatotoxicity of recipient mice. When treated with berberine, the DSS-induced enteric dysbacteriosis could be mitigated and their fecal bacteria were able to reduce acute hepatotoxicity in recipient mice. This study indicates that berberine could improve intestinal dysbacteriosis, which reduces the hepatotoxicity caused by pathological or pharmacological intervention. Fecal microbiota transplantation might be a useful method to directly explore homeostatic alteration in gut microbiota.

  8. The role of chronic hepatitis in isoniazid hepatotoxicity during treatment for latent tuberculosis infection.

    PubMed

    Bliven, E E; Podewils, L J

    2009-09-01

    To examine chronic viral hepatitis (CVH) as a risk factor for hepatotoxicity during isoniazid (INH) treatment for latent tuberculosis infection (LTBI). A search of MEDLINE (1966-May 2008) was conducted using the terms 'tuberculosis', 'antitubercular', 'therapeutics', 'treatment', 'prevention', 'prophylaxis', 'hepatitis', 'toxic hepatitis', 'hepatotoxic', 'liver' and 'injury'. Peer-reviewed, English-language articles describing the relationship between a history of CVH and occurrence of hepatotoxicity during LTBI treatment were selected. We limited CVH diagnoses to reports with positive serological test or biopsy for hepatitis B or C. Risk ratios and 95% confidence intervals were abstracted or derived. We reviewed 486 abstracts, and 11 studies met the selection criteria. Populations included in the studies were the general population (n = 6) and transplant recipients (n = 5). The variability in study designs and case finding practices precluded performing a quantitative meta-analysis. Two studies of former or current drug users reported a consistent, positive association between chronic hepatitis C infection and INH hepatotoxicity. Other risk ratios did not significantly or consistently show any association between CVH in patients treated for LTBI and the development of INH hepatotoxicity. Owing to the limited number of published papers, CVH was not established as a risk factor for INH hepatotoxicity during LTBI treatment. Controlled studies are needed to define the safety and tolerability of LTBI treatment in those with CVH and to provide an evidence base for recommendations for LTBI treatment in persons with CVH.

  9. Synthesis of potent agonists of substance P by replacement of Met11 with Glu(OBzl) and N-terminal glutamine with Glp of the C-terminal hexapeptide and heptapeptide of substance P.

    PubMed

    Stavropoulos, G; Karagiannis, K; Anagnostides, S; Ministrouski, I; Selinger, Z; Chorev, M

    1995-06-01

    The analogues [Glp6,Glu(OBzl)11]SP(6-11) and [Glp5,Glu(OBzl)11]SP(5-11) of the C-terminal hexapeptide and heptapeptide of Substance P have been synthesized by conventional solution methods. In each analogue the N-terminal glutamine has been replaced by pyroglutamic acid, while the COOCH2C6H5 ester group has replaced the SCH3 group of the Met11 side chain. The in vitro activity of both analogues has been determined on three biological preparations: guinea pig ileum (GPI), rat vas deferens (RVD) and rat portal vein (RPV). The results showed that both analogues are highly potent and selective agonists on GPI through the NK-1 receptor. They are more potent than SP itself, with 1.54 and 1.25 respective values of relative potency on GPI. Their selectivity has been studied by utilizing atropine-treated guinea pig ileum (GPI+At). The analogues showed low activity on RVD and RPV tissues, which represent NK-2 and NK-3 monoreceptor assay, respectively.

  10. Three months of weekly rifapentine plus isoniazid is less hepatotoxic than nine months of daily isoniazid for LTBI.

    PubMed

    Bliven-Sizemore, E E; Sterling, T R; Shang, N; Benator, D; Schwartzman, K; Reves, R; Drobeniuc, J; Bock, N; Villarino, M E

    2015-09-01

    Nine months of daily isoniazid (9H) and 3 months of once-weekly rifapentine plus isoniazid (3HP) are recommended treatments for latent tuberculous infection (LTBI). The risk profile for 3HP and the contribution of hepatitis C virus (HCV) infection to hepatotoxicity are unclear. To evaluate the hepatotoxicity risk associated with 3HP compared to 9H, and factors associated with hepatotoxicity. Hepatotoxicity was defined as aspartate aminotransferase (AST) >3 times the upper limit of normal (ULN) with symptoms (nausea, vomiting, jaundice, or fatigue), or AST >5 x ULN. We analyzed risk factors among adults who took at least 1 dose of their assigned treatment. A nested case-control study assessed the role of HCV. Of 6862 participants, 77 (1.1%) developed hepatotoxicity; 52 (0.8%) were symptomatic; 1.8% (61/3317) were on 9H and 0.4% (15/3545) were on 3HP (P < 0.0001). Risk factors for hepatotoxicity were age, female sex, white race, non-Hispanic ethnicity, decreased body mass index, elevated baseline AST, and 9H. In the case-control study, HCV infection was associated with hepatotoxicity when controlling for other factors. The risk of hepatotoxicity during LTBI treatment with 3HP was lower than the risk with 9H. HCV and elevated baseline AST were risk factors for hepatotoxicity. For persons with these risk factors, 3HP may be preferred.

  11. Hepatotoxicity due to first-line anti-tuberculosis drugs: a five-year experience in a Taiwan medical centre.

    PubMed

    Shu, C-C; Lee, C-H; Lee, M-C; Wang, J-Y; Yu, C-J; Lee, L-N

    2013-07-01

    Hepatotoxicity with first-line drugs, a major complication of anti-tuberculosis treatment, has not been studied by time-dependent analysis. Adult patients diagnosed with pulmonary tuberculosis (PTB) from 2005 to 2009 were reviewed retrospectively. Hepatotoxicity during anti-tuberculosis treatment was defined by symptomatic elevation of liver transaminases ≥3 times the upper limit of normal, or ≥5 times if asymptomatic. Risk factors for hepatotoxicity were investigated using time-dependent Cox regression analysis. Of 926 patients identified and followed for 4122.9 person-months (pm), 111 (12.0%) developed hepatotoxicity after a median 38.0 days from start of treatment. Around 3.5% had severe hepatotoxicity. The most common symptoms were general malaise and poor appetite. The incidence rate of hepatotoxicity was 0.59, 0.69 and 3.71/100 pm for isoniazid, rifampicin (RMP) and pyrazinamide (PZA), respectively. Old age, female sex, autoimmune disease, human immunodeficiency virus infection, more days with PZA in the last 8-14 days, and fewer days with RMP in the last 15-21 days before hepatotoxicity were independent risk factors for hepatotoxicity during treatment. A significant number of adult patients on first-line treatment experience hepatotoxicity. PZA is the most common causative drug. For high-risk patients, careful adjustment of the anti-tuberculosis regimen and regular monitoring of liver transaminases are necessary.

  12. Early prediction of thiopurine-induced hepatotoxicity in inflammatory bowel disease.

    PubMed

    Wong, D R; Coenen, M J H; Derijks, L J J; Vermeulen, S H; van Marrewijk, C J; Klungel, O H; Scheffer, H; Franke, B; Guchelaar, H-J; de Jong, D J; Engels, L G J B; Verbeek, A L M; Hooymans, P M

    2017-02-01

    Hepatotoxicity, gastrointestinal complaints and general malaise are common limiting adverse reactions of azathioprine and mercaptopurine in IBD patients, often related to high steady-state 6-methylmercaptopurine ribonucleotide (6-MMPR) metabolite concentrations. To determine the predictive value of 6-MMPR concentrations 1 week after treatment initiation (T1) for the development of these adverse reactions, especially hepatotoxicity, during the first 20 weeks of treatment. The cohort study consisted of the first 270 IBD patients starting thiopurine treatment as part of the Dutch randomised-controlled trial evaluating pre-treatment thiopurine S-methyltransferase genotype testing (ClinicalTrials.gov NCT00521950). Blood samples for metabolite assessment were collected at T1. Hepatotoxicity was defined by alanine aminotransaminase elevations >2 times the upper normal limit or a ratio of alanine aminotransaminase/alkaline phosphatase ≥5. Forty-seven patients (17%) presented hepatotoxicity during the first 20 weeks of thiopurine treatment. A T1 6-MMPR threshold of 3615 pmol/8 × 10 8 erythrocytes was defined. Analysis of patients on stable thiopurine dose (n = 174) showed that those exceeding the 6-MMPR threshold were at increased risk of hepatotoxicity: OR = 3.8 (95% CI: 1.8-8.0). Age, male gender and BMI were significant determinants. A predictive algorithm was developed based on these determinants and the 6-MMPR threshold to assess hepatotoxicity risk [AUC = 0.83 (95% CI: 0.75-0.91)]. 6-MMPR concentrations above the threshold also correlated with gastrointestinal complaints: OR = 2.4 (95% CI: 1.4-4.3), and general malaise: OR = 2.0 (95% CI: 1.1-3.7). In more than 80% of patients, thiopurine-induced hepatotoxicity could be explained by elevated T1 6-MMPR concentrations and the independent risk factors age, gender and BMI, allowing personalised thiopurine treatment in IBD to prevent early failure. © 2016 John Wiley & Sons Ltd.

  13. Cyclic mixmaster universes

    NASA Astrophysics Data System (ADS)

    Barrow, John D.; Ganguly, Chandrima

    2017-04-01

    We investigate the behavior of bouncing Bianchi type IX "mixmaster" universes in general relativity. This generalizes all previous studies of the cyclic behavior of closed spatially homogeneous universes with and without an entropy increase. We determine the behavior of models containing radiation by analytic and numerical integration and show that an increase of radiation entropy leads to an increasing cycle size and duration. We introduce a null energy condition violating ghost field to create a smooth, nonsingular bounce of finite size at the end of each cycle and compute the evolution through many cycles with and without an entropy increase injected at the start of each cycle. In the presence of increasing entropy, we find that the cycles grow larger and longer and the dynamics approach flatness, as in the isotropic case. However, successive cycles become increasingly anisotropic at the expansion maxima which is dominated by the general-relativistic effects of anisotropic 3-curvature. When the dynamics are significantly anisotropic, the 3-curvature is negative. However, it becomes positive after continued expansion drives the dynamics close enough to isotropy for the curvature to become positive and for gravitational collapse to ensue. In the presence of a positive cosmological constant, radiation, and a ghost field, we show that, for a very wide range of cosmological constant values, the growing oscillations always cease and the dynamics subsequently approach those of the isotropic de Sitter universe at late times. This model is not included in the scope of earlier cosmic no-hair theorems because the 3-curvature can be positive. In the case of a negative cosmological constant, radiation, and an ultrastiff field (to create nonsingular bounces), we show that a sequence of chaotic oscillations also occurs, with sensitive dependence on initial conditions. In all cases, we follow the oscillatory evolution of the scale factors, the shear, and the 3-curvature from

  14. Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity.

    PubMed

    Elinav, Eran; Pinsker, Galia; Safadi, Rifaat; Pappo, Orit; Bromberg, Michal; Anis, Emilia; Keinan-Boker, Lital; Broide, Efrat; Ackerman, Zvi; Kaluski, Dorit Nitzan; Lev, Boaz; Shouval, Daniel

    2007-10-01

    Nutritional supplements are frequently considered to be harmless but indiscriminate use of unlabelled ingredients may lead to significant adverse reactions. In 2004, identification of four index cases of acute hepatitis associated with Herbalife intake led to a ministry of health investigation in all Israeli hospitals. Twelve patients with acute idiopathic liver injury in association with consumption of Herbalife products were investigated. Eleven of the patients were females, aged 49.5+/-13.4 y. One patient had stage I primary biliary cirrhosis and another had hepatitis B. Acute liver injury was diagnosed after 11.9+/-11.1 months of initiation of Herbalife consumption. Liver biopsies demonstrated active hepatitis, portal inflammation rich with eosinophils, ductular reaction and parenchymal inflammation with peri-central accentuation. One patient developed sub-fulminant and two fulminant episodes of hepatic failure. Hepatitis resolved in eleven patients, while one patient succumbed to complications following liver transplantation. Three patients resumed consumption of Herbalife products following normalization of liver enzymes, resulting in a second bout of hepatitis. An association between intake of Herbalife products and acute hepatitis was identified in Israel. We call for prospective evaluation of Herbalife products for possible hepatotoxicity. Until then, caution should be exercised by consumers, especially among individuals suffering from underlying liver disease.

  15. Subchronic hepatotoxicity of selenomethionine ingestion in mallard ducks

    Hoffman, D.J.; Heinz, G.H.; LeCaptain, L.J.; Bunck, C.M.; Green, D.E.

    1991-01-01

    Twoyearold male mallards (Anas platyrhynchos) received a control diet (0.2 ppm Se) or diets containing 1, 2, 4, 8, 16, or 32 ppm Se as selenomethionine for 14 wk. Se accumulated readily in the liver in a dosedependent manner, reaching a mean concentration of 29 ppm (wet weight) in the 32 ppm group. Dietary Se of 2 ppm or greater increased plasma glutathione peroxidase activity. Mortality (10%) and histopathological effects, including bile duct hyperplasia and hemosiderin pigmentation of the liver and spleen, occurred in the 32 ppm group. These histopathological effects were accompanied by lower hemoglobin concentrations (16 and 32 ppm groups) and hematocrit (32 ppm group), and elevated plasma alkaline phosphatase activity (32 ppm group) indicative of cholestatic liver inJury. Other manifestations of hepatotoxicity included significant linear dose responses for hepatic oxidized glutathione (GSSG) concentrations and ratio of GSSG to reduced glutathione (GSH). Means for both of these responses differed from controls in groups receiving 832 ppm Se. Mean hepatic GSH and malondialdehyde (a measure of lipid peroxidation) concentrations were significantly elevated in the 16 and 32 ppm groups. Subchronic effects of selenomethionine, which occurs in vegetation, are of particular interest with respect to the health of wild aquatic birds in seleniferous locations.

  16. Effect of Ranitidine on Acetaminophen-Induced Hepatotoxicity in Dogs

    PubMed Central

    Panella, C.; Makowka, L.; Barone, M.; Polimeno, L.; Rizzi, S.; Demetris, J.; Bell, S.; Guglielmi, F. W.; Prelich, J. G.; Van Thiel, D. H.; Starzl, T. E.; Francavilla, A.

    2010-01-01

    The effect of ranitidine administration upon the hepatotoxic effect produced by a multidose acetaminophen administration regimen was examined. Seventy-two dogs received three subcutaneous injections of acetaminophen (750, 200, 200 mg/kg body wt) in DMSO (600 mg/ml) at time zero, 9 hr later, and 24 hr after the first dose. Ten control animals (group I) were not given ranitidine, the remaining 62 dogs received an intramuscular injection of ranitidine 30 min before each acetaminophen dose. Three different doses of ranitidine were used (mg/kg body wt): 50 mg, group II (33 dogs); 75 mg, group III (14 dogs); 120 mg, group IV (15 dogs). Ranitidine reduced the expected acetaminophen-induced hepatoxicity in a dose–response manner. Moreover, a significant correlation was found between the ranitidine dose and the survival rate, as evidenced by transaminase levels in the serum and histology of the liver. This model of fulminant hepatic failure induced by acetaminophen and its modulation with ranitidine provides clinical investigators with a research tool that will be useful in the future investigation of putative medical and surgical therapies being investigated for use in the clinical management of fulminant hepatic failure. Because of the size of the animal used in this model, frequent and serial analyses of blood and liver were available for study to determine the effect of therapy within a given animal as opposed to within groups of animals. PMID:2307085

  17. Functionalized linear and cyclic polyolefins

    DOEpatents

    Tuba, Robert; Grubbs, Robert H.

    2018-02-13

    This invention relates to methods and compositions for preparing linear and cyclic polyolefins. More particularly, the invention relates to methods and compositions for preparing functionalized linear and cyclic polyolefins via olefin metathesis reactions. Polymer products produced via the olefin metathesis reactions of the invention may be utilized for a wide range of materials applications. The invention has utility in the fields of polymer and materials chemistry and manufacture.

  18. Computer Simulation Of Cyclic Oxidation

    NASA Technical Reports Server (NTRS)

    Probst, H. B.; Lowell, C. E.

    1990-01-01

    Computer model developed to simulate cyclic oxidation of metals. With relatively few input parameters, kinetics of cyclic oxidation simulated for wide variety of temperatures, durations of cycles, and total numbers of cycles. Program written in BASICA and run on any IBM-compatible microcomputer. Used in variety of ways to aid experimental research. In minutes, effects of duration of cycle and/or number of cycles on oxidation kinetics of material surveyed.

  19. Analysis of 90 cases of antithyroid drug-induced severe hepatotoxicity over 13 years in China.

    PubMed

    Yang, Jun; Li, Lin-Fa; Xu, Qin; Zhang, Jun; Weng, Wan-Wen; Zhu, Yang-Jun; Dong, Meng-Jie

    2015-03-01

    Antithyroid drug (ATD)-induced severe hepatotoxicity is a rare but serious complication of ATD therapy. The characteristics of severe hepatotoxicity have been reported in only a small number of patients. Ninety patients with ATD-induced severe hepatotoxicity presenting during a 13 year period (2000-2013) who were about to undergo nuclear medicine therapy with (131)I from a sample of 8864 patients with hyperthyroidism were studied, and the outcomes were evaluated. The mean age of the patients with ATD-induced severe hepatotoxicity was 41.6±12.5 years (mean±standard deviation), and the female to male ratio was 2.2:1. The methimazole (MMI) dose given at the onset was 19.1±7.4 mg/day. The propylthiouracil (PTU) dose given at the onset was 212.8±105.0 mg/day. ATD-induced severe hepatotoxicity occurred in 63.3%, 75.6%, and 81.1% of patients within 4, 8, and 12 weeks of the onset of ATD therapy, respectively. The types of severe hepatotoxicity did not differ significantly between the MMI and PTU groups (p=0.188). The frequency of the cholestatic type in the MMI group (35.3%, 18/51) was higher than that in the PTU group (17.9%, 7/39), but these frequencies were not significantly different (p=0.069). The patients who were treated with (131)I received an average dose of 279.1±86.1 MBq (n=84). Therapy was successful in 60 of the 67 patients (89.6%). The success rate was equivalent (p=0.696) between the groups receiving MMI (91.7%, 33/36) and PTU (87.1%, 27/31). Severe hepatotoxicity tends to occur within the first three months after the onset of ATD therapy. The type of ATD-induced severe hepatotoxicity did not differ between the MMI and PTU groups. (131)I therapy is an effective treatment approach for patients with ATD-induced severe hepatotoxicity.

  20. Identification of metabolites, clinical chemistry markers and transcripts associated with hepatotoxicity.

    PubMed

    Buness, Andreas; Roth, Adrian; Herrmann, Annika; Schmitz, Oliver; Kamp, Hennicke; Busch, Kristina; Suter, Laura

    2014-01-01

    Early and accurate pre-clinical and clinical biomarkers of hepatotoxicity facilitate the drug development process and the safety monitoring in clinical studies. We selected eight known model compounds to be administered to male Wistar rats to identify biomarkers of drug induced liver injury (DILI) using transcriptomics, metabolite profiling (metabolomics) and conventional endpoints. We specifically explored early biomarkers in serum and liver tissue associated with histopathologically evident acute hepatotoxicity. A tailored data analysis strategy was implemented to better differentiate animals with no treatment-related findings in the liver from animals showing evident hepatotoxicity as assessed by histopathological analysis. From the large number of assessed parameters, our data analysis strategy allowed us to identify five metabolites in serum and five in liver tissue, 58 transcripts in liver tissue and seven clinical chemistry markers in serum that were significantly associated with acute hepatotoxicity. The identified markers comprised metabolites such as taurocholic acid and putrescine (measured as sum parameter together with agmatine), classical clinical chemistry markers like AST (aspartate aminotransferase), ALT (alanine aminotransferase), and bilirubin, as well as gene transcripts like Igfbp1 (insulin-like growth factor-binding protein 1) and Egr1 (early growth response protein 1). The response pattern of the identified biomarkers was concordant across all types of parameters and sample matrices. Our results suggest that a combination of several of these biomarkers could significantly improve the robustness and accuracy of an early diagnosis of hepatotoxicity.

  1. Toxicogenomic analysis identifies the apoptotic pathway as the main cause of hepatotoxicity induced by tributyltin.

    PubMed

    Zhou, Mi; Feng, Mei; Fu, Ling-Ling; Ji, Lin-Dan; Zhao, Jin-Shun; Xu, Jin

    2016-11-01

    Tributyltin (TBT) is one of the most widely used organotin biocides, which has severe endocrine-disrupting effects on marine species and mammals. Given that TBT accumulates at higher levels in the liver than in any other organ, and it acts mainly as a hepatotoxic agent, it is important to clearly delineate the hepatotoxicity of TBT. However, most of the available studies on TBT have focused on observations at the cellular level, while studies at the level of genes and proteins are limited; therefore, the molecular mechanisms of TBT-induced hepatotoxicity remains largely unclear. In the present study, we applied a toxicogenomic approach to investigate the effects of TBT on gene expression in the human normal liver cell line HL7702. Gene expression profiling identified the apoptotic pathway as the major cause of hepatotoxicity induced by TBT. Flow cytometry assays confirmed that medium- and high-dose TBT treatments significantly increased the number of apoptotic cells, and more cells underwent late apoptosis in the high-dose TBT group. The genes encoding heat shock proteins (HSPs), kinases and tumor necrosis factor receptors mediated TBT-induced apoptosis. These findings revealed novel molecular mechanisms of TBT-induced hepatotoxicity, and the current microarray data may also provide clues for future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Neonicotinoid formaldehyde generators: possible mechanism of mouse-specific hepatotoxicity/hepatocarcinogenicity of thiamethoxam.

    PubMed

    Swenson, Tami L; Casida, John E

    2013-02-04

    Thiamethoxam (TMX), an important insecticide, is hepatotoxic and hepatocarcinogenic in mice but not rats. Studies of Syngenta Central Toxicology Laboratory on species specificity in metabolism established that TMX is a much better substrate for mouse liver microsomal CYPs than the corresponding rat or human enzymes in forming desmethyl-TMX (dm-TMX), which is also hepatotoxic, and clothianidin (CLO), which is not hepatotoxic or hepatocarcinogenic. They proposed that TMX hepatotoxicity/hepatocarcinogencity is due to dm-TMX and a further metabolite desmethyl-CLO (dm-CLO) (structurally analogous to a standard inducible nitric oxide synthase inhibitor) acting synergistically. The present study considers formation of formaldehyde (HCHO) and N-methylol intermediates as an alternative mechanism of TMX hepatotoxicity/hepatocarcinogenicity. Comparison of neonicotinoid metabolism by mouse, rat and human microsomes with NADPH showed two important points. First, TMX and dm-TMX yield more HCHO than any other commercial neonicotinoid. Second, mouse microsomes give much higher conversion than rat or human microsomes. These observations provide an alternative hypothesis of HCHO and N-methylol intermediates from CYP-mediated oxidative oxadiazinane ring cleavage as the bioactivated hepatotoxicants. However, the proposed mono-N-methylol CYP metabolites are not observed, possibly further reacting in situ. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  3. Acute hepatotoxicity after ingestion of Morinda citrifolia (Noni Berry) juice in a 14-year-old boy.

    PubMed

    Yu, Elizabeth L; Sivagnanam, Mamata; Ellis, Linda; Huang, Jeannie S

    2011-02-01

    We present a case of a 14-year-old previously healthy boy with acute hepatotoxicity after noni berry juice consumption. As the popularity of noni berry consumption continues to increase, heightened awareness of the relation between noni berry consumption and acute hepatotoxicity is important.

  4. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity

    SciT

    Cover, Cathleen; Liu Jie; Farhood, Anwar

    Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP in C3Heb/FeJ and C57BL/6 mice. Although there was no relevant difference in liver injury (assessed by the increase of plasma alanine aminotransferase activities and the areas of necrosis), the number of neutrophils and the expression of several pro-inflammatory genes (e.g., tumor necrosis factor-{alpha}, interleukin-1{beta} and macrophage inflammatory protein-2)more » was higher in C3Heb/FeJ than in C57BL/6 mice. In contrast, the expression of the anti-inflammatory genes interleukin-10 and heme oxygenase-1 was higher in C57BL/6 mice. Despite substantial hepatic neutrophil accumulation, none of the liver sections from both strains stained positive for hypochlorite-modified proteins, a specific marker for a neutrophil-induced oxidant stress. In addition, treatment with the NADPH oxidase inhibitors diphenyleneiodonium chloride or apocynin or the anti-neutrophil antibody Gr-1 did not protect against AAP hepatotoxicity. Furthermore, although intercellular adhesion molecule-1 (ICAM-1) was previously shown to be important for neutrophil extravasation and tissue injury in several models, ICAM-1-deficient mice were not protected against AAP-mediated liver injury. Together, these data do not support the hypothesis that neutrophils aggravate liver injury induced by AAP overdose.« less

  5. Evaluation of an in vitro toxicogenetic mouse model for hepatotoxicity

    SciT

    Martinez, Stephanie M.; Bradford, Blair U.; Soldatow, Valerie Y.

    2010-12-15

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

  6. The hepatotoxicity of multi-walled carbon nanotubes in mice

    NASA Astrophysics Data System (ADS)

    Ji, Zongfei; Zhang, Danying; Li, Ling; Shen, Xizhong; Deng, Xiaoyong; Dong, Ling; Wu, Minhong; Liu, Yuanfang

    2009-11-01

    The hepatotoxicity of two types of multi-walled carbon nanotubes (MWCNTs), acid-oxidized MWCNTs (O-MWCNTs) and Tween-80-dispersed MWCNTs (T-MWCNTs), were investigated with Kunming mice exposed to 10 and 60 mg kg-1 by intravenous injection for 15 and 60 d. Compared with the PBS group, the body-weight gain of the mice decreased and the level of total bilirubin and aspartate aminotransferase increased in the MWCNT-exposed group with a significant dose-effect relationship, while tumor necrosis factor alpha level did not show significant statistical change within 60 d. Spotty necrosis, inflammatory cell infiltration in portal region, hepatocyte mitochondria swelling and lysis were observed with a significant dose-effect relationship in the MWCNT groups. Liver damage of the T-MWCNT group was more severe than that of the O-MWCNT group according to the Roenigk classification system. Furthermore, T-MWCNTs induce slight liver oxidative damage in mice at 15 d, which was recovered at 60 d. Part of the gene expressions of mouse liver in the MWCNT groups changed compared to the PBS group, including GPCRs (G protein-coupled receptors), cholesterol biosynthesis, metabolism by cytochrome P450, natural-killer-cell-mediated cytotoxicity, TNF- α, NF-κB signaling pathway, etc. In the P450 pathway, the gene expressions of Gsta2 (down-regulated), Cyp2B19 (up-regulated) and Cyp2C50 (down-regulated) had significant changes in the MWCNT groups. These results show that a high dose of T-MWCNTs can induce hepatic toxicity in mice while O-MWCNTs seem to have less toxicity.

  7. Hepatotoxicity After Continuous Amiodarone Infusion in a Postoperative Cardiac Infant

    PubMed Central

    Kicker, Jennifer S.; Haizlip, Julie A.; Buck, Marcia L.

    2012-01-01

    A former 34-week-old female infant with Down syndrome underwent surgical correction of a congenital heart defect at 5 months of age. Her postoperative course was complicated by severe pulmonary hypertension and junctional ectopic tachycardia. Following treatment with amiodarone infusion, she developed laboratory indices of acute liver injury. At their peak, liver transaminase levels were 19 to 35 times greater than the upper limit of normal. Transaminitis was accompanied by coagulopathy, hyperammonemia, and high serum lactate and lipid levels. Hepatic laboratory abnormalities began to resolve within 48 hr of stopping amiodarone infusion. Heart rate control was achieved concurrently with discovery of laboratory test result abnormalities, and no further antiarrhythmic therapy was required. The intravenous formulation of amiodarone contains the diluent polysorbate 80, which may have hepatotoxic effects. Specifically, animal studies suggest that polysorbate 80 may destabilize cell membranes and predispose to fatty change within liver architecture. Polysorbate was implicated in infant fatalities from E-ferol use in the 1980s. This case illustrates a possible adverse event by the Naranjo probability scale. Given the extent of clinically apparent hepatic injury, this patient was not rechallenged with amiodarone during the remainder of her hospitalization. With amiodarone now used as first-line pharmacologic therapy for critical tachyarrhythmia in this population, the number of children exposed to this drug should be expected to increase. Laboratory indices of liver function should be evaluated at initiation of amiodarone therapy, as well as frequently throughout duration of therapy. Consideration should be given to polysorbate-free formulation of intravenous amiodarone for use in the cohort with congenital cardiac disease. PMID:23118673

  8. Hepatotoxicity after continuous amiodarone infusion in a postoperative cardiac infant.

    PubMed

    Kicker, Jennifer S; Haizlip, Julie A; Buck, Marcia L

    2012-04-01

    A former 34-week-old female infant with Down syndrome underwent surgical correction of a congenital heart defect at 5 months of age. Her postoperative course was complicated by severe pulmonary hypertension and junctional ectopic tachycardia. Following treatment with amiodarone infusion, she developed laboratory indices of acute liver injury. At their peak, liver transaminase levels were 19 to 35 times greater than the upper limit of normal. Transaminitis was accompanied by coagulopathy, hyperammonemia, and high serum lactate and lipid levels. Hepatic laboratory abnormalities began to resolve within 48 hr of stopping amiodarone infusion. Heart rate control was achieved concurrently with discovery of laboratory test result abnormalities, and no further antiarrhythmic therapy was required. The intravenous formulation of amiodarone contains the diluent polysorbate 80, which may have hepatotoxic effects. Specifically, animal studies suggest that polysorbate 80 may destabilize cell membranes and predispose to fatty change within liver architecture. Polysorbate was implicated in infant fatalities from E-ferol use in the 1980s. This case illustrates a possible adverse event by the Naranjo probability scale. Given the extent of clinically apparent hepatic injury, this patient was not rechallenged with amiodarone during the remainder of her hospitalization. With amiodarone now used as first-line pharmacologic therapy for critical tachyarrhythmia in this population, the number of children exposed to this drug should be expected to increase. Laboratory indices of liver function should be evaluated at initiation of amiodarone therapy, as well as frequently throughout duration of therapy. Consideration should be given to polysorbate-free formulation of intravenous amiodarone for use in the cohort with congenital cardiac disease.

  9. Mechanisms of circadian rhythmicity of carbon tetrachloride hepatotoxicity.

    PubMed

    Bruckner, James V; Ramanathan, Raghupathy; Lee, K Monica; Muralidhara, Srinivasa

    2002-01-01

    The toxicity of carbon tetrachloride (CCl(4)) and certain other chemicals varies over a 24-h period. Because the metabolism of some drugs follows a diurnal rhythm, it was decided to investigate whether the hepatic metabolic activation of CCl(4) was rhythmic and coincided in time with maximum susceptibility to CCl(4) hepatotoxicity. A related objective was to test the hypothesis that abstinence from food during the sleep cycle results in lipolysis and formation of acetone, which participates in induction of liver microsomal cytochrome P450IIE1 (CYP2E1), resulting in a diurnal increase in CCl(4) metabolic activation and acute liver injury. Groups of fed and fasted male Sprague-Dawley rats were given a single oral dose of 800 mg of CCl(4)/kg at 2- to 4-h intervals over a 24-h period. Serum enzyme activities, measured 24 h post dosing as indices of acute liver injury, exhibited distinct maxima in both fed and fasted animals dosed with CCl(4) near the beginning of their dark/active cycle. Blood acetone, hepatic CYP2E1 activity, and covalent binding of (14)CCl(4)/metabolites to hepatic microsomal proteins in untreated rats fed ad libitum followed circadian rhythms similar to that of susceptibility to CCl(4). Parallel fluctuations of greater amplitude were seen in rats fasted for 24 h. Hepatic glutathione levels were lowest at the time of greatest susceptibility to CCl(4). Acetone dose-response experiments showed high correlations between blood acetone levels, CYP2E1 induction, and CCl(4)-induced liver injury. Pretreatment with diallyl sulfide suppressed CYP2E1 and abolished the circadian rhythmicity of susceptibility to CCl(4). These findings provide additional support for acetone's physiological role in CYP2E1 induction and for CYP2E1's role in modulating CCl(4) chronotoxicity in rats.

  10. Bicalutamide-induced hepatotoxicity: A rare adverse effect.

    PubMed

    Hussain, Salwa; Haidar, Abdallah; Bloom, Robert E; Zayouna, Nafea; Piper, Michael H; Jafri, Syed-Mohammed R

    2014-01-01

    Male, 81 FINAL DIAGNOSIS: Prostate cancer Symptoms: Anorexia • dark urine • joundice • letargy Casodex Clinical Procedure: - Specialty: Oncology. Adverse events of drug therapy. Bicalutamide is a nonsteroidal anti-androgen used extensively during the initiation of androgen deprivation therapy with a luteinizing hormone-releasing hormone (LHRH) agonist to reduce the symptoms of tumor flare in patients with metastatic prostate neoplasm. It can cause gynecomastia, hot flashes, fatigue, and decreased libido through competitive androgen receptor blockade. Although not as common, acute drug-induced liver injury is also possible with bicalutamide therapy. Typically, this results in transient derangement of liver function and patients remain asymptomatic. We share our experience with a case of symptomatic acute hepatotoxicity secondary to the use of bicalutamide and use this opportunity to present a brief review of existing literature. An 81-year-old African American male with metastatic prostate neoplasm presented with nonspecific symptoms along with jaundice of 1-day duration. He was started on a trial of bicalutamide 3 weeks prior to presentation. On physical examination, scleral icterus was noted. Workup revealed acutely elevated liver transaminases (>5 times the upper limit of normal), alkaline phosphatase, conjugated hyperbilirubinemia, and coagulopathy. Other etiologies, including viruses, common toxins, drugs, autoimmune, and copper-induced hepatitis, were considered. Bicalutamide was discontinued and the patient was managed with supportive care. He showed improvement of clinical and laboratory abnormalities within days. While rare, clinically significant and potentially life-threatening liver injury can result from use of bicalutamide. Prompt recognition and discontinuation of bicalutamide is necessary to avoid serious complications from this adverse reaction.

  11. Identifying 2 prenylflavanones as potential hepatotoxic compounds in the ethanol extract of Sophora flavescens.

    PubMed

    Yu, Qianqian; Cheng, Nengneng; Ni, Xiaojun

    2013-11-01

    Zhixue capsule is a prescription for hemorrhoid commonly used in traditional Chinese medicine. This drug was recalled by the State Food and Drug Administration in 2008 because of severe adverse hepatic reactions. Zhixue capsule is composed of ethanol extracts of Cortex Dictamni (ECD) and Sophora flavescens (ESF). In our preliminary study, we observed the hepatotoxic effects of ESF on rat primary hepatocytes. However, ECD did not exhibit hepatotoxicity at the same concentration range. In this study, ESF was evaluated for its potential hepatotoxic effects on rats. Bioassay-guided isolation was used to identify the material basis for hepatotoxicity. Treatment with 1.25 g/kg and 2.5 g/kg ESF significantly elevated the alanine aminotransferase and aspartate aminotransferase levels in the serum. The changes in the levels of transaminases were supported by the remarkable fatty degeneration of liver histopathology. Further investigations using bioassay-guided isolation and analysis indicated that prenylated flavanones accounted for the positive hepatotoxic results. Two isolated compounds were identified, kurarinone and sophoraflavanone G, using nuclear magnetic resonance and mass spectrometry techniques. These compounds have potent toxic effects on primary rat hepatocytes (with IC50 values of 29.9 μM and 16.5 μM) and human HL-7702 liver cells (with IC50 values of 48.2 μM and 40.3 μM), respectively. Consequently, the hepatotoxic constituents of S. flavescens were determined to be prenylated flavanones, kurarinone, and sophoraflavanone G. © 2013 Institute of Food Technologists®

  12. Acetaminophen hepatotoxicity and sterile inflammation: The mechanism of protection of Chlorogenic acid.

    PubMed

    Jaeschke, Hartmut

    2016-01-05

    Acetaminophen hepatotoxicity is characterized by extensive necrotic cell death and a sterile inflammatory response. A recent report suggested that a therapeutic intervention with chlorogenic acid, a dietary polyphenolic compound, protects against acetaminophen-induced liver injury by inhibiting the inflammatory injury. The purpose of this letter is to discuss a number of reasons why the protective mechanism of chlorogenic acid against acetaminophen hepatotoxicity does not involve an anti-inflammatory effect and provides an alternative explanation for the observed protection. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Hydroxycut hepatotoxicity: A case series and review of liver toxicity from herbal weight loss supplements

    PubMed Central

    Dara, Lily; Hewett, Jennifer; Lim, Joseph Kartaik

    2008-01-01

    Dietary supplements represent an increasingly common source of drug-induced liver injury. Hydroxycut is a popular weight loss supplement which has previously been linked to hepatotoxicity, although the individual chemical components underlying liver injury remain poorly understood. We report two cases of acute hepatitis in the setting of Hydroxycut exposure and describe possible mechanisms of liver injury. We also comprehensively review and summarize the existing literature on commonly used weight loss supplements, and their individual components which have demonstrated potential for liver toxicity. An increased effort to screen for and educate patients and physicians about supplement-associated hepatotoxicity is warranted. PMID:19058338

  14. Infliximab Modulates Cisplatin-Induced Hepatotoxicity in Rats

    PubMed Central

    Cüre, Medine Cumhur; Cüre, Erkan; Kalkan, Yıldıray; Kırbaş, Aynur; Tümkaya, Levent; Yılmaz, Arif; Türkyılmaz, Ayşegül Küçükali; Şehitoğlu, İbrahim; Yüce, Süleyman

    2016-01-01

    Background: Cisplatin (Cis) is one of the most commonly used antineoplastic drugs. It is used as chemotherapy for many solid organ malignancies such as brain, neck, male and female urogenital, vesical and pulmonary cancers. Infliximab blocks tumor necrosis factor alpha (TNF-α). Several studies have reported that infliximab ameliorates cell damage by reducing cytokine levels. Aims: We aimed to investigate whether infliximab has a preventive effect against cisplatin-induced hepatotoxicity and whether it has a synergistic effect when combined with Cis. Study Design: Animal experimentation. Methods: Male Wistar albino rats were divided in three groups as follows: Cis group, infliximab + Cis (CIN) group and the control group. Each group comprised 10 animals. Animals in the Cis group received an intraperitoneal single-dose injection of Cis (7 mg/kg). In the CIN group, a single dose of infliximab (7 mg/kg) was administered 72 h prior to the Cis injection. After 72 h, a single dose of Cis (7 mg/kg) was administered. All rats were sacrificed five days after Cis injection. Results: TNF-α levels in the Cis group were significantly higher (345.5±40.0 pg/mg protein) than those of the control (278.7±62.1 pg/mg protein, p=0.003) and CIN groups (239.0±64.2 pg/mg protein, p=0.013). The Cis group was found to have high carbonic anhydrase (CA)-II and low carbamoyl phosphate synthetase-1 (CPS-1) levels. Aspartate transaminase (AST) and alanine transaminase (ALT) levels were lower in the CIN group as compared to the Cis group. Total histological damage was greater in the Cis group as compared to the control and CIN groups. Conclusion: Cis may lead to liver damage by increasing cytokine levels. It may increase oxidative stress-induced tissue damage by increasing carbonic anhydrase II (CA-II) enzyme levels and decreasing CPS-1 enzyme levels. Infliximab decreases Cis-induced hepatic damage by blocking TNF-α and it may also protect against liver damage by regulating CPS-1 and CA

  15. Color visualization of cyclic magnitudes

    NASA Astrophysics Data System (ADS)

    Restrepo, Alfredo; Estupiñán, Viviana

    2014-02-01

    We exploit the perceptual, circular ordering of the hues in a technique for the visualization of cyclic variables. The hue is thus meaningfully used for the indication of variables such as the azimuth and the units of the measurement of time. The cyclic (or circular) variables may be both of the continuous type or the discrete type; among the first there is azimuth and among the last you find the musical notes and the days of the week. A correspondence between the values of a cyclic variable and the chromatic hues, where the natural circular ordering of the variable is respected, is called a color code for the variable. We base such a choice of hues on an assignment of of the unique hues red, yellow, green and blue, or one of the 8 even permutations of this ordered list, to 4 cardinal values of the cyclic variable, suitably ordered; color codes based on only 3 cardinal points are also possible. Color codes, being intuitive, are easy to remember. A possible low accuracy when reading instruments that use this technique is compensated by fast, ludic and intuitive readings; also, the use of a referential frame makes readings precise. An achromatic version of the technique, that can be used by dichromatic people, is proposed.

  16. The protective role of quercetin and arginine on gold nanoparticles induced hepatotoxicity in rats.

    PubMed

    Abdelhalim, Mohamed Anwar K; Moussa, Sherif A Abdelmottaleb; Qaid, Huda Abdo Yahya

    2018-01-01

    The aim of the study was to confirm the hepatotoxicity induced by small-sized gold nanoparticles (GNPs) and evaluate the role of quercetin (Qur) and arginine (Arg) against hepatotoxicity caused by GNPs. Twenty-five healthy male Wistar-Kyoto rats were used. GNPs were administered intraperitoneally to these rats at the dose of 50 μL for seven consecutive days. The role of Qur and Arg antioxidants against toxicity induced by GNPs was detected through the measurement of serum liver function and oxidative stress biomarkers in the liver tissues. Coadministration of Qur and Arg along with GNPs significantly induced dramatic alterations in the biochemical parameters. Levels of malondialdehyde, gamma-glutamyl transferase, alanine aminotransferase, alkaline phosphatase, and total protein increased significantly in the GNPs injected group than in the control group, while reduced glutathione was greatly reduced in the GNPs group than in the control group. It also significantly decreased liver enzymes and the oxidative stress, therefore improving the liver damage and hepatotoxicity induced by GNPs. This study demonstrated that Qur and Arg antioxidants effectively improved the hepatic oxidative damage induced by GNPs. It also substantiates the application of Qur and Arg as protecting stand-in against GNPs' hepatotoxicity.

  17. Advancing Predictive Hepatotoxicity at the Intersection of Experimental, in Silico, and Artificial Intelligence Technologies.

    PubMed

    Fraser, Keith; Bruckner, Dylan M; Dordick, Jonathan S

    2018-06-18

    Adverse drug reactions, particularly those that result in drug-induced liver injury (DILI), are a major cause of drug failure in clinical trials and drug withdrawals. Hepatotoxicity-mediated drug attrition occurs despite substantial investments of time and money in developing cellular assays, animal models, and computational models to predict its occurrence in humans. Underperformance in predicting hepatotoxicity associated with drugs and drug candidates has been attributed to existing gaps in our understanding of the mechanisms involved in driving hepatic injury after these compounds perfuse and are metabolized by the liver. Herein we assess in vitro, in vivo (animal), and in silico strategies used to develop predictive DILI models. We address the effectiveness of several two- and three-dimensional in vitro cellular methods that are frequently employed in hepatotoxicity screens and how they can be used to predict DILI in humans. We also explore how humanized animal models can recapitulate human drug metabolic profiles and associated liver injury. Finally, we highlight the maturation of computational methods for predicting hepatotoxicity, the untapped potential of artificial intelligence for improving in silico DILI screens, and how knowledge acquired from these predictions can shape the refinement of experimental methods.

  18. Acute Hepatotoxicity of Intravenous Amiodarone: Case Report and Review of the Literature.

    PubMed

    Chen, Chia-Chi; Wu, Chien-Chih

    2016-01-01

    Amiodarone is a class III antiarrhythmic drug widely used for the treatment of both supraventricular and ventricular arrhythmias in intensive care unit. Hepatotoxicity of amiodarone is usually mild and delayed onset. Acute hepatotoxicity is a rare side effect and usually correlated to intravenous form use. In this case, acute hepatocellular injury occurred within 24 hours after the administration of intravenous amiodarone. Liver enzyme significantly improved after holding intravenous amiodarone use. Because ventricular arrhythmia persisted and side effects occurred to alternative therapy, low dose of oral amiodarone was resumed and hepatotoxicity did not occur afterward. Acute hepatotoxicity of intravenous amiodarone is possibly related to polysorbate 80, the solubilizer of amiodarone infusion or higher dose. As a result, when intravenous amiodarone is prescribed, closely monitoring liver enzyme is highly suggested. If acute hepatitis takes place secondary to intravenous amiodarone, oral therapy should not be resumed afterward. If there is no alternative treatment, lower dose of oral amiodarone (≤200 mg/d) could be tried and should monitor liver function regularly.

  19. Protective effect of rutin in comparison to silymarin against induced hepatotoxicity in rats.

    PubMed

    Reddy, M Kasi; Reddy, A Gopala; Kumar, B Kala; Madhuri, D; Boobalan, G; Reddy, M Anudeep

    2017-01-01

    The aim of this study is to evaluate the hepatoprotective effect of rutin (RTN) in comparison to silymarin (SLM) against acetaminophen (APAP)-induced hepatotoxicity in rats. Male Wistar albino rats (n=24) of 3 months age were equally divided into four groups. Group 1 served as normal control. Hepatotoxicity was induced in the remaining three groups with administration of 500 mg/kg po APAP from day 1-3. Groups 2, 3, and 4 were subsequently administered orally with distilled water, 25 mg/kg of SLM, and 20 mg/kg of RTN, respectively, for 11 days. The mean body weights and biomarkers of hepatotoxicity were estimated on day 0, 4 (confirmation of toxicity), and 15 (at the end of treatment). Hematological parameters were evaluated on day 4 and 15. Antioxidant profile and adenosine triphosphatases (ATPases) were assessed at the end of the experiment. Liver tissues were subjected to histopathology and transmission electron microscopy after the sacrifice on day 15. Antioxidant profile, ATPases, and hematological and sero-biochemical parameters were significantly altered, and histopathological changes were noticed in the liver of toxic control group. These changes were reversed in groups 3 and 4 that were administered with SLM and RTN, respectively. The results of the present investigation enunciated that SLM has potent hepatoprotective activity though the RTN was found superior in restoring the pathological alterations in paracetamol-induced hepatotoxicity in Wistar albino rats.

  20. Mechanistic Biomarkers in Acetaminophen-induced Hepatotoxicity and Acute Liver Failure: From Preclinical Models to Patients

    PubMed Central

    McGill, Mitchell R.; Jaeschke, Hartmut

    2015-01-01

    SUMMARY Introduction Drug hepatotoxicity is a major clinical issue. Acetaminophen (APAP) overdose is especially common. Serum biomarkers used to follow patient progress reflect either liver injury or function, but focus on biomarkers that can provide insight into the basic mechanisms of hepatotoxicity is increasing and enabling us to translate mechanisms of toxicity from animal models to humans. Areas covered We review recent advances in mechanistic serum biomarker research in drug hepatotoxicity. Specifically, biomarkers for reactive drug intermdiates, mitochondrial dysfunction, nuclear DNA damage, mode of cell death and inflammation are discussed, as well as microRNAs. Emphasis is placed on APAP-induced liver injury. Expert Opinion Several serum biomarkers of reactive drug intermediates, mitochondrial damage, nuclear DNA damage, apoptosis and necrosis, and inflammation have been described. These studies have provided evidence that mitochondrial damage is critical in APAP hepatotoxicity in humans, while apoptosis has only a minor role, and inflammation is important for recovery and regeneration after APAP overdose. Additionally, mechanistic serum biomarkers have been shown to predict outcome as well as, or better than, some clinical scores. In the future, such biomarkers will help determine the need for liver transplantation and, with improved understanding of the human pathophysiology, identify novel therapeutic targets. PMID:24836926

  1. [Hepatotoxicity of emodin based on UGT1A1 enzyme-mediated bilirubin in liver microsomes].

    PubMed

    Wang, Qi; Dai, Zhong; Zhang, Yu-Jie; Ma, Shuang-Cheng

    2016-12-01

    To study the hepatotoxicity of emodin based on bilirubin metabolism mediated by glucuronidation of UGT1A1 enzyme. In this study, three different incubation systems were established by using RLM, HLM, and rUGT1A1, with bilirubin as the substrate. Different concentrations of bilirubin and emodin were added in the incubation systems. The double reciprocal Michaelis equation was drawn based on the total amount of bilirubin glucuronidation. The apparent inhibition constant Ki was then calculated with the slope curve to predict the hepatotoxicity. The results indicated that emodin had a significant inhibition to the UGT1A1 enzyme in all of the three systems, with Ki=5.400±0.956(P<0.05) in HLM system, Ki =10.020±0.611(P<0.05) in RLM system, Ki=4.850±0.528(P<0.05) in rUGT1A1 system. Meanwhile, emodin had no significant difference between rat and human in terms of inhibition of UGT1A1 enzyme. Emodin had a potential risk of the hepatotoxicity by inhibiting the UGT1A1 enzyme activity. And the method established in this study provides a new thought and new method to evaluate hepatotoxicity and safety of traditional Chinese medicines. Copyright© by the Chinese Pharmaceutical Association.

  2. POTENTIATION OF CARBON TETRACHLORIDE HEPATOTOXICITY BY INHALED METHANOL:TIME COURSE INJURY AND RECOVERY

    EPA Science Inventory

    Increases in the use of methanol (MeOH) as a transportation fuel would result in greater potential for inhalation exposure. ecause oral exposure to MeOH potentates the hepatotoxicity of carbon tetrachloride (CCl4), we examined the ability of inhaled MeOH to potentiate CCl4 hepato...

  3. VIRTUAL LIVER: AN IN SILICO FRAMEWORK FOR ANALYZING CHEMICAL-INDUCED HEPATOTOXICITY

    EPA Science Inventory

    The US EPA Virtual Liver (v-LiverTM) is an in silico framework for the dose-dependent perturbation of normal hepatic functions by chemicals using in vitro data. The framework consists of a computable knowledge-base (KB) to infer putative pathways in hepatotoxicity and a cellular...

  4. Establishment of a methodology for investigating protectants against ethanol-induced hepatotoxicity.

    PubMed

    Ruan, Xueqing; Shen, Chong; Meng, Qin

    2010-05-01

    Ethanol-induced liver injury has been extensively reported in clinic, but still lacks an efficient in vitro platform for investigating its hepatotoxicity and protectants. This study aimed to establish a methodology on the culture conditions regarding the sealability against evaporation of ethanol, culture medium and 2D/3D culture of hepatocytes. Based on the experimental findings, it was indicated that the ethanol evaporation from culture plates was a severe problem reducing its toxicity in hepatocyte. According to the detected ethanol toxic response marked by reduced cell viability, 3D cultured hepatocytes in gel entrapment were suggested to be better than 2D hepatocyte in monolayer, but the cultures in either William's Medium E or DMEM exhibited comparable sensitivity to ethanol toxicity. Subsequently, 3D cultured hepatocytes with Parafilm sealing were systematically illustrated to well reflect the ethanol-induced lipid accumulation, reactive oxygen species/malondialdehyde generation, glutathione depletion and cytochrome 2E1 induction. Finally, such hepatocyte models were proposed as a platform for screening of herbal component against ethanol hepatotoxicity. Nano-silibinin, for the first time, found to perform significant protection against ethanol-induced hepatotoxicity while silibinin in normal particles could not inhibit such toxicity. This protection of nano-silibinin might relate to its improved bioavailability compared to normal insoluble silibinin and could act as an anti-oxidative and anti-steatosis agent against ethanol-induced hepatotoxicity. Copyright (c) 2010. Published by Elsevier Ltd.

  5. Hepatoprotective and antioxidant effects of Cuscuta chinensis against acetaminophen-induced hepatotoxicity in rats.

    PubMed

    Yen, Feng-Lin; Wu, Tzu-Hui; Lin, Liang-Tzung; Lin, Chun-Ching

    2007-04-20

    Tu-Si-Zi, the seeds of Cuscuta chinensis Lam. (Convolvulaceae), is a traditional Chinese medicine that is commonly used to nourish and improve the liver and kidney conditions in China and other Asian countries. As oxidative stress promotes the development of acetaminophen (APAP)-induced hepatotoxicity, the aim of the present study was to evaluate and compare the hepatoprotective effect and antioxidant activities of the aqueous and ethanolic extracts of C chinensis on APAP-induced hepatotoxicity in rats. The C chinensis ethanolic extract at an oral dose of both 125 and 250mg/kg showed a significant hepatoprotective effect relatively to the same extent (P<0.05) by reducing levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), and alkaline phosphatase (ALP). In addition, the same ethanolic extract prevented the hepatotoxicity induced by APAP-intoxicated treatment as observed when assessing the liver histopathology. Regarding the antioxidant activity, C chinensis ethanolic extract exhibited a significant effect (P<0.05) by increasing levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and by reducing malondialdehyde (MDA) levels. In contrast, the same doses of the aqueous extract of C chinensis did not present any hepatoprotective effect as seen in the ethanolic extract, and resulted in further liver deterioration. In conclusion, these data suggest that the ethanolic extract of Cuscuta chinensis can prevent hepatic injuries from APAP-induced hepatotoxicity in rats and this is likely mediated through its antioxidant activities.

  6. HEPATOTOXIC EVALUATION OF THE BINARY INTERACTIONS OF BROMODICHLOROMETHANE WITH CHLOROFORM, CHLORODIBROMOMETHANE AND BROMOFORM

    EPA Science Inventory

    HEPATOTOXIC EVALUATION OF THE BINARY INTERACTIONS OF BROMODICHLOROMETHANE (BDCM) WITH CHLOROFORM (CHC13), CHLORODIBROMOMETHANE (CDBM) AND BROMOFORM (CHBr3). Y M Se'', C Gennings2, A McDonald', L K Teuschler3, A Hamm2and J E Simmons .'NHEERL, ORD, U.S. EPA, RTP, NC; 2MCV, VCU, Ric...

  7. Methoxyflurane enhances allyl alcohol hepatotoxicity in rats. Possible involvement of increased acrolein formation.

    PubMed

    Kershaw, W C; Barsotti, D A; Leonard, T B; Dent, J G; Lage, G L

    1989-01-01

    The effect of methoxyflurane anesthesia on allyl alcohol-induced hepatotoxicity and the metabolism of allyl alcohol was studied in male rats. Hepatotoxicity was assessed by the measurement of serum alanine aminotransferase activity and histopathological examination. Allyl alcohol-induced hepatotoxicity was enhanced when allyl alcohol (32 mg/kg) was administered 4 hr before or up to 8 days after a single 10-min exposure to methoxyflurane vapors. The possibility that methoxyflurane increases alcohol dehydrogenase-dependent oxidation of allyl alcohol to acrolein, the proposed toxic metabolite, was evaluated by measuring the rate of acrolein formation in the presence of allyl alcohol and liver cytosol. The effect of methoxyflurane on alcohol dehydrogenase activity in liver cytosol was also assessed by measuring the rate of NAD+ utilization in the presence of ethyl alcohol or allyl alcohol. Alcohol dehydrogenase activity and rate of acrolein formation were elevated in methoxyflurane-pretreated rats. The results suggest that a modest increase in alcohol dehydrogenase activity and rate of acrolein formation markedly enhances allyl alcohol-induced hepatotoxicity.

  8. Sequencing Cyclic Peptides by Multistage Mass Spectrometry

    PubMed Central

    Mohimani, Hosein; Yang, Yu-Liang; Liu, Wei-Ting; Hsieh, Pei-Wen; Dorrestein, Pieter C.; Pevzner, Pavel A.

    2012-01-01

    Some of the most effective antibiotics (e.g., Vancomycin and Daptomycin) are cyclic peptides produced by non-ribosomal biosynthetic pathways. While hundreds of biomedically important cyclic peptides have been sequenced, the computational techniques for sequencing cyclic peptides are still in their infancy. Previous methods for sequencing peptide antibiotics and other cyclic peptides are based on Nuclear Magnetic Resonance spectroscopy, and require large amount (miligrams) of purified materials that, for most compounds, are not possible to obtain. Recently, development of mass spectrometry based methods has provided some hope for accurate sequencing of cyclic peptides using picograms of materials. In this paper we develop a method for sequencing of cyclic peptides by multistage mass spectrometry, and show its advantages over single stage mass spectrometry. The method is tested on known and new cyclic peptides from Bacillus brevis, Dianthus superbus and Streptomyces griseus, as well as a new family of cyclic peptides produced by marine bacteria. PMID:21751357

  9. Altered Protein S-Glutathionylation Identifies a Potential Mechanism of Resistance to Acetaminophen-Induced Hepatotoxicity

    PubMed Central

    McGarry, David J.; Chakravarty, Probir; Wolf, C. Roland

    2015-01-01

    Acetaminophen (APAP) is the most commonly used over-the-counter analgesic. However, hepatotoxicity induced by APAP is a major clinical issue, and the factors that define sensitivity to APAP remain unclear. We have previously demonstrated that mice nulled for glutathione S-transferase Pi (GSTP) are resistant to APAP-induced hepatotoxicity. This study aims to exploit this difference to delineate pathways of importance in APAP toxicity. We used mice nulled for GSTP and heme oxygenase-1 oxidative stress reporter mice, together with a novel nanoflow liquid chromatography–tandem mass spectrometry methodology to investigate the role of oxidative stress, cell signaling, and protein S-glutathionylation in APAP hepatotoxicity. We provide evidence that the sensitivity difference between wild-type and Gstp1/2−/− mice is unrelated to the ability of APAP to induce oxidative stress, despite observing significant increases in c-Jun N-terminal kinase and extracellular signal-regulated kinase phosphorylation in wild-type mice. The major difference in response to APAP was in the levels of protein S-glutathionylation: Gstp1/2−/− mice exhibited a significant increase in the number of S-glutathionylated proteins compared with wild-type animals. Remarkably, these S-glutathionylated proteins are involved in oxidative phosphorylation, respiratory complexes, drug metabolism, and mitochondrial apoptosis. Furthermore, we found that S-glutathionylation of the rate-limiting glutathione-synthesizing enzyme, glutamate cysteine ligase, was markedly increased in Gstp1/2−/− mice in response to APAP. The data demonstrate that S-glutathionylation provides an adaptive response to APAP and, as a consequence, suggest that this is an important determinant in APAP hepatotoxicity. This work identifies potential novel avenues associated with cell survival for the treatment of chemical-induced hepatotoxicity. PMID:26311813

  10. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps.

    PubMed

    Teschke, Rolf; Eickhoff, Axel

    2015-01-01

    Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although, herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences) scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM) are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality.

  11. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps

    PubMed Central

    Teschke, Rolf; Eickhoff, Axel

    2015-01-01

    Plants are natural producers of chemical substances, providing potential treatment of human ailments since ancient times. Some herbal chemicals in medicinal plants of traditional and modern medicine carry the risk of herb induced liver injury (HILI) with a severe or potentially lethal clinical course, and the requirement of a liver transplant. Discontinuation of herbal use is mandatory in time when HILI is first suspected as diagnosis. Although, herbal hepatotoxicity is of utmost clinical and regulatory importance, lack of a stringent causality assessment remains a major issue for patients with suspected HILI, while this problem is best overcome by the use of the hepatotoxicity specific CIOMS (Council for International Organizations of Medical Sciences) scale and the evaluation of unintentional reexposure test results. Sixty five different commonly used herbs, herbal drugs, and herbal supplements and 111 different herbs or herbal mixtures of the traditional Chinese medicine (TCM) are reported causative for liver disease, with levels of causality proof that appear rarely conclusive. Encouraging steps in the field of herbal hepatotoxicity focus on introducing analytical methods that identify cases of intrinsic hepatotoxicity caused by pyrrolizidine alkaloids, and on omics technologies, including genomics, proteomics, metabolomics, and assessing circulating micro-RNA in the serum of some patients with intrinsic hepatotoxicity. It remains to be established whether these new technologies can identify idiosyncratic HILI cases. To enhance its globalization, herbal medicine should universally be marketed as herbal drugs under strict regulatory surveillance in analogy to regulatory approved chemical drugs, proving a positive risk/benefit profile by enforcing evidence based clinical trials and excellent herbal drug quality. PMID:25954198

  12. Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity.

    PubMed

    Hayashi, Paul H; Fontana, Robert J; Chalasani, Naga P; Stolz, Andrew A; Talwalkar, Jay A; Navarro, Victor J; Lee, William M; Davern, Timothy J; Kleiner, David E; Gu, Jiezhun; Hoofnagle, Jay H

    2015-09-01

    Isoniazid is a leading cause of liver injury but it is not clear how many cases are reported or how many clinicians and patients adhere to American Thoracic Society (ATS) guidelines. We collected data on cases of isoniazid hepatotoxicity and assessed adherence to ATS guidelines and reports to the Centers for Disease Control's (CDC) isoniazid severe adverse events program. We analyzed Drug-Induced Liver Injury Network (DILIN) cases considered definite, highly likely, or probable for isoniazid injury from 2004 through 2013. We assessed the delays in isoniazid discontinuance according to ATS criteria and hepatotoxicity severity by Severity Index Score. We checked reporting to the CDC by matching cases based on age, latency, indication, reporting period, and comorbidities. Isoniazid was the second most commonly reported agent in the DILIN, with 69 cases; 60 of these met inclusion criteria. The median age of cases was 49 years (range, 4-68 y), 70% were female, 97% had latent tuberculosis, and 62% were hospitalized. Patients took a median of 9 days to stop taking isoniazid (range, 0-99 days). Thirty-three cases (55%) continued taking isoniazid for more than 7 days after the ATS criteria for stopping were met. Twenty-four cases (40%) continued isoniazid for more than 14 days after meeting criteria for stopping. A delay in stopping was associated with more severe injury (P < .05). Of 13 patients who died or underwent liver transplantation, 9 (70%) continued taking isoniazid for more than 7 days after meeting criteria for stopping. Only 1 of 25 cases of isoniazid hepatotoxicity eligible for reporting to the CDC was reported. Poor adherence to ATS guidelines is common in cases of hepatotoxicity and is associated with more severe outcomes including hospitalization, death, and liver transplantation. Isoniazid continues to be a leading cause of DILI in the United States, and its hepatotoxicity is under-reported significantly. Copyright © 2015 AGA Institute. Published by

  13. Role of the Sympathetic Nervous System in Carbon Tetrachloride-Induced Hepatotoxicity and Systemic Inflammation

    PubMed Central

    Lin, Jung-Chun; Peng, Yi-Jen; Wang, Shih-Yu; Young, Ton-Ho; Salter, Donald M.; Lee, Herng-Sheng

    2015-01-01

    Carbon tetrachloride (CCl4) is widely used as an animal model of hepatotoxicity and the mechanisms have been arduously studied, however, the contribution of the sympathetic nervous system (SNS) in CCl4-induced acute hepatotoxicity remains controversial. It is also known that either CCl4 or SNS can affect systemic inflammatory responses. The aim of this study was to establish the effect of chemical sympathectomy with 6-hydroxydopamine (6-OHDA) in a mouse model of CCl4-induced acute hepatotoxicity and systemic inflammatory response. Mice exposed to CCl4 or vehicle were pretreated with 6-OHDA or saline. The serum levels of aminotransferases and alkaline phosphatase in the CCl4-poisoning mice with sympathetic denervation were significantly lower than those without sympathetic denervation. With sympathetic denervation, hepatocellular necrosis and fat infiltration induced by CCl4 were greatly decreased. Sympathetic denervation significantly attenuated CCl4-induced lipid peroxidation in liver and serum. Acute CCl4 intoxication showed increased expression of inflammatory cytokines/chemokines [eotaxin-2/CCL24, Fas ligand, interleukin (IL)-1α, IL-6, IL-12p40p70, monocyte chemoattractant protein-1 (MCP-1/CCL2), and tumor necrosis factor-α (TNF-α)], as well as decreased expression of granulocyte colony-stimulating factor and keratinocyte-derived chemokine. The overexpressed levels of IL-1α, IL-6, IL-12p40p70, MCP-1/CCL2, and TNF-α were attenuated by sympathetic denervation. Pretreatment with dexamethasone significantly reduced CCl4-induced hepatic injury. Collectively, this study demonstrates that the SNS plays an important role in CCl4-induced acute hepatotoxicity and systemic inflammation and the effect may be connected with chemical- or drug-induced hepatotoxicity and circulating immune response. PMID:25799095

  14. Cytochrome P450 binding studies of novel tacrine derivatives: Predicting the risk of hepatotoxicity.

    PubMed

    McEneny-King, Alanna; Osman, Wesseem; Edginton, Andrea N; Rao, Praveen P N

    2017-06-01

    The 1,2,3,4-tetrahydroacridine derivative tacrine was the first drug approved to treat Alzheimer's disease (AD). It is known to act as a potent cholinesterase inhibitor. However, tacrine was removed from the market due to its hepatotoxicity concerns as it undergoes metabolism to toxic quinonemethide species through the cytochrome P450 enzyme CYP1A2. Despite these challenges, tacrine serves as a useful template in the development of novel multi-targeting anti-AD agents. In this regard, we sought to evaluate the risk of hepatotoxicity in a series of C9 substituted tacrine derivatives that exhibit cholinesterase inhibition properties. The hepatotoxic potential of tacrine derivatives was evaluated using recombinant cytochrome (CYP) P450 CYP1A2 and CYP3A4 enzymes. Molecular docking studies were conducted to predict their binding modes and potential risk of forming hepatotoxic metabolites. Tacrine derivatives compound 1 (N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) and 2 (6-chloro-N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) which possess a C9 3,4-dimethoxybenzylamino substituent exhibited weak binding to CYP1A2 enzyme (1, IC 50 =33.0µM; 2, IC 50 =8.5µM) compared to tacrine (CYP1A2 IC 50 =1.5µM). Modeling studies show that the presence of a bulky 3,4-dimethoxybenzylamino C9 substituent prevents the orientation of the 1,2,3,4-tetrahydroacridine ring close to the heme-iron center of CYP1A2 thereby reducing the risk of forming hepatotoxic species. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

  15. Hepatotoxicity induced by acute and chronic paracetamol overdose in children: Where do we stand?

    PubMed

    Tong, Hoi Yan; Medrano, Nicolás; Borobia, Alberto Manuel; Ruiz, José Antonio; Martínez, Ana María; Martín, Julia; Quintana, Manuel; García, Santos; Carcas, Antonio José; Ramírez, Elena

    2017-02-01

    There are few data on hepatotoxicity induced by acute or chronic paracetamol poisoning in the pediatric population. Paracetamol poisoning data can reveal the weaknesses of paracetamol poisoning management guidelines. We retrospectively studied the patients of less than 18 years old with measurable paracetamol levels, who were brought to the emergency department (ED) of La Paz University Hospital, Madrid, Spain, for suspected paracetamol overdoses between 2005 and 2010. Ninety-two patients with suspected paracetamol poisoning were identified. In 2007, the incidence of paracetamol poisoning in the pediatric population was 0.8 [Poisson-95% confidence interval (CI): 0.03-3.69] per 10 000 inhabitants aged less than 18 years. The incidence in the same year was 1.53 (Poisson-95% CI: 0.24-5.57) per 10 000 patients in the pediatric ED. The most common cause of poisoning was attempted suicide (47.8%) in teenagers with a median age of 15 years, followed by accidental poisoning (42.2%) in babies with a median age of 2.65 years. Difference was seen in the frequency of hepatotoxicity between acute and chronic poisoning cases. Only 1 of 49 patients with acute poisoning showed hepatotoxicity [acute liver failure (ALF)], whereas 7 of 8 patients with chronic poisoning showed hepatotoxicity (3 cases of ALF). The average time to medical care was 6.83 hours for acute poisoning and 52.3 hours for chronic poisoning (P<0.001). Chronic paracetamol poisoning is a potential risk factor for hepatotoxicity and acute liver failure. Delays in seeking medical help might be a contributing factor. Clinicians should have a higher index of clinical suspicion for this entity.

  16. 40 CFR 721.2120 - Cyclic amide.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Cyclic amide. 721.2120 Section 721... Cyclic amide. (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as a cyclic amide (PMN P-92-131) is subject to reporting under this section for the...

  17. A cup product structure for cyclic cohomology

    NASA Astrophysics Data System (ADS)

    Espinosa Tintos, Jose Eduardo

    In this work we construct a cup product structure for cyclic cohomology of a cyclic set X. introduced by Comics. We make use of a categorical construction of cyclic homology by Fiedorowicz and Loday to define our cup product structure by using a large resolution of the cyclic category. We also provide a way to construct a chain map from a smaller resolution where the action of the finite groups is clear. and in the process of constructing this map we learn the large complex can be viewed as all factorizations in the category DeltaC using the cyclic structure of X.

  18. GENE EXPRESSION PROFILING IN THE LIVER OF CD-1 MICE TO CHARACTERIZE THE HEPATOTOXICITY OF TRIAZOLE FUNGICIDES.

    EPA Science Inventory

    Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and ...

  19. GENE EXPRESSION PROFILING IN THE LIVER OF CD-1 MICE TO CHARACTERIZE THE HEPATOTOXICITY OF TRIAZOLE FUNGICIDES

    EPA Science Inventory

    Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and ...

  20. Synthesis and Biological Evaluation of Benzochromenopyrimidinones as Cholinesterase Inhibitors and Potent Antioxidant, Non-Hepatotoxic Agents for Alzheimer's Disease.

    PubMed

    Dgachi, Youssef; Bautista-Aguilera, Oscar M; Benchekroun, Mohamed; Martin, Hélène; Bonet, Alexandre; Knez, Damijan; Godyń, Justyna; Malawska, Barbara; Gobec, Stanislav; Chioua, Mourad; Janockova, Jana; Soukup, Ondrej; Chabchoub, Fakher; Marco-Contelles, José; Ismaili, Lhassane

    2016-05-14

    We report herein the straightforward two-step synthesis and biological assessment of novel racemic benzochromenopyrimidinones as non-hepatotoxic, acetylcholinesterase inhibitors with antioxidative properties. Among them, compound 3Bb displayed a mixed-type inhibition of human acetylcholinesterase (IC50 = 1.28 ± 0.03 μM), good antioxidant activity, and also proved to be non-hepatotoxic on human HepG2 cell line.

  1. Protective effect of the edible brown alga Ecklonia stolonifera on doxorubicin-induced hepatotoxicity in primary rat hepatocytes.

    PubMed

    Jung, Hyun Ah; Kim, Jae-I; Choung, Se Young; Choi, Jae Sue

    2014-08-01

    As part of our efforts to isolate anti-hepatotoxic agents from marine natural products, we screened the ability of 14 edible varieties of Korean seaweed to protect against doxorubicin-induced hepatotoxicity in primary rat hepatocytes. Among the crude extracts of two Chlorophyta (Codium fragile and Capsosiphon fulvescens), seven Phaeophyta (Undaria pinnatifida, Sargassum thunbergii, Pelvetia siliquosa, Ishige okamurae, Ecklonia cava, Ecklonia stolonifera and Eisenia bicyclis), five Rhodophyta (Chondrus ocellatus, Gelidium amansii, Gracilaria verrucosa, Symphycladia latiuscula and Porphyra tenera), and the extracts of Ecklonia stolonifera, Ecklonia cava, Eisenia bicyclis and Pelvetia siliquosa exhibited significant protective effects on doxorubicin-induced hepatotoxicity, with half maximal effective concentration (EC50) values of 2.0, 2.5, 3.0 and 15.0 μg/ml, respectively. Since Ecklonia stolonifera exhibits a significant protective potential and is frequently used as foodstuff, we isolated six phlorotannins, including phloroglucinol (1), dioxinodehydroeckol (2), eckol (3), phlorofucofuroeckol A (4), dieckol (5) and triphloroethol-A (6). Phlorotannins 2 ∼ 6 exhibited potential protective effects on doxorubicin-induced hepatotoxicity, with corresponding EC50 values of 3.4, 8.3, 4.4, 5.5 and 11.5 μg/ml, respectively. The results clearly demonstrated that the anti-hepatotoxic effects of Ecklonia stolonifera and its isolated phlorotannins are useful for further exploration and development of therapeutic modalities for treatment of hepatotoxicity. © 2014 Royal Pharmaceutical Society.

  2. Tetrahydropyranodiquinolin-8-amines as new, non hepatotoxic, antioxidant, and acetylcholinesterase inhibitors for Alzheimer's disease therapy.

    PubMed

    Dgachi, Youssef; Sokolov, Olga; Luzet, Vincent; Godyń, Justyna; Panek, Dawid; Bonet, Alexandre; Martin, Hélène; Iriepa, Isabel; Moraleda, Ignacio; García-Iriepa, Cristina; Janockova, Jana; Richert, Lysiane; Soukup, Ondrej; Malawska, Barbara; Chabchoub, Fakher; Marco-Contelles, José; Ismaili, Lhassane

    2017-01-27

    Herein we report an efficient two step synthesis and biological assessment of 12 racemic tetrahydropyranodiquinolin-8-amines derivatives as antioxidant, cholinesterase inhibitors and non-hepatotoxic agents. Based on the results of the primary screening, we identified 7-(3-methoxyphenyl)-9,10,11,12-tetrahydro-7H-pyrano[2,3-b:5,6-h']diquinolin-8-amine (2h) as a particularly interesting non-hepatotoxic compound that shows moderate antioxidant activity (1.83 equiv Trolox in the ORAC assay), a non competitive inhibition of hAChE (IC 50  = 0.75 ± 0.01 μM), and brain permeable as determined by the PAMPA-Blood Brain Barrier assay. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  3. Scientific and Regulatory Perspectives in Herbal and Dietary Supplement Associated Hepatotoxicity in the United States

    PubMed Central

    Avigan, Mark I.; Mozersky, Robert P.; Seeff, Leonard B.

    2016-01-01

    In the United States (US), the risk of hepatotoxicity linked to the widespread use of certain herbal products has gained increased attention among regulatory scientists. Based on current US law, all dietary supplements sold domestically, including botanical supplements, are regulated by the Food and Drug Administration (FDA) as a special category of foods. Under this designation, regulatory scientists do not routinely evaluate the efficacy of these products prior to their marketing, despite the content variability and phytochemical complexity that often characterizes them. Nonetheless, there has been notable progress in the development of advanced scientific methods to qualitatively and quantitatively measure ingredients and screen for contaminants and adulterants in botanical products when hepatotoxicity is recognized. PMID:26950122

  4. On numerically pluricanonical cyclic coverings

    NASA Astrophysics Data System (ADS)

    Kulikov, V. S.; Kharlamov, V. M.

    2014-10-01

    We investigate some properties of cyclic coverings f\\colon Y\\to X (where X is a complex surface of general type) branched along smooth curves B\\subset X that are numerically equivalent to a multiple of the canonical class of X. Our main results concern coverings of surfaces of general type with p_g=0 and Miyaoka-Yau surfaces. In particular, such coverings provide new examples of multi-component moduli spaces of surfaces with given Chern numbers and new examples of surfaces that are not deformation equivalent to their complex conjugates.

  5. Potential Role of Activated Nonparenchymal Cells in Acetaminophen-Induced Potentiation of Hepatotoxicity

    DTIC Science & Technology

    1991-06-14

    ALT is either being degraded or the activity is inhibited by something in the 133 media. AST activity in cocultures of NPCs and hepatocytes was... Paracetamol Hepatotoxicity: IN VITRO Studies in Isolated Mouse Hepatocytes. Toxicology Letters. 2229: 37-48. Casini, A. M., P. A. Ferrali and M...Acute Liver Necrosis Following Overdose of Paracetamol . British Medical Journal. 2: 497-499. Decker, T., M. L. Lohmann-Matthes, U. Karck, T. Peters

  6. Acetaminophen hepatotoxicity in mice: Effect of age, frailty and exposure type

    PubMed Central

    Kane, Alice E.; Mitchell, Sarah J.; Mach, John; Huizer-Pajkos, Aniko; McKenzie, Catriona; Jones, Brett; Cogger, Victoria; Le Couteur, David G.; de Cabo, Rafael; Hilmer, Sarah N.

    2018-01-01

    Acetaminophen is a commonly used analgesic that can cause severe hepatotoxicity in overdose. Despite old age and frailty being associated with extensive and long-term utilization of acetaminophen and a high prevalence of adverse drug reactions, there is limited information on the risks of toxicity from acetaminophen in old age and frailty. This study aimed to assess changes in the risk and mechanisms of hepatotoxicity from acute, chronic and sub-acute acetaminophen exposure with old age and frailty in mice. Young and old male C57BL/6 mice were exposed to either acute (300 mg/kg via oral gavage), chronic (100 mg/kg/day in diet for six weeks) or sub-acute (250 mg/kg, t.i.d., for three days) acetaminophen, or saline control. Pre-dosing mice were scored for the mouse clinical frailty index, and after dosing serum and liver tissue were collected for assessment of toxicity and mechanisms. There were no differences with old age or frailty in the degree of hepatotoxicity induced by acute, chronic or subacute acetaminophen exposure as assessed by serum liver enzymes and histology. Age-related changes in the acetaminophen toxicity pathways included increased liver GSH concentrations, increased NQO1 activity and an increased pro- and anti-inflammatory response to acetaminophen in old age. Frailty-related changes included a negative correlation between frailty index and serum protein, albumin and ALP concentrations for some mouse groups. In conclusion, although there were changes in some pathways that would be expected to influence susceptibility to acetaminophen toxicity, there was no overall increase in acetaminophen hepatotoxicity with old age or frailty in mice. PMID:26615879

  7. Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats.

    PubMed

    Tan, Gang; Pan, Shangha; Li, Jie; Dong, Xuesong; Kang, Kai; Zhao, Mingyan; Jiang, Xian; Kanwar, Jagat R; Qiao, Haiquan; Jiang, Hongchi; Sun, Xueying

    2011-01-01

    Hydrogen sulfide (H(2)S) displays vasodilative, anti-oxidative, anti-inflammatory and cytoprotective activities. Impaired production of H(2)S contributes to the increased intrahepatic resistance in cirrhotic livers. The study aimed to investigate the roles of H(2)S in carbon tetrachloride (CCl(4))-induced hepatotoxicity, cirrhosis and portal hypertension. Sodium hydrosulfide (NaHS), a donor of H(2)S, and DL-propargylglycine (PAG), an irreversible inhibitor of cystathionine γ-lyase (CSE), were applied to the rats to investigate the effects of H(2)S on CCl(4)-induced acute hepatotoxicity, cirrhosis and portal hypertension by measuring serum levels of H(2)S, hepatic H(2)S producing activity and CSE expression, liver function, activity of cytochrome P450 (CYP) 2E1, oxidative and inflammatory parameters, liver fibrosis and portal pressure. CCl(4) significantly reduced serum levels of H(2)S, hepatic H(2)S production and CSE expression. NaHS attenuated CCl(4)-induced acute hepatotoxicity by supplementing exogenous H(2)S, which displayed anti-oxidative activities and inhibited the CYP2E1 activity. NaHS protected liver function, attenuated liver fibrosis, inhibited inflammation, and reduced the portal pressure, evidenced by the alterations of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hyaluronic acid (HA), albumin, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6 and soluble intercellular adhesion molecule (ICAM)-1, liver histology, hepatic hydroxyproline content and α-smooth muscle actin (SMA) expression. PAG showed opposing effects to NaHS on most of the above parameters. Exogenous H(2)S attenuates CCl(4)-induced hepatotoxicity, liver cirrhosis and portal hypertension by its multiple functions including anti-oxidation, anti-inflammation, cytoprotection and anti-fibrosis, indicating that targeting H(2)S may present a promising approach, particularly for its prophylactic effects, against liver cirrhosis and portal hypertension.

  8. Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi

    PubMed Central

    Henderson, Colin J.; Wolf, C. Roland; Kitteringham, Neil; Powell, Helen; Otto, Diana; Park, B. Kevin

    2000-01-01

    Overdose of acetaminophen, a widely used analgesic drug, can result in severe hepatotoxicity and is often fatal. This toxic reaction is associated with metabolic activation by the P450 system to form a quinoneimine metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which covalently binds to proteins and other macromolecules to cause cellular damage. At low doses, NAPQI is efficiently detoxified, principally by conjugation with glutathione, a reaction catalyzed in part by the glutathione S-transferases (GST), such as GST Pi. To assess the role of GST in acetaminophen hepatotoxicity, we examined acetaminophen metabolism and liver damage in mice nulled for GstP (GstP1/P2(−/−)). Contrary to our expectations, instead of being more sensitive, GstP null mice were highly resistant to the hepatotoxic effects of this compound. No significant differences between wild-type (GstP1/P2(+/+)) mice and GstP1/P2(−/−) nulls in either the rate or route of metabolism, particularly to glutathione conjugates, or in the levels of covalent binding of acetaminophen-reactive metabolites to cellular protein were observed. However, although a similar rapid depletion of hepatic reduced glutathione (GSH) was found in both GstP1/P2(+/+) and GstP1/P2(−/−) mice, GSH levels only recovered in the GstP1/P2(−/−) mice. These data demonstrate that GstP does not contribute in vivo to the formation of glutathione conjugates of acetaminophen but plays a novel and unexpected role in the toxicity of this compound. This study identifies new ways in which GST can modulate cellular sensitivity to toxic effects and suggests that the level of GST Pi may be an important and contributing factor in the sensitivity of patients with acetaminophen-induced hepatotoxicity. PMID:11058152

  9. Screening for main components associated with the idiosyncratic hepatotoxicity of a tonic herb, Polygonum multiflorum.

    PubMed

    Li, Chunyu; Niu, Ming; Bai, Zhaofang; Zhang, Congen; Zhao, Yanling; Li, Ruiyu; Tu, Can; Li, Huifang; Jing, Jing; Meng, Yakun; Ma, Zhijie; Feng, Wuwen; Tang, Jinfa; Zhu, Yun; Li, Jinjie; Shang, Xiaoya; Zou, Zhengsheng; Xiao, Xiaohe; Wang, Jiabo

    2017-06-01

    The main constituents of a typical medicinal herb, Polygonum multiflorum (Heshouwu in Chinese), that induces idiosyncratic liver injury remain unclear. Our previous work has shown that cotreatment with a nontoxic dose of lipopolysaccharide (LPS) and therapeutic dose of Heshouwu can induce liver injury in rats, whereas the solo treatment cannot induce observable injury. In the present work, using the constituent "knock-out" and "knock-in" strategy, we found that the ethyl acetate (EA) extract of Heshouwu displayed comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Results indicated a significant elevation of plasma alanine aminotransferase, aspartate aminotransferase, and liver histologic changes, whereas other separated fractions failed to induce liver injury. The mixture of EA extract with other separated fractions induced comparable idiosyncratic hepatotoxicity to the whole extract in LPS-treated rats. Chemical analysis further revealed that 2,3,5,4'-tetrahydroxy trans-stilbene-2-O-β-glucoside (trans-SG) and its cis-isomer were the two major compounds in EA extract. Furthermore, the isolated cis-, and not its trans-isomer, displayed comparable idiosyncratic hepatotoxicity to EA extract in LPS-treated rats. Higher contents of cis-SG were detected in Heshouwu liquor or preparations from actual liver intoxication patients associated with Heshouwu compared with general collected samples. In addition, plasma metabolomics analysis showed that cis-SG-disturbing enriched pathways remarkably differed from trans-SG ones in LPS-treated rats. All these results suggested that cis-SG was closely associated with the idiosyncratic hepatotoxicity of Heshouwu. Considering that the cis-trans isomerization of trans-SG was mediated by ultraviolet light or sunlight, our findings serve as reference for controlling photoisomerization in drug discovery and for the clinical use of Heshouwu and stilbene-related medications.

  10. The altered liver microRNA profile in hepatotoxicity induced by rhizome Dioscorea bulbifera in mice.

    PubMed

    Yang, Rui; Bai, Qingyun; Zhang, Jiaqi; Sheng, Yuchen; Ji, Lili

    2017-08-01

    MicroRNA (miRNA) has been reported to play important roles in regulating drug-induced liver injury. Ethyl acetate extract isolated from rhizoma Dioscoreae bulbifera (EF) has been reported to induce hepatotoxicity in our previous studies. This study aims to observe the altered liver miRNA profile and its related signalling pathway involved in EF-induced hepatotoxicity. Serum alanine/aspartate aminotransferase assay showed that EF (450 mg/kg)-induced hepatotoxicity in mice. Results of miRNA chip analysis showed that the expression of eight miRNAs was up-regulated and of other nine miRNAs was down-regulated in livers from EF-treated mice. Further, the altered expression of miR-200a-3p, miR-5132-5p and miR-5130 was validated using real-time polymerase chain reaction (PCR) assay. There were total seven predicted target genes of miR-200a-3p, miR-5132-5p and miR-5130. Only one kyoto encyclopedia genes and genomes pathway was annotated using those target genes, which is protein processing in endoplasmic reticulum (ER). Furthermore, liver expression of DnaJ subfamily A member 1, a key gene involved in protein processing in ER based on the altered miRNAs, was increased in EF-treated mice. In conclusion, the results demonstrated that EF altered the expression of liver miRNA profile and its related signalling pathway, which may be involved in EF-induced hepatotoxicity.

  11. The crucial protective role of glutathione against tienilic acid hepatotoxicity in rats

    SciT

    Nishiya, Takayoshi; Mori, Kazuhiko; Hattori, Chiharu

    2008-10-15

    To investigate the hepatotoxic potential of tienilic acid in vivo, we administered a single oral dose of tienilic acid to Sprague-Dawley rats and performed general clinicopathological examinations and hepatic gene expression analysis using Affymetrix microarrays. No change in the serum transaminases was noted at up to 1000 mg/kg, although slight elevation of the serum bile acid and bilirubin, and very mild hepatotoxic changes in morphology were observed. In contrast to the marginal clinicopathological changes, marked upregulation of the genes involved in glutathione biosynthesis [glutathione synthetase and glutamate-cysteine ligase (Gcl)], oxidative stress response [heme oxygenase-1 and NAD(P)H dehydrogenase quinone 1] andmore » phase II drug metabolism (glutathione S-transferase and UDP glycosyltransferase 1A6) were noted after 3 or 6 h post-dosing. The hepatic reduced glutathione level decreased at 3-6 h, and then increased at 24 or 48 h, indicating that the upregulation of NF-E2-related factor 2 (Nrf2)-regulated gene and the late increase in hepatic glutathione are protective responses against the oxidative and/or electrophilic stresses caused by tienilic acid. In a subsequent experiment, tienilic acid in combination with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of Gcl caused marked elevation of serum alanine aminotransferase (ALT) with extensive centrilobular hepatocyte necrosis, whereas BSO alone showed no hepatotoxicity. The elevation of ALT by this combination was observed at the same dose levels of tienilic acid as the upregulation of the Nrf2-regulated genes by tienilic acid alone. In conclusion, these results suggest that the impairment of glutathione biosynthesis may play a critical role in the development of tienilic acid hepatotoxicity through extensive oxidative and/or electrophilic stresses.« less

  12. Grey-scale ultrasonography for monitoring industrial exposure to hepatotoxic agents.

    PubMed

    Taylor, K J; Williams, D M; Smith, P M; Duck, B W

    1975-05-31

    Industrial exposure to several potentially hepatotoxic agents, such as vinyl-chloride monomer may occur, and there is a need for non-vasive, diagnostic techniques to detect and monitor progressive pathological processes in liver or spleen. Grey-scale ultrasonography permits display of detailed anatomy and pathology in the liver, portal veins, and spleen. The combination of fine resolution, non-invasiveness, absence of ionising radiation hazard, and portable equipment makes the technique ideal for screening populations at risk.

  13. Antithyroid drug-related hepatotoxicity in hyperthyroidism patients: a population-based cohort study

    PubMed Central

    Wang, Meng-Ting; Lee, Wan-Ju; Huang, Tien-Yu; Chu, Che-Li; Hsieh, Chang-Hsun

    2014-01-01

    Aims The evidence of hepatotoxicity of antithyroid drugs (ATDs) is limited to case reports or spontaneous reporting. This study aimed to quantify the incidence and comparative risks of hepatotoxicity for methimazole (MMI)/carbimazole (CBM) vs. propylthiouracil (PTU) in a population-based manner. Methods We conducted a cohort study of hyperthyroidism patients initially receiving MMI/CBM or PTU between 1 January 2004 and 31 December 2008 using the Taiwan National Health Insurance Research Database. The examined hepatotoxicity consisted of cholestasis, non-infectious hepatitis, acute liver failure and liver transplant, with the incidences and relative risks being quantified by Poisson exact methods and Cox proportional hazard models, respectively. Results The study cohort comprised 71 379 ATD initiators, with a median follow-up of 196 days. MMI/CBM vs. PTU users had a higher hepatitis incidence rate (3.17/1000 vs. 1.19/1000 person-years) but a lower incidence of acute liver failure (0.32/1000 vs. 0.68/1000 person-years). The relative risk analysis indicated that any use of MMI/CBM was associated with a 2.89-fold (95% CI 1.81, 4.60) increased hepatitis risk compared with PTU, with the risk increasing to 5.08-fold for high dose MMI/CBM (95% CI 3.15, 8.18). However, any MMI/CBM use vs. PTU was not related to an increased risk of cholestasis (adjusted hazard ratio [HR] 1.14, 95% CI 0.40, 3.72) or acute liver failure (adjusted HR 0.54, 95% CI 0.24, 1.22). Conclusions MMI/CBM and PTU exert dissimilar incidence rates of hepatotoxicity. Compared to PTU, MMI/CBM are associated in a dose-dependent manner with an increased risk for hepatitis while the risks are similar for acute liver failure and cholestasis. PMID:25279406

  14. Phenotypic and biomarker evaluation of zebrafish larvae as an alternative model to predict mammalian hepatotoxicity.

    PubMed

    Verstraelen, Sandra; Peers, Bernard; Maho, Walid; Hollanders, Karen; Remy, Sylvie; Berckmans, Pascale; Covaci, Adrian; Witters, Hilda

    2016-09-01

    Zebrafish phenotypic assays have shown promise to assess human hepatotoxicity, though scoring of liver morphology remains subjective and difficult to standardize. Liver toxicity in zebrafish larvae at 5 days was assessed using gene expression as the biomarker approach, complementary to phenotypic analysis and analytical data on compound uptake. This approach aimed to contribute to improved hepatotoxicity prediction, with the goal of identifying biomarker(s) as a step towards the development of transgenic models for prioritization. Morphological effects of hepatotoxic compounds (acetaminophen, amiodarone, coumarin, methapyrilene and myclobutanil) and saccharin as the negative control were assessed after exposure in zebrafish larvae. The hepatotoxic compounds induced the expected zebrafish liver degeneration or changes in size, whereas saccharin did not have any phenotypic adverse effect. Analytical methods based on liquid chromatography-mass spectrometry were optimized to measure stability of selected compounds in exposure medium and internal concentration in larvae. All compounds were stable, except amiodarone for which precipitation was observed. There was a wide variation between the levels of compound in the zebrafish larvae with a higher uptake of amiodarone, methapyrilene and myclobutanil. Detection of hepatocyte markers (CP, CYP3A65, GC and TF) was accomplished by in situ hybridization of larvae to coumarin and myclobutanil and confirmed by real-time reverse transcription-quantitative polymerase chain reaction. Experiments showed decreased expression of all markers. Next, other liver-specific biomarkers (i.e. FABP10a and NR1H4) and apoptosis (i.e. CASP-3 A and TP53) or cytochrome P450-related (CYP2K19) and oxidoreductase activity-related (ZGC163022) genes, were screened. Links between basic mechanisms of liver injury and results of biomarker responses are described. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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

    PubMed Central

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

    2017-01-01

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

  16. Long-enduring primary hepatocyte-based co-cultures improve prediction of hepatotoxicity.

    PubMed

    Novik, Eric I; Dwyer, Jacquelyn; Morelli, James K; Parekh, Amit; Cho, Cheul; Pludwinski, Eitan; Shrirao, Anil; Freedman, Robert M; MacDonald, James S; Jayyosi, Zaid

    2017-12-01

    The failure of drug candidates during clinical trials and post-marketing withdrawal due to Drug Induced Liver Injury (DILI), results in significant late-stage attrition in the pharmaceutical industry. Animal studies have proven insufficient to definitively predict DILI in the clinic, therefore a variety of in vitro models are being tested in an effort to improve prediction of human hepatotoxicity. The model system described here consists of cryopreserved primary rat, dog or human hepatocytes co-cultured together with a fibroblast cell line, which aids in the hepatocytes' maintenance of more in vivo-like characteristics compared to traditional hepatic mono-cultures, including long term viability and retention of activity of cytochrome P450 isozymes. Cell viability was assessed by measurement of ATP following treatment with 29 compounds having known hepatotoxic liabilities. Hμrelrat™, Hμreldog™, and Hμrelhuman™ hepatic co-cultures were treated for 24h, or under repeat-dosing for 7 or 13days, and compared to rat and human hepatic mono-cultures following single-dose exposure for 24h. The results allowed for a comparison of cytotoxicity, species-specific responses and the effect of repeat compound exposure on the prediction of hepatotoxic potential in each model. Results show that the co-culture model had greater sensitivity compared to that of the hepatic mono-cultures. In addition, "time-based ratios" were determined by dividing the compounds' 24-hour TC 50 /C max values by TC 50 /C max values measured after dosing for either 7 or 13days. The results suggest that this approach may serve as a useful adjunct to traditional measurements of hepatotoxicity, improving the predictive value of early screening studies. Copyright © 2017 Elsevier Inc. All rights reserved.

  17. Assessment of hepatotoxicity of first-line anti-tuberculosis drugs on Wistar rats.

    PubMed

    Sharma, Radhika; Kaur, Ramneek; Mukesh, Manishi; Sharma, Vijay L

    2018-01-01

    Adverse drug reactions are inevitable risk factors associated with use of modern medicines. First-line anti-tuberculosis drugs contribute to diverse pathological complications, and hepatotoxicity is one of them. This study investigated the effects of anti-TB drugs in combination (rifampicin [RIF] + isoniazid [INH] + pyrazinamide [PZA]) on Wistar rats. Rats were grouped as control group (saline), toxicant group that was given (30.85 mg/kg b.wt., INH + 61.7 mg/kg b.wt., RIF + 132.65 mg/kg b.wt. PZA in dosage extrapolated from dose that is used in human). Different anti-oxidant enzymes were measured in the liver along with histopathology, hematology, genotoxic effect on bone marrow chromosomes, and DNA fragmentation. In addition, gene and protein expression of CYP2E1, NR1I2, NAT, and CYP7A1 was measured by qPCR and western blot. After administration of anti-TB drugs to Wistar rats for 28 days, there was an increase in thiobarbituric acid reactive substances and a decrease in anti-oxidant enzymes. Marked changes in histopathology, hematology, DNA fragmentation, chromosomes, and in gene expression were observed. Results of the study proved increased hepatotoxicity due to combinational treatment of anti-TB drugs and also that CYP2E1, NR1I2, NAT, and CYP7A1 genes play a vital role in anti-TB drug-induced hepatotoxicity.

  18. In silico models for the prediction of dose-dependent human hepatotoxicity

    NASA Astrophysics Data System (ADS)

    Cheng, Ailan; Dixon, Steven L.

    2003-12-01

    The liver is extremely vulnerable to the effects of xenobiotics due to its critical role in metabolism. Drug-induced hepatotoxicity may involve any number of different liver injuries, some of which lead to organ failure and, ultimately, patient death. Understandably, liver toxicity is one of the most important dose-limiting considerations in the drug development cycle, yet there remains a serious shortage of methods to predict hepatotoxicity from chemical structure. We discuss our latest findings in this area and present a new, fully general in silico model which is able to predict the occurrence of dose-dependent human hepatotoxicity with greater than 80% accuracy. Utilizing an ensemble recursive partitioning approach, the model classifies compounds as toxic or non-toxic and provides a confidence level to indicate which predictions are most likely to be correct. Only 2D structural information is required and predictions can be made quite rapidly, so this approach is entirely appropriate for data mining applications and for profiling large synthetic and/or virtual libraries.

  19. Comparison of mouse strains for susceptibility to styrene-induced hepatotoxicity and pneumotoxicity

    SciT

    Carlson, G.P.

    1997-10-01

    Styrene is known to cause both hepatotoxicity and pneumotoxicity in mice. Strain differences have been reported by other investigators suggesting that Swiss mice are less susceptible than non-Swiss mice to styrene-induced liver damage. In this study, All and C57BL16 mice were found to be similar to non-Swiss albino (NSA) mice in susceptibility whereas CD-1 (Swiss) mice were more resistant to hepatotoxicity as assessed by serum sorbitol dehydrogenase levels and pneumotoxicity as determined by gamma-glutamyltranspeptidase and lactate dehydrogenase measurements in bronchoalveolar ravage fluid. Styrene was hepatotoxic in CD-1 mice treated with pyridine to induce CYP2E1. CYP2E1 apoprotein levels and p-nitrophenol hydroxylasemore » activities in control and pyridine-induced mice were similar in the two strains. Hepatic and pulmonary microsomal preparations from both strains metabolized styrene to styrene oxide at similar rates. CD-1 mice were as susceptible as the NSA mice to the effects of styrene oxide. The data suggest that there are no differences in the bioactivation of styrene to styrene oxide or innate susceptibility to the active metabolite that would account for the differences between the CD-1 and NSA mice. 26 refs., 6 tabs.« less

  20. Investigation of Drug-Induced Hepatotoxicity and Its Remediation Pathway with Reaction-Based Fluorescent Probes.

    PubMed

    Cheng, Dan; Xu, Wang; Yuan, Lin; Zhang, Xiaobing

    2017-07-18

    Drug-induced liver injury (DILI) is considered a serious problem related to public health, due to its unpredictability and acute response. The level of peroxynitrite (ONOO - ) generated in liver has long been regarded as a biomarker for the prediction and measurement of DILI. Herein we present two reaction-based fluorescent probes (Naph-ONOO - and Rhod-ONOO - ) for ONOO - through a novel and universally applicable mechanism: ONOO - -mediated deprotection of α-keto caged fluorophores. Among them, Rhod-ONOO - can selectively accumulate and react in mitochondria, one of the main sources of ONOO - , with a substantial lower nanomolar sensitivity of 43 nM. The superior selectivity and sensitivity of two probes enable real-time imaging of peroxynitrite generation in lipopolysaccharide-stimulated live cells, with a remarkable difference from cells doped with other interfering reactive oxygen species, in either one- or two-photon imaging modes. More importantly, we elucidated the drug-induced hepatotoxicity pathway with Rhod-ONOO - and revealed that CYP450/CYP2E1-mediated enzymatic metabolism of acetaminophen leads to ONOO - generation in liver cells. This is the first time to showcase the drug-induced hepatotoxicity pathways by use of a small-molecule fluorescent probe. We hence conclude that fluorescent probes can engender a deeper understanding of reactive species and their pathological revelations. The reaction-based fluorescent probes will be a potentially useful chemical tool to assay drug-induced hepatotoxicity.

  1. Protective Effect of Korean Red Ginseng against Aflatoxin B1-Induced Hepatotoxicity in Rat

    PubMed Central

    Kim, Yong-Seong; Kim, Yong-Hoon; Noh, Jung-Ran; Cho, Eun-Sang; Park, Jong-Ho; Son, Hwa-Young

    2011-01-01

    Korean red ginseng (KRG), the steamed root of Panax ginseng Meyer, has a variety of biological properties, including anti-inflammatory, antioxidant and anticancer effects. Aflatoxin B1 (AFB1) produced by the Aspergillus spp. causes acute hepatotoxicity by lipid peroxidation and oxidative DNA damage, and induces liver carcinoma in humans and laboratory animals. This study was performed to examine the protective effects of KRG against hepatotoxicity induced by AFB1 using liver-specific serum marker analysis, histopathology, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. In addition, to elucidate the possible mechanism of hepatoprotective effects, superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde were analyzed. Rats were treated with 250 mg/kg of KRG (KRG group) or saline (AFB1 group) for 4 weeks and then received 150 μg/kg of AFB1 intraperitoneally for 3 days. Rats were sacrificed at 12 h, 24 h, 48 h, 72 h, or 1 wk after AFB1 treatment. In the KRG pre-treatment group, serum alanine aminotransferase, aspartate aminotransferase, and malondialdehyde levels were low, but superoxide dismutase, catalase, and glutathione peroxidase activities were high as compared to the AFB1 alone group. Histopathologically, AFB1 treatment induced necrosis and apoptosis in hepatocytes, and led to inflammatory cells infiltration in the liver. KRG pre-treatment ameliorated these changes. These results indicate that KRG may have protective effects against hepatotoxicity induced by AFB1 that involve the antioxidant properties of KRG. PMID:23717067

  2. Reparation of Isoniazid and Rifampicin Combinatorial Therapy-Induced Hepatotoxic Effects by Bacopa monnieri.

    PubMed

    Evan Prince, Sabina; Udhaya, Lavinya B; Sunitha, Priyadharshini S; Arumugam, Geetha

    2016-01-01

    Drug-induced liver injury is a major challenge in treating tuberculosis with isoniazid (INH) and rifampicin (RIF). This study was aimed at evaluating the protective effects of Bacopamonnieri (Brahmi) against INH and RIF-induced hepatotoxicity in a rat model and also to study the patterns of interaction between pregnane X receptor (PXR) and chosen active compounds of B. monnieri. Hepatotoxicity was induced in the experimental animals by the oral administration of INH and RIF (50 mg/kg b.w. each/day) for 28 days. The effects of co-administration of B. monnieri (500 mg/kg b.w./day) in INH- and RIF-induced rats were studied by the estimation of biochemical analyses. The standard hepatoprotective drug silymarin (25 mg/kg b.w./day) was used for the purpose of comparison. In silico docking experiments were carried out using the PatchDock server and the results were analysed on the PyMol molecular viewer. There was significant reduction in the antioxidant status of INH and RIF-induced rats. Also, there was significant elevation in the levels of serum liver function markers in the INH- and RIF-induced rats. B. monnieri was able to normalise the tested parameters. In silico studies reveal significant interaction between PXR and bacopaside I. B. monnieri exerts significant protective effects against INH and RIF-induced hepatotoxicity in rats. © 2016 S. Karger AG, Basel.

  3. Successful oral desensitization with osimertinib following osimertinib-induced fever and hepatotoxicity: a case report.

    PubMed

    Hirabayashi, Ryosuke; Fujimoto, Daichi; Satsuma, Yukari; Hirabatake, Masaki; Tomii, Keisuke

    2018-05-02

    Osimertinib is a standard second-line therapy for patients who develop EGFR Thr790Met resistance mutation after treatment with first-line epidermal growth factor receptor tyrosine kinase inhibitors. Although no other effective targeted treatment option exists for these patients, osimertinib might be permanently discontinued owing to the onset of severe drug-induced toxicities like hepatotoxicity. Herein, we report a case of successful oral desensitization with osimertinib after the patient developed osimertinib-induced fever and hepatotoxicity. In the present case report, a 62-year-old Japanese woman received osimertinib as the sixth-line therapy for non-small cell lung carcinoma harboring EGFR Thr790Met-mutation. After 15 days of treatment, she developed general malaise. Although we reduced the drug at a lower dose, she again presented with high fever and elevated serum AST/ALT levels three days after re-initiating treatment. We then attempted oral desensitization with osimertinib over a two-week period. Thereafter, the patient continued osimertinib treatment for 6 months without the recurrence of side effects. In conclusion, oral desensitization may be a useful method in treating hepatotoxicity and drug fever caused by osimertinib.

  4. The protective effect of vildagliptin in chronic experimental cyclosporine A-induced hepatotoxicity.

    PubMed

    El-Sherbeeny, Nagla A; Nader, Manar A

    2016-03-01

    The study examined the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor, vildagliptin, in cyclosporine (CsA)-induced hepatotoxicity. Rats were divided into 4 groups treated for 28 days: control (vehicle), vildagliptin (10 mg/kg, orally), CsA (20 mg/kg, s.c.), and CsA-vildagliptin group. Liver function was assessed by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (γGT), lactate dehydrogenase (LDH), and albumin, and histopathological changes of liver were examined. Oxidative stress markers were evaluated. Assessment of nuclear factor-kappa B (NF-κB) activity in hepatic nuclear extract, serum DPP-4, and expression of Bax and Bcl2 were also done. CsA-induced hepatotoxicity was evidenced by increase in serum levels of AST, ALT, and γGT; a decrease in serum albumin; and a significant alteration in hepatic architecture. Also, significant increase in thiobarbituric acid reactive substance (TBARS) and decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) levels, increased expression Bax proteins with deceased expression of Bcl2, and increased hepatic activity of NF-κB and serum DPP-4 level were observed upon CsA treatment. Vildagliptin significantly improved all altered parameters induced by CsA administration. Vildagliptin has the potential to protect the liver against CsA-induced hepatotoxicity by reducing oxidative stress, DPP-4 activity, apoptosis, and inflammation.

  5. Comparative Hepatotoxicity of Fluconazole, Ketoconazole, Itraconazole, Terbinafine, and Griseofulvin in Rats.

    PubMed

    Khoza, Star; Moyo, Ishmael; Ncube, Denver

    2017-01-01

    Oral ketoconazole was recently the subject of regulatory safety warnings because of its association with increased risk of inducing hepatic injury. However, the relative hepatotoxicity of antifungal agents has not been clearly established. The aim of this study was to compare the hepatotoxicity induced by five commonly prescribed oral antifungal agents. Rats were treated with therapeutic oral doses of griseofulvin, fluconazole, itraconazole, ketoconazole, and terbinafine. After 14 days, only ketoconazole had significantly higher ALT levels ( p = 0.0017) and AST levels ( p = 0.0008) than the control group. After 28 days, ALT levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, griseofulvin, and terbinafine, respectively. The AST levels were highest in the rats treated with ketoconazole followed by itraconazole, fluconazole, terbinafine, and griseofulvin, respectively. All drugs significantly elevated ALP levels after 14 days and 28 days of treatment ( p < 0.0001). The liver enzyme levels suggested that ketoconazole had the highest risk in causing liver injury followed by itraconazole, fluconazole, terbinafine, and griseofulvin. However, histopathological changes revealed that fluconazole was the most hepatotoxic, followed by ketoconazole, itraconazole, terbinafine, and griseofulvin, respectively. Given the poor correlation between liver enzymes and the extent of liver injury, it is important to confirm liver injury through histological examination.

  6. A single acute hepatotoxic dose of CCl4 causes oxidative stress in the rat brain.

    PubMed

    Ritesh, K R; Suganya, A; Dileepkumar, H V; Rajashekar, Y; Shivanandappa, T

    2015-01-01

    Carbon tetrachloride (CCl 4 ), a hepatotoxic agent is widely used to study the toxic mechanisms in experimental animals. We have investigated whether oxidative stress is induced in the brain at a single hepatotoxic dosage (1 ml/kg bw) of CCl 4 . Increased lipid peroxidation (LPO), protein carbonyls (PC) content and glutathione (GSH) depletion were observed in the brain regions of rats treated with CCl 4 which was higher than that of liver. A drastic reduction in the activity of glutathione- S -transferase (GST) was seen in the brain regions which was higher than that of liver. Similarly, activities of glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), NADH- and NADPH-dehydrogenase were reduced in the brain regions similar to that of liver. Higher induction of oxidative stress in the brain compared to that of liver implies vulnerability of the brain for CCl 4 neurotoxicity. Our study shows that a single hepatotoxic dose of CCl 4 is equally neurotoxic to rats.

  7. The liver-gut microbiota axis modulates hepatotoxicity of tacrine in the rat.

    PubMed

    Yip, Lian Yee; Aw, Chiu Cheong; Lee, Sze Han; Hong, Yi Shuen; Ku, Han Chen; Xu, Winston Hecheng; Chan, Jessalyn Mei Xuan; Cheong, Eleanor Jing Yi; Chng, Kern Rei; Ng, Amanda Hui Qi; Nagarajan, Niranjan; Mahendran, Ratha; Lee, Yuan Kun; Browne, Edward R; Chan, Eric Chun Yong

    2018-01-01

    The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver-gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus, Bacteroides, and Enterobacteriaceae) and approximately 9% higher β-glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral β-glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo. This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (Hepatology 2018;67:282-295). © 2017 by the American Association for the Study of Liver Diseases.

  8. Effects of ebselen on radiocontrast media-induced hepatotoxicity in rats.

    PubMed

    Basarslan, Fatmagul; Yilmaz, Nigar; Davarci, Isil; Akin, Mustafa; Ozgur, Mustafa; Yilmaz, Cahide; Ulutas, Kemal Turker

    2013-09-01

    Oxidative stress is accepted as a potential responsible mechanism in the pathogenesis of radiocontrast media (RCM)-induced hepatotoxicity. Therefore, we aimed to investigate the protective effects of ebselen against RCM-induced hepatotoxicity by measuring tissue oxidant/antioxidant parameters and histological changes in rats. Wistar albino rats were randomly separated into four groups consisting of eight rats per group. Normal saline was given to the rats in control group (group 1). RCM was given to the rats in group 2, and both RCM and ebselen were given to the rats in group 3. Only ebselen was given to the rats in group 4. Liver sections of the killed animals were analyzed to measure the levels of malondialdehyde (MDA) and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as histopathological changes. In RCM group, SOD and CAT levels were found increased. In RCM-ebselen group, MDA, SOD and CAT levels were found decreased. In RCM-ebselen group, however, GSH-Px activities of liver tissue increased. All these results indicated that ebselen produced a protective mechanism against RCM-induced hepatotoxicity and took part in oxidative stress.

  9. Ginseng alleviates cyclophosphamide-induced hepatotoxicity via reversing disordered homeostasis of glutathione and bile acid.

    PubMed

    Zhu, He; Long, Min-Hui; Wu, Jie; Wang, Meng-Meng; Li, Xiu-Yang; Shen, Hong; Xu, Jin-Di; Zhou, Li; Fang, Zhi-Jun; Luo, Yi; Li, Song-Lin

    2015-12-02

    Cyclophosphamide (CP), a chemotherapeutic agent, is restricted due to its side effects, especially hepatotoxicity. Ginseng has often been clinically used with CP in China, but whether and how ginseng reduces the hepatotoxicity is unknown. In this study, the hepatoprotective effects and mechanisms under the combined usage were investigated. It was found that ginseng could ameliorate CP-induced elevations of ALP, ALT, ALS, MDA and hepatic deterioration, enhance antioxidant enzymes' activities and GSH's level. Metabolomics study revealed that 33 endogenous metabolites were changed by CP, 19 of which were reversed when ginseng was co-administrated via two main pathways, i.e., GSH metabolism and primary bile acids synthesis. Furthermore, ginseng could induce expression of GCLC, GCLM, GS and GST, which associate with the disposition of GSH, and expression of FXR, CYP7A1, NTCP and MRP 3, which play important roles in the synthesis and transport of bile acids. In addition, NRF 2, one of regulatory elements on the expression of GCLC, GCLM, GS, GST, NTCP and MRP3, was up-regulated when ginseng was co-administrated. In conclusion, ginseng could alleviate CP-induced hepatotoxicity via modulating the disordered homeostasis of GSH and bile acid, which might be mediated by inducing the expression of NRF 2 in liver.

  10. 6-gingerol, an active ingredient of ginger, protects acetaminophen-induced hepatotoxicity in mice.

    PubMed

    Sabina, Evan Prince; Pragasam, Samuel Joshua; Kumar, Suresh; Rasool, Mahaboobkhan

    2011-11-01

    To investigate the hepatoprotective efficacy of 6-gingerol against acetaminophen-induced hepatotoxicity in mice. Mice were injected with a single dose of acetaminophen (900 mg/kg) to induce hepatotoxicity, while 6-gingerol (30 mg/kg) or the standard drug silymarin (25 mg/kg) was given 30 min after the acetaminophen administration. The mice were sacrificed 4 h after acetaminophen injection to determine the activities of liver marker enzymes such as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), total bilirubin in serum, and lipid peroxidation and antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glutathione transferase and glutathione) in liver homogenate. The treatment of 6-gingerol and silymarin to acetaminophen-induced hepatotoxicity showed significant hepatoprotective effect by lowering the hepatic marker enzymes (AST, ALT, and ALP) and total bilirubin in serum (P<0.05). In addition, 6-gingerol and silymarin treatment prevented the elevation of hepatic malondialdehyde formation and the depletion of antioxidant status in the liver of acetaminophen-intoxicated mice (P<0.05). The results evidently demonstrate that 6-gingerol has promising hepatoprotective effect which is comparable to the standard drug silymarin.

  11. [Nevirapine related hepatotoxicity: the prevalence and risk factors in a cohort of ART naive Han Chinese with AIDS].

    PubMed

    Gao, Shi-cheng; Gui, Xi-en; Deng, Li-ping; Zhang, Yong-xi; Yan, Ya-jun; Rong, Yu-ping; Liang, Ke; Yang, Rong-rong

    2010-09-01

    To investigate the incidence of hepatotoxicity in acquired immunodeficiency syndrome (AIDS) patients on combined anti-retroviral therapy (cART) containing nevirapine (NVP) and to assess the risk factors and its impact on cART. 330 AIDS patients from March 2003 to June 2008 at local county were enrolled and a retrospective study using Kaplan-meier survival and Multivariate logistic regression modeling was conducted. 267 out of 330 patients received NVP based cART and 63 cases received EFV-based cART. The deference of prevalences of hepatotoxicity between the two groups is statistically significant (Chi2 = 6.691, P = 0.01). 133 out of 267 (49.8%) patients on NVP based cART had at least one episode of ALT elevation during a median 21 months (interquartile ranges, IQR 6, 37) follow-up time, amounts for 28.5 cases per 100 person-years. Baseline ALT elevation (OR = 14.368, P = 0.017)and HCV co-infection (OR = 3.009, P = 0.000) were risk factors for cART related hepatotoxicity, while greatly increased CD4+ T(CD4) cell count was protective against hepatotoxicity development (OR = 0.996, P = 0.000). Patients co-infected with HCV received NVP-based cART had the higher probability of hepatotoxicity than those without HCV co-infection (Log rank: Chi2 = 16.764, P = 0.000). 23 out of the 133 subjects (17.3%) with NVP related hepatotoxicity discontinued cART temporarily or shifted NVP to efavirenz. NVP related hepatotoxicity was common among ARV naive HIV infected subjects in our cohort. Baseline ALT elevation and HCV co-infection were associated statistically with the development of hepatotoxicity. Hepatotoxicity led to discontinuing cART temporarily or switching to other regimens in some subjects. It suggested that NVP should be used with caution in patients co-infected with HCV among whom anti-HCV therapy before cART initiation may contribute to minimizing the probability of NVP associated hepatotoxicity.

  12. Advances in targeting cyclic nucleotide phosphodiesterases

    PubMed Central

    Maurice, Donald H.; Ke, Hengming; Ahmad, Faiyaz; Wang, Yousheng; Chung, Jay; Manganiello, Vincent C.

    2014-01-01

    Cyclic nucleotide phosphodiesterases (PDEs) catalyse the hydrolysis of cyclic AMP and cyclic GMP, thereby regulating the intracellular concentrations of these cyclic nucleotides, their signalling pathways and, consequently, myriad biological responses in health and disease. Currently, a small number of PDE inhibitors are used clinically for treating the pathophysiological dysregulation of cyclic nucleotide signalling in several disorders, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication and chronic obstructive pulmonary disease. However, pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual PDEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants. PMID:24687066

  13. [Cyclic Cushing's Syndrome - rare or rarely recognized].

    PubMed

    Kiałka, Marta; Doroszewska, Katarzyna; Mrozińska, Sandra; Milewicz, Tomasz; Stochmal, Ewa

    2015-01-01

    Cyclic Cushing's syndrome is a type of Cushing's disease which is characterized by alternating periods of increasing and decreasing levels of cortisol in the blood. The diagnostic criteria for cyclic Cushing's syndrome are at least three periods of hypercortisolism alternating with at least two episodes of normal levels of serum cortisol concentration. The epidemiology, signs, symptoms, pathogenesis and treatment of cyclic Cushing's syndrome have been discussed.

  14. [Erythromycin in therapy of cyclic vomiting syndrome].

    PubMed

    Pavlović, Momcilo; Radlović, Nedeljko; Leković, Zoran; Berenji, Karolina

    2007-01-01

    Cyclic vomiting syndrome is an insufficiently understood disorder which manifests itself in stereotypical episodes of vomiting with no detectable organic cause. Considering its unknown aetiology, drugs borrowed from various medication classes are applied in the therapy of this disorder, with variable success. Among other medicaments, erythromycin is also used in treatment of cyclic vomiting syndrome. This is a case study in which the application of erythromycin led to the prevention of attacks of cyclic vomiting syndrome. Our case report presents how periodical erythromycin therapy in two-week intervals at expected attack periods in a girl led to disappearance of cyclic vomiting. Adverse effects of erythromycin did not show up.

  15. Nonlinear, nonbinary cyclic group codes

    NASA Technical Reports Server (NTRS)

    Solomon, G.

    1992-01-01

    New cyclic group codes of length 2(exp m) - 1 over (m - j)-bit symbols are introduced. These codes can be systematically encoded and decoded algebraically. The code rates are very close to Reed-Solomon (RS) codes and are much better than Bose-Chaudhuri-Hocquenghem (BCH) codes (a former alternative). The binary (m - j)-tuples are identified with a subgroup of the binary m-tuples which represents the field GF(2 exp m). Encoding is systematic and involves a two-stage procedure consisting of the usual linear feedback register (using the division or check polynomial) and a small table lookup. For low rates, a second shift-register encoding operation may be invoked. Decoding uses the RS error-correcting procedures for the m-tuple codes for m = 4, 5, and 6.

  16. Cyclic Disilylated and Digermylated Germylenes

    PubMed Central

    2013-01-01

    The preparation of triethylphosphine adducts of cyclic disilylated or digermylated germylenes was achieved by reaction of 1,4-dipotassio-1,1,4,4-tetrakis(trimethylsilyl)tetramethyltetrasilane with GeBr2·(dioxane) and PEt3. Phosphine abstraction with B(C6F5)3 allowed formation of the base-free germylenes, which undergo 1,2-trimethylsilyl shifts to the germylene atom to form the respective silagermene or digermene, which further dimerize in [2 + 2] cycloadditions to tricyclic compounds. The reasons responsible for the germylenes’ completely different reactivities in comparison to the previously studied analogous stannylenes and plumbylenes were elucidated in a theoretical study. PMID:23874054

  17. Cyclic nucleotide content of tobacco BY-2 cells.

    PubMed

    Richards, Helen; Das, Swadipa; Smith, Christopher J; Pereira, Louisa; Geisbrecht, Alan; Devitt, Nicola J; Games, David E; van Geyschem, Jan; Gareth Brenton, A; Newton, Russell P

    2002-11-01

    The cyclic nucleotide content of cultured tobacco bright yellow-2 (BY-2) cells was determined, after freeze-killing, perchlorate extraction and sequential chromatography, by radioimmunoassay. The identities of the putative cyclic nucleotides, adenosine 3',5'-cyclic monophosphate (cyclic AMP), guanosine 3',5'-cyclic monophosphate (cyclic GMP) and cytidine 3',5'-cyclic monophosphate (cyclic CMP) were unambiguously confirmed by tandem mass spectrometry. The potential of BY-2 cell cultures as a model system for future investigations of cyclic nucleotide function in higher plants is discussed.

  18. Accuracy of the paracetamol-aminotransferase multiplication product to predict hepatotoxicity in modified-release paracetamol overdose.

    PubMed

    Wong, Anselm; Sivilotti, Marco L A; Graudins, Andis

    2017-06-01

    The paracetamol-aminotransferase multiplication product (APAP × ALT) is a risk predictor of hepatotoxicity that is somewhat independent of time and type of ingestion. However, its accuracy following ingestion of modified-release formulations is not known, as the product has been derived and validated after immediate-release paracetamol overdoses. The aim of this retrospective cohort study was to evaluate the accuracy of the multiplication product to predict hepatotoxicity in a cohort of patients with modified-release paracetamol overdose. We assessed all patients with modified-release paracetamol overdose presenting to our hospital network from October 2009 to July 2016. Ingestion of a modified-release formulation was identified by patient self-report or retrieval of the original container. Hepatotoxicity was defined as peak alanine aminotransferase ≥1000 IU/L, and acute liver injury (ALI) as a doubling of baseline ALT to more than 50 IU/L. Of 1989 paracetamol overdose presentations, we identified 73 modified-release paracetamol exposures treated with acetylcysteine. Five patients developed hepatotoxicity, including one who received acetylcysteine within eight hours of an acute ingestion. No patient with an initial multiplication product <10,000 mg/L × IU/L developed hepatotoxicity (sensitivity 100% [95%CI 48%, 100%], specificity 97% [90%, 100%]). Specificity fell to 54% (95%CI: 34, 59%) at a product cut-off point <1500 mg/L × IU/L. When calculated within eight hours of ingestion, mild elevations of the multiplication product fell quickly on repeat testing in patients without ALI or hepatotoxicity. In modified-release paracetamol overdose treated with acetylcysteine, the paracetamol-aminotransferase multiplication product demonstrated similar accuracy and temporal profile to previous reports involving mostly immediate-release formulations. Above a cut-point of 10,000 mg/L × IU/L, it was very strongly associated with the development

  19. Ginger for Prevention of Antituberculosis-induced Gastrointestinal Adverse Reactions Including Hepatotoxicity: A Randomized Pilot Clinical Trial.

    PubMed

    Emrani, Zahra; Shojaei, Esphandiar; Khalili, Hossein

    2016-06-01

    In this study, the potential benefits of ginger in preventing antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity have been evaluated in patients with tuberculosis. Patients in the ginger and placebo groups (30 patients in each group) received either 500 mg ginger (Zintoma)(®) or placebo one-half hour before each daily dose of antituberculosis drugs for 4 weeks. Patients' gastrointestinal complaints (nausea, vomiting, dyspepsia, and abdominal pain) and antituberculosis drug-induced hepatotoxicity were recorded during the study period. In this cohort, nausea was the most common antituberculosis drug-induced gastrointestinal adverse reactions. Forty eight (80%) patients experienced nausea. Nausea was more common in the placebo than the ginger group [27 (90%) vs 21 (70%), respectively, p = 0.05]. During the study period, 16 (26.7%) patients experienced antituberculosis drug-induced hepatotoxicity. Patients in the ginger group experienced less, but not statistically significant, antituberculosis drug-induced hepatotoxicity than the placebo group (16.7% vs 36.7%, respectively, p = 0.07). In conclusion, ginger may be a potential option for prevention of antituberculosis drug-induced gastrointestinal adverse reactions including hepatotoxicity. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  20. Toward structure prediction of cyclic peptides.

    PubMed

    Yu, Hongtao; Lin, Yu-Shan

    2015-02-14

    Cyclic peptides are a promising class of molecules that can be used to target specific protein-protein interactions. A computational method to accurately predict their structures would substantially advance the development of cyclic peptides as modulators of protein-protein interactions. Here, we develop a computational method that integrates bias-exchange metadynamics simulations, a Boltzmann reweighting scheme, dihedral principal component analysis and a modified density peak-based cluster analysis to provide a converged structural description for cyclic peptides. Using this method, we evaluate the performance of a number of popular protein force fields on a model cyclic peptide. All the tested force fields seem to over-stabilize the α-helix and PPII/β regions in the Ramachandran plot, commonly populated by linear peptides and proteins. Our findings suggest that re-parameterization of a force field that well describes the full Ramachandran plot is necessary to accurately model cyclic peptides.

  1. Cyclic completion of the anamorphic universe

    NASA Astrophysics Data System (ADS)

    Ijjas, Anna

    2018-04-01

    Cyclic models of the universe have the advantage of avoiding initial conditions problems related to postulating any sort of beginning in time. To date, the best known viable examples of cyclic models have been ekpyrotic. In this paper, we show that the recently proposed anamorphic scenario can also be made cyclic. The key to the cyclic completion is a classically stable, non-singular bounce. Remarkably, even though the bounce construction was originally developed to connect a period of contraction with a period of expansion both described by Einstein gravity, we show here that it can naturally be modified to connect an ordinary contracting phase described by Einstein gravity with a phase of anamorphic smoothing. The paper will present the basic principles and steps in constructing cyclic anamorphic models.

  2. Hepatotoxicity of high affinity gapmer antisense oligonucleotides is mediated by RNase H1 dependent promiscuous reduction of very long pre-mRNA transcripts

    PubMed Central

    Burel, Sebastien A.; Hart, Christopher E.; Cauntay, Patrick; Hsiao, Jill; Machemer, Todd; Katz, Melanie; Watt, Andy; Bui, Huynh-hoa; Younis, Husam; Sabripour, Mahyar; Freier, Susan M.; Hung, Gene; Dan, Amy; Prakash, T.P.; Seth, Punit P.; Swayze, Eric E.; Bennett, C. Frank; Crooke, Stanley T.; Henry, Scott P.

    2016-01-01

    High affinity antisense oligonucleotides (ASOs) containing bicylic modifications (BNA) such as locked nucleic acid (LNA) designed to induce target RNA cleavage have been shown to have enhanced potency along with a higher propensity to cause hepatotoxicity. In order to understand the mechanism of this hepatotoxicity, transcriptional profiles were collected from the livers of mice treated with a panel of highly efficacious hepatotoxic or non-hepatotoxic LNA ASOs. We observed highly selective transcript knockdown in mice treated with non-hepatotoxic LNA ASOs, while the levels of many unintended transcripts were reduced in mice treated with hepatotoxic LNA ASOs. This transcriptional signature was concurrent with on-target RNA reduction and preceded transaminitis. Remarkably, the mRNA transcripts commonly reduced by toxic LNA ASOs were generally not strongly associated with any particular biological process, cellular component or functional group. However, they tended to have much longer pre-mRNA transcripts. We also demonstrate that the off-target RNA knockdown and hepatotoxicity is attenuated by RNase H1 knockdown, and that this effect can be generalized to high affinity modifications beyond LNA. This suggests that for a certain set of ASOs containing high affinity modifications such as LNA, hepatotoxicity can occur as a result of unintended off-target RNase H1 dependent RNA degradation. PMID:26553810

  3. Review article: Herbal hepatotoxicity--an update on traditional Chinese medicine preparations.

    PubMed

    Teschke, R; Wolff, A; Frenzel, C; Schulze, J

    2014-07-01

    Although evidence for their therapeutic efficacy is limited, herbal traditional Chinese medicine (TCM) preparations increasingly gain popularity. In contrast to other herbal products, adverse effects by herbal TCM including liver toxicity were rarely reported. In recent years, more cases were published, providing new clinical challenges. To summarise comprehensively the literature on herbal TCM hepatotoxicity since 2011. PubMed was searched using key words related to TCM, the results were restricted to full English-language publications and abstracts published since 2011. In addition, the database of the National Institutes of Health (NIH) and LiverTox was accessed under the topic 'Drug record: Chinese and other Asian herbal medicines'. Since 2011, new case reports and case series provided evidence for herbal hepatotoxicity by TCM, focusing on nine TCM herbal mixtures and four individual TCM herbs with potential health hazards. These were the TCM products Ban Tu Wan, Chai Hu, Du Huo, Huang Qin, Jia Wei Xia Yao San, Jiguja, Kamishoyosan, Long Dan Xie Gan Tang, Lu Cha, Polygonum multiflorum products, Shan Chi, 'White flood' containing the herbal TCM Wu Zhu Yu and Qian Ceng Ta, and Xiao Chai Hu Tang. Other developments include the establishment of a new and early diagnostic serum marker for hepatotoxicity caused by pyrrolizidine alkaloids, assessed using ultra performance liquid chromatography-mass spectrometry analysis, and new regulatory details to improve herbal TCM product quality and safety. Stringent evaluation of the risk/benefit ratio is essential to protect traditional Chinese medicines users from health hazards including liver injury. © 2014 John Wiley & Sons Ltd.

  4. Improved Hepatoprotective Effect of Liposome-Encapsulated Astaxanthin in Lipopolysaccharide-Induced Acute Hepatotoxicity

    PubMed Central

    Chiu, Chun-Hung; Chang, Chun-Chao; Lin, Shiang-Ting; Chyau, Charng-Cherng; Peng, Robert Y.

    2016-01-01

    Lipopolysaccharide (LPS)-induced acute hepatotoxicity is significantly associated with oxidative stress. Astaxanthin (AST), a xanthophyll carotenoid, is well known for its potent antioxidant capacity. However, its drawbacks of poor aqueous solubility and low bioavailability have limited its utility. Liposome encapsulation is considered as an effective alternative use for the improvement of bioavailability of the hydrophobic compound. We hypothesized that AST encapsulated within liposomes (LA) apparently shows improved stability and transportability compared to that of free AST. To investigate whether LA administration can efficiently prevent the LPS-induced acute hepatotoxicity, male Sprague-Dawley rats (n = six per group) were orally administered liposome-encapsulated AST at 2, 5 or 10 mg/kg-day (LA-2, LA-5, and LA-10) for seven days and then were LPS-challenged (i.p., 5 mg/kg). The LA-10 administered group, but not the other groups, exhibited a significant amelioration of serum glutamic pyruvic transaminase (GPT), glutamic oxaloacetic transaminase (GOT), blood urea nitrogen (BUN), creatinine (CRE), hepatic malondialdehyde (MDA) and glutathione peroxidase (GSH-Px), IL-6, and hepatic nuclear NF-κB and inducible nitric oxide synthase (iNOS), suggesting that LA at a 10 mg/kg-day dosage renders hepatoprotective effects. Moreover, the protective effects were even superior to that of positive control N-acetylcysteine (NAC, 200 mg/kg-day). Histopathologically, NAC, free AST, LA-2 and LA-5 partially, but LA-10 completely, alleviated the acute inflammatory status. These results indicate that hydrophobic AST after being properly encapsulated by liposomes improves bioavailability and can also function as potential drug delivery system in treating hepatotoxicity. PMID:27428953

  5. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate.

    PubMed

    Humphreys, Jenny H; Warner, Alexander; Costello, Ruth; Lunt, Mark; Verstappen, Suzanne M M; Dixon, William G

    2017-09-01

    Patients with rheumatoid arthritis (RA) who take methotrexate (MTX) are advised to limit their alcohol intake due to potential combined hepatotoxicity. However, data are limited to support this. The aim of this study was to quantify the risk of developing abnormal liver blood tests at different levels of alcohol consumption, using routinely collected data from primary care. Patients with RA in the Clinical Practice Research Datalink starting MTX between 1987 and 2016 were included. Hepatotoxicity was defined as transaminitis: alanine transaminase or aspartate aminotransferase more than three times the upper limit of normal. Crude rates of transaminitis were calculated per 1000 person-years, categorised by weekly alcohol consumption in units. Cox proportional hazard models tested the association between alcohol consumption and transaminitis univariately, then age and gender adjusted. 11 839 patients were included, with 530 episodes of transaminitis occurring in 47 090 person-years follow-up. Increased weekly alcohol consumption as a continuous variable was associated with increased risk of transaminitis, adjusted HR (95% CI) per unit consumed 1.01 (1.00 to 1.02); consuming between 15 and 21 units was associated with a possible increased risk of hepatotoxicity, while drinking >21 units per week significantly increased rates of transaminitis, adjusted HR (95% CI) 1.85 (1.17 to 2.93). Weekly alcohol consumption of <14 units per week does not appear to be associated with an increased risk of transaminitis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  6. Ameliorative effect of vitamin C against hepatotoxicity induced by emamectin benzoate in rats.

    PubMed

    Khaldoun Oularbi, H; Richeval, C; Lebaili, N; Zerrouki-Daoudi, N; Baha, M; Djennas, N; Allorge, D

    2017-07-01

    In the present study, we aimed to assess the potential protective effect of ascorbic acid (AA) against emamectin benzoate (EMB)-induced hepatotoxicity. For this purpose, biochemical, histopathological and analytical investigations were performed. Male Wistar rats were distributed into three groups, that is, a control group, an EMB group given 10 mg EMB/kg body weight (BW) by gavage and an EMB + AA group given 10 mg EMB/kg BW and vitamin C intraperitoneally (200 mg/kg). The duration of the treatment was 28 days and the duration of the study was 42 days. There was a statistically significant increase of all hepatic biomarkers, that is, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase activities, and glycemia, in EMB-treated group when compared with the control group. Light microscopic observations revealed variable signs of hepatotoxicity in the EMB group, which were represented by alteration of normal hepatic architecture, inflammatory cell infiltration, hepatocellular steatosis and foci of necrosis at 28 and 42 days post-treatment. However, co-treatment with vitamin C reduced EMB-related liver toxicity and diminished the abnormal biochemical and architectural damage. Emamectin B1a and B1b residues were detectable in all plasma samples of treated rats at 14, 21 and 28 days of treatment. The drug liver tissue concentration was significantly lower in EMB + AA group compared with EMB group at 28 and 42 days. In conclusion, the findings of the present study clearly indicate a significant protective action of vitamin C against EMB hepatotoxicity.

  7. Effects of platelet-rich plasma on liver regeneration in CCl4-induced hepatotoxicity model.

    PubMed

    Mafi, Afsaneh; Dehghani, Farzaneh; Moghadam, Abbas; Noorafshan, Ali; Vojdani, Zahra; Talaei-Khozani, Tahereh

    2016-12-01

    Numerous bioactive growth factors and cytokines in platelet-rich plasma (PRP) have recently made it an attractive biomaterial for therapeutic purposes. These growth factors have the potential to regenerate the injured tissues. The aim of this study was to investigate the therapeutic effects of PRP in hepatotoxic animal model. Hepatotoxicity was induced in rats by oral administration of 4 mL/kg/week of CCl 4 diluted 1:1 in corn oil for 10 weeks. To confirm the hepatotoxicity, 24 h after the last CCl 4 administration, blood samples were collected via cardiac puncture to assess the serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, albumin, total protein, and total bilirubin. Twenty-four hours after blood collection, the experimental animals received a single injection of PRP (1 mL) via the anterior mesenteric vein. One week later, all biochemical tests were performed again, and the rats were scarified and their livers were removed, prepared histologically, and stained. The stereological analyses were performed to evaluate the effects of PRP on histopathological features of CCl 4 -treated livers. The results were compared statistically with the corresponding control and CCl 4 +normal saline (NS)-treated animals. A significant decrease in the number and volume of hepatocytes (p = 0.01), and also a reduction in the volume of sinusoids (p = 0.001) and connective tissue (p = 0.04), were observed in the PRP-treated animals compared with the CCl 4 +NS-treated ones. Our findings demonstrated that application of PRP had beneficial effects on CCl 4 -induced fibrosis; however, it had detrimental effects on the total number of hepatocytes and the volume of hepatocytes and sinusoidal spaces.

  8. 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.

  9. Inhibition of acetaminophen-induced hepatotoxicity in mice by exogenous thymosinβ4 treatment.

    PubMed

    Wang, Lei; Li, Xiankui; Chen, Cai

    2018-05-21

    To study the effects of exogenous thymosinβ4 (Tβ4) treatment in acetaminophen (APAP)-induced hepatotoxicity. Liver injury was induced in mice by a single intraperitoneal injection of APAP (500 mg/kg). Exogenous Tβ4 was intraperitoneally administrated at 0 h, 2 h and 4 h after APAP injection. Chloroquine (CQ) (60 mg/kg) was intraperitoneally injected 2 h before APAP administration to inhibit autophagy. Six hours after APAP injection liver injury was evaluated by histological examinations, biochemical measurements and enzyme linked immunosorbent assay (ELISAs). Western blots were performed to detect proteins expression. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were significantly increased 6 h after APAP administration, but were significantly reduced by co-administration of Tβ4. Histological examinations demonstrated that Tβ4 reduced necrosis and inflammation induced by APAP. Immunofluorescence showed that Tβ4 suppressed APAP-induced translocation of high mobility group box-1 protein (HMGB1) from the nucleus to cytosol and intercellular space. Hepatic glutathione (GSH) depletion, malondialdehyde (MDA) formation and decreased superoxide dismutase (SOD) activities induced by APAP were all attenuated by Tβ4. APAP-induced increases in hepatic nuclear factor-κB (NF-κB) p65 protein expression and inflammatory cytokines production including interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were reduced by Tβ4 treatment. Increased LC3 and p62 proteins in the liver tissues of APAP-treated mice were decreased by Tβ4 treatment, which indicated the enhancement of autophagy flux by Tβ4. Furthermore, inhibiting autophagy by CQ abrogated the protective effects of Tβ4 against APAP hepatotoxicity. Exogenous Tβ4 treatment exerts protective effects against APAP-induced hepatotoxicity in mice. The underneath molecular mechanisms may involve autophagy enhancement and inhibition of oxidative stress by Tβ4

  10. Activation of Sirt1/FXR Signaling Pathway Attenuates Triptolide-Induced Hepatotoxicity in Rats.

    PubMed

    Yang, Jing; Sun, Lixin; Wang, Lu; Hassan, Hozeifa M; Wang, Xuan; Hylemon, Phillip B; Wang, Tao; Zhou, Huiping; Zhang, Luyong; Jiang, Zhenzhou

    2017-01-01

    Triptolide (TP), a diterpenoid isolated from Tripterygium wilfordii Hook F, has an excellent pharmacological profile of immunosuppression and anti-tumor activities, but its clinical applications are severely restricted due to its severe and cumulative toxicities. The farnesoid X receptor (FXR) is the master bile acid nuclear receptor and plays an important role in maintaining hepatic metabolism homeostasis. Hepatic Sirtuin (Sirt1) is a key regulator of the FXR signaling pathway and hepatic metabolism homeostasis. The aims of this study were to determine whether Sirt1/FXR signaling pathway plays a critical role in TP-induced hepatotoxicity. Our study revealed that the intragastric administration of TP (400 μg/kg body weight) for 28 consecutive days increased bile acid accumulation, suppressed hepatic gluconeogenesis in rats. The expression of bile acid transporter BSEP was significantly reduced and cholesterol 7α-hydroxylase (CYP7A1) was markedly increased in the TP-treated group, whereas the genes responsible for hepatic gluconeogenesis were suppressed in the TP-treated group. TP also modulated the FXR and Sirt1 by decreasing its expression both in vitro and in vivo . The Sirt1 agonist SRT1720 and the FXR agonist obeticholic acid (OCA) were used both in vivo and in vitro . The remarkable liver damage induced by TP was attenuated by treatment with either SRT1720 or OCA, as reflected by decreased levels of serum total bile acids and alkaline phosphatase and increased glucose levels. Meanwhile, SRT1720 significantly alleviated TP-induced FXR suppression and FXR-targets involved in hepatic lipid and glucose metabolism. Based on these results, we conclude that Sirt1/FXR inactivation plays a critical role in TP-induced hepatotoxicity. Moreover, Sirt1/FXR axis represents a novel therapeutic target that could potentially ameliorate TP-induced hepatotoxicity.

  11. The Role of RAAS Inhibition by Aliskiren on Paracetamol-Induced Hepatotoxicity Model in Rats.

    PubMed

    Karcioglu, Saliha Sena; Palabiyik, Saziye Sezin; Bayir, Yasin; Karakus, Emre; Mercantepe, Tolga; Halici, Zekai; Albayrak, Abdulmecit

    2016-03-01

    Paracetamol is one of the most popular and widely used analgesic and antipyretic agents, but an overdose can cause hepatotoxicity and lead to acute liver failure. Aliskiren directly inhibits renin which downregulates the renin-angiotensin-aldosterone system (RAAS). Recent findings suggest that RAAS system takes part in the pathogenesis of liver fibrosis. We aimed to reveal the relationship between hepatotoxicity and the RAAS by examining paracetamol induced hepatotoxicity. Rats were separated into five groups as follows: control, 100 mg/kg aliskiren (p.o.), 2 g/kg paracetamol (per os (p.o.)), 2 g/kg paracetamol + 50mg/kg aliskiren (p.o.), and 2 g/kg paracetamol + 100 mg/kg aliskiren(p.o.). Samples were analyzed at the biochemical, molecular, and histopathological levels. Paracetamol toxicity increased alanine aminotransferases (ALT), aspartate aminotransferases (AST), renin, and angiotensin II levels in the serum samples. In addition, the SOD activity and glutathione (GSH) levels decreased while Lipid Peroxidation (MDA) levels increased in the livers of the rats treated with paracetamol. Paracetamol toxicity caused a significant increase in TNF-α and TGF-β. Both aliskiren doses showed an improvement in ALT, AST, oxidative parameters, angiotensin II, and inflammatory cytokines. Only renin levels increased in aliskiren treatment groups due to its pharmacological effect. A histopathological examination of the liver showed that aliskiren administration ameliorated the paracetamol-induced liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the paracetamol group but not in other treatment groups when compared to the control group. In light of these observations, we suggest that the therapeutic administration of aliskiren prevented oxidative stress and cytokine changes and also protected liver tissues during paracetamol toxicity by inhibiting the RAAS. © 2015 Wiley Periodicals

  12. Ketoconazole hepatotoxicity in a patient treated for environmental illness and systemic candidiasis

    SciT

    Brusko, C.S.; Marten, J.T.

    1991-12-01

    Environmental illness, a hypothesized disease caused by exposure to substances such as combustion products, pesticides, food additives, and Candida albicans, is discussed. The case of a patient with environmental illness and systemic candidiasis for six weeks with ketoconazole, liver enzyme concentrations increased. One month after discontinuation of ketoconazole, the liver enzyme concentrations decreased; however, over the next five months, liver enzymes and bilirubin increased. The patient developed encephalopathy and eventually was transferred to a medical center for possible liver transplant. A review of the literature pertaining to ketoconazole hepatotoxicity is also presented.16 references.

  13. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity

    SciT

    Henninger, Christian; Institute of Toxicology, University Duesseldorf, Medical Faculty, Universitätsstrasse 1, D-40225 Duesseldorf; Huelsenbeck, Johannes

    2012-05-15

    Liver is the main detoxifying organ and therefore the target of high concentrations of genotoxic compounds, such as environmental carcinogens and anticancer drugs. Here, we investigated the usefulness of lovastatin, which is nowadays widely used for lipid lowering purpose, as a hepatoprotective drug following the administration of the anthracycline derivative doxorubicin in vivo. To this end, BALB/c mice were exposed to either a single high dose or three consecutive low doses of doxorubicin. Acute and subacute hepatotoxicities were analyzed with or without lovastatin co-treatment. Lovastatin protected the liver against doxorubicin-induced acute pro-inflammatory and pro-fibrotic stress responses as indicated by anmore » attenuated mRNA expression of tumor necrosis factor alpha (TNFα) and connective tissue growth factor (CTGF), respectively. Hepatoprotection by lovastatin was due to a reduced induction of DNA damage following doxorubicin treatment. The statin also mitigated subacute anthracycline-provoked hepatotoxicity as shown on the level of doxorubicin- and epirubicin-stimulated CTGF mRNA expression as well as histopathologically detectable fibrosis and serum concentration of marker enzymes of hepatotoxicity (GPT/GLDH). Kidney damage following doxorubicin exposure was not detectable under our experimental conditions. Moreover, lovastatin showed multiple inhibitory effects on doxorubicin-triggered hepatic expression of genes involved in oxidative stress response, drug transport, DNA repair, cell cycle progression and cell death. Doxorubicin also stimulated the formation of ceramides. Ceramide production, however, was not blocked by lovastatin, indicating that hepatoprotection by lovastatin is independent of the sphingolipid metabolism. Overall, the data show that lovastatin is hepatoprotective following genotoxic stress induced by anthracyclines. Based on the data, we hypothesize that statins might be suitable to lower hepatic injury following anthracycline

  14. A Systematic Strategy for Screening and Application of Specific Biomarkers in Hepatotoxicity Using Metabolomics Combined With ROC Curves and SVMs.

    PubMed

    Li, Yubo; Wang, Lei; Ju, Liang; Deng, Haoyue; Zhang, Zhenzhu; Hou, Zhiguo; Xie, Jiabin; Wang, Yuming; Zhang, Yanjun

    2016-04-01

    Current studies that evaluate toxicity based on metabolomics have primarily focused on the screening of biomarkers while largely neglecting further verification and biomarker applications. For this reason, we used drug-induced hepatotoxicity as an example to establish a systematic strategy for screening specific biomarkers and applied these biomarkers to evaluate whether the drugs have potential hepatotoxicity toxicity. Carbon tetrachloride (5 ml/kg), acetaminophen (1500 mg/kg), and atorvastatin (5 mg/kg) are established as rat hepatotoxicity models. Fifteen common biomarkers were screened by multivariate statistical analysis and integration analysis-based metabolomics data. The receiver operating characteristic curve was used to evaluate the sensitivity and specificity of the biomarkers. We obtained 10 specific biomarker candidates with an area under the curve greater than 0.7. Then, a support vector machine model was established by extracting specific biomarker candidate data from the hepatotoxic drugs and nonhepatotoxic drugs; the accuracy of the model was 94.90% (92.86% sensitivity and 92.59% specificity) and the results demonstrated that those ten biomarkers are specific. 6 drugs were used to predict the hepatotoxicity by the support vector machines model; the prediction results were consistent with the biochemical and histopathological results, demonstrating that the model was reliable. Thus, this support vector machine model can be applied to discriminate the between the hepatic or nonhepatic toxicity of drugs. This approach not only presents a new strategy for screening-specific biomarkers with greater diagnostic significance but also provides a new evaluation pattern for hepatotoxicity, and it will be a highly useful tool in toxicity estimation and disease diagnoses. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  15. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity: lessons learned from the bromfenac experience.

    PubMed

    Goldkind, Lawrence; Laine, Loren

    2006-04-01

    Drug-induced hepatotoxicity is the leading cause of acute liver failure (ALF) in the US and the most common adverse event causing drug non-approval and drug withdrawal by the U.S. Food and Drug Administration (FDA). Three different nonsteroidal anti-inflammatory drugs (NSAIDs) have been withdrawn in the UK and/or the US due to hepatotoxicity (bromfenac, ibufenac, and benoxaprofen). A systematic review of clinical trials data for these drugs was performed in an effort to identify possible early signals that could have predicted post-marketing serious hepatoxicity. There were very limited published data on benoxaprofen and none on ibufenac or bromfenac. The publicly accessible archives of the FDA provided information on bromfenac. Flu-like symptoms associated with hepatic enzyme elevation and a case of possible drug-related hepatocellular jaundice may in retrospect have been signals for serious hepatotoxicity in the database of 1195 subjects reviewed by the FDA. Following approval, rates of acute liver failure for bromfenac were estimated to be in the range of 1:10 000. In addition, the safety databases of several drugs also accessed through FDA archives have been reviewed (simvastatin, tacrine, troglitazone, and ximelagatran). These data suggest that while ALT elevations alone do not reliably signal serious hepatotoxicity, elevated transaminases in association with symptomatic hepatitis or jaundice may be predictors of an increased risk of ALF. At present, however, pre-approval databases are generally not large enough to rule out low rates of serious hepatotoxicity. Therefore, it remains critical that clinicians report such cases to the FDA through the MEDWATCH system and that active post-marketing monitoring studies be used to identify potential rare cases of hepatotoxicity. Copyright (c) 2006 John Wiley & Sons, Ltd.

  16. Accuracy of the paracetamol-aminotransferase product to predict hepatotoxicity in paracetamol overdose treated with a 2-bag acetylcysteine regimen.

    PubMed

    Wong, Anselm; Sivilotti, Marco L A; Gunja, Naren; McNulty, Richard; Graudins, Andis

    2018-03-01

    Paracetamol concentration is a highly accurate risk predictor for hepatotoxicity following overdose with known time of ingestion. However, the paracetamol-aminotransferase multiplication product can be used as a risk predictor independent of timing or ingestion type. Validated in patients treated with the traditional, "three-bag" intravenous acetylcysteine regimen, we evaluated the accuracy of the multiplication product in paracetamol overdose treated with a two-bag acetylcysteine regimen. We examined consecutive patients treated with the two-bag regimen from five emergency departments over a two-year period. We assessed the predictive accuracy of initial multiplication product for the primary outcome of hepatotoxicity (peak alanine aminotransferase ≥1000IU/L), as well as for acute liver injury (ALI), defined peak alanine aminotransferase ≥2× baseline and above 50IU/L). Of 447 paracetamol overdoses treated with the two-bag acetylcysteine regimen, 32 (7%) developed hepatotoxicity and 73 (16%) ALI. The pre-specified cut-off points of 1500 mg/L × IU/L (sensitivity 100% [95% CI 82%, 100%], specificity 62% [56%, 67%]) and 10,000 mg/L × IU/L (sensitivity 70% [47%, 87%], specificity of 97% [95%, 99%]) were highly accurate for predicting hepatotoxicity. There were few cases of hepatotoxicity irrespective of the product when acetylcysteine was administered within eight hours of overdose, when the product was largely determined by a high paracetamol concentration but normal aminotransferase. The multiplication product accurately predicts hepatotoxicity when using a two-bag acetylcysteine regimen, especially in patients treated more than eight hours post-overdose. Further studies are needed to assess the product as a method to adjust for exposure severity when testing efficacy of modified acetylcysteine regimens.

  17. Metabolism by conjugation appears to confer resistance to paracetamol (acetaminophen) hepatotoxicity in the cynomolgus monkey.

    PubMed

    Yu, Hong; Barrass, Nigel; Gales, Sonya; Lenz, Eva; Parry, Tony; Powell, Helen; Thurman, Dale; Hutchison, Michael; Wilson, Ian D; Bi, Luke; Qiao, Junwen; Qin, Qiuping; Ren, Jin

    2015-03-01

    1. Paracetamol overdose remains the leading cause of acute liver failure in humans. This study was undertaken in cynomolgus monkeys to study the pharmacokinetics, metabolism and the potential for hepatotoxic insult from paracetamol administration as a possible model for human toxicity. 2. No adverse effects were observed for doses of up to 900 mg/kg/d for 14 d. Only minor sporadic increases in alanine aminotransferase, aspartate aminotransferase and glutamate dehydrogenase in a number of animals were observed, with no clear dose response. 3. Toxicokinetic analysis showed good plasma exposure, albeit with less than proportional rises in Cmax and AUC, with increasing dose. The Cmax values in monkey were up to 3.5 times those associated with human liver toxicity and the AUC approx. 1000 times those associated with liver enzyme changes in 31-44% of human subjects. 4. Metabolite profiling of urine by (1)H NMR spectroscopy revealed paracetamol and its glucuronide and sulphate metabolites. Glutathione-derived metabolites, e.g. the cysteinyl conjugate, were only present in very low concentrations whilst the mercapturate was not detected. 5. These in vivo observations demonstrated that the cynomolgus monkey is remarkably resistant to paracetamol-induced toxicity and a poor model for investigating paracetamol-related hepatotoxicity in humans.

  18. Paracetamol causes endocrine disruption and hepatotoxicity in male fish Rhamdia quelen after subchronic exposure.

    PubMed

    Guiloski, Izonete Cristina; Ribas, João Luiz Coelho; Piancini, Laercio Dante Stein; Dagostim, Ana Carolina; Cirio, Silvana Maris; Fávaro, Luis Fernando; Boschen, Suelen Lúcio; Cestari, Marta Margarete; da Cunha, Cláudio; Silva de Assis, Helena Cristina

    2017-07-01

    Paracetamol is one of the most widely sold non-prescription drugs. This study aimed to evaluate the effects of the paracetamol on reproductive, biochemical, genetic, histopathological and hematogical biomarkers by waterborne exposure. Male fish of Rhamdia quelen were exposed to environmental concentrations of paracetamol (0, 0.25, 2.5μg/L) in a semi-static bioassay for 21days. Hemoglobin and hematocrit were reduced upon exposure to 0.25μg/L of paracetamol. Leukocytes and thrombocytes increased after paracetamol exposure. Paracetamol reduced testosterone levels in all exposed groups and increased estradiol levels at higher concentration. Serotonin and dopamine levels increased at exposure to 0.25μg/L. Paracetamol also caused protein carbonyls and increased SOD activity in fish exposed to 2.5μg/L and in addition led to an inhibition of EROD and GST activities in both concentrations. Hepatic genotoxicity occurred at the 0.25μg/L concentration. Hepatic tissues of exposed fish showed mild blood congestion and leucocytes infiltration. The results showed that paracetamol disrupted the hypothalamic-pituitary-gonadal axis, changed hematological parameters and caused hepatotoxicity in Rhamdia quelen. The findings suggest that this drug merits attention relative to its potential endocrine disrupter effect and hepatotoxicity, even at concentrations found in the aquatic environment. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. A Case of Hepatotoxicity Induced by Adulterated "Tiger King", a Chinese Herbal Medicine Containing Sildenafil.

    PubMed

    Nissan, Ran; Poperno, Alina; Stein, Gideon Y; Shapira, Barak; Fuchs, Shmuel; Berkovitz, Ronny; Hess, Zipora; Arieli, Mickey

    2016-01-01

    Detection of Phosphodiesterase Type 5 (PDE-5) inhibitors and their analogues in "100% natural" or "herbal" supplements have been described in numerous reports. However, few reports have been published in relation to actual harm caused by counterfeit erectile dysfunction herbal supplements. We describe a case of a 65-year old male admitted to a tertiary hospital with acute liver toxicity, possibly induced by adulterated "Chinese herbal" supplement "Tiger King" for sexual enhancement. Chemical analysis of the tablets discovered the presence of therapeutic doses of sildenafil with no other herbal components. Other medications were excluded as potential causes of the hepatic impairment. According to the Naranjo adverse drug reaction scale and the Roussel Uclaf Causality Assessment Method (RUCAM) the probability of association of Hepatotoxicity with Sildenafil was "possible" and "probable" respectively (Naranjo score of 4, RUCAM score of 7). Within three days of admission, the patient's clinical status and liver function improved without any specific treatment. His liver function tests normalized 30 days post discharge. Further pharmacovigilance actions should be taken by regulatory authorities and pharmaceutical companies in order to determine the relation between sildenafil and hepatotoxicity. This case emphasizes the importance of raising public awareness on the potential dangers of "Tiger king" in particular, and other counterfeit medications or herbal supplements of unknown origin.

  20. Moringa oleifera-based diet protects against nickel-induced hepatotoxicity in rats.

    PubMed

    Stephen Adeyemi, Oluyomi; Sokolayemji Aroge, Cincin; Adewumi Akanji, Musbau

    2017-07-13

    Multiple health-promoting effects have been attributed to the consumption of Moringa oleifera leaves, as part of diet without adequate scientific credence. This study evaluated the effect of M. oleifera-based diets on nickel (Ni) - induced hepatotoxicity in rats. Male rats assigned into six groups were given oral administration of 20 mg/kg body weight nickel sulfate in normal saline and either fed normal diet orM. oleifera-based diets for 21 days. All animals were sacrificed under anesthesia 24 hours after the last treatment. Ni exposure elevated the rat plasma activities of alanine transaminase, aspartate transaminase and alkaline phosphatase significantly. Ni exposure also raised the levels of triglyceride, total cholesterol and low-density lipoprotein cholesterol while depleting the high-density lipoprotein cholesterol concentration. Further, Ni exposure raised rat plasma malondialdehyde but depleted reduced glutathione concentrations. The histopathological presentations revealed inflammation and cellular degeneration caused by Ni exposure. We show evidence thatM. oleifera-based diets protected against Ni-induced hepatotoxicity by improving the rat liver function indices, lipid profile as well as restoring cellular architecture and integrity. Study lends credence to the health-promoting value ofM. oleifera as well as underscores its potential to attenuate hepatic injury.

  1. The use of cultured hepatocytes to investigate the metabolism of drugs and mechanisms of drug hepatotoxicity.

    PubMed

    Gómez-Lechón, M J; Ponsoda, X; Bort, R; Castell, J V

    2001-01-01

    Hepatotoxins can be classified as intrinsic when they exert their effects on all individuals in a dose-dependent manner, and as idiosyncratic when their effects are the consequence of an abnormal metabolism of the drug by susceptible individuals (metabolic idiosyncrasy) or of an immune-mediated injury to hepatocytes (allergic hepatitis). Some xenobiotics are electrophilic, and others are biotransformed by the liver into highly reactive metabolites that are usually more toxic than the parent compound. This activation process is the key to many hepatotoxic phenomena. Mitochondria are a frequent target of hepatotoxic drugs, and the alteration of their function has immediate effects on the energy balance of cells (depletion of ATP). Lipid peroxidation, oxidative stress, alteration of Ca(2+) homeostasis, and covalent binding to cell macromolecules are the molecular mechanisms that are frequently involved in the toxicity of xenobiotics. Against these potential hazards, cells have their own defence mechanisms (for example, glutathione, DNA repair, suicide inactivation). Ultimately, toxicity is the balance between bioactivation and detoxification, which determines whether a reactive metabolite elicits a toxic effect. The ultimate goal of in vitro experiments is to generate the type of scientific information needed to identify compounds that are potentially toxic to man. For this purpose, both the design of the experiments and the interpretation of the results are critical.

  2. Protective effects of silymarin against acetaminophen-induced hepatotoxicity and nephrotoxicity in mice.

    PubMed

    Bektur, Nuriye Ezgi; Sahin, Erhan; Baycu, Cengiz; Unver, Gonul

    2016-04-01

    This study was designed to estimate protective effects of silymarin on acetaminophen (N-acetyl-p-aminophenol, paracetamol; APAP)-induced hepatotoxicity and nephrotoxicity in mice. Treatment of mice with overdose of APAP resulted in the elevation of aspartate aminotransferase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), and serum creatinine (SCr) levels in serum, liver, and kidney nitric oxide (NO) levels and significant histological changes including decreased body weight, swelling of hepatocytes, cell infiltration, dilatation and congestion, necrosis and apoptosis in liver, and dilatation of Bowman's capsular space and glomerular capillaries, pale-stained tubules epithelium, cell infiltration, and apoptosis in kidney. Posttreatment with silymarin 1 h after APAP injection for 7 days, however, significantly normalized the body weight, histological damage, serum ALT, AST, BUN, SCr, and tissue NO levels. Our observation suggested that silymarin ameliorated the toxic effects of APAP-induced hepatotoxicity and nephrotoxicity in mice. The protective role of silymarin against APAP-induced damages might result from its antioxidative and anti-inflammatory effects. © The Author(s) 2013.

  3. Human hepatocytes derived from pluripotent stem cells: a promising cell model for drug hepatotoxicity screening.

    PubMed

    Gómez-Lechón, María José; Tolosa, Laia

    2016-09-01

    Drug-induced liver injury (DILI) is a frequent cause of failure in both clinical and post-approval stages of drug development, and poses a key challenge to the pharmaceutical industry. Current animal models offer poor prediction of human DILI. Although several human cell-based models have been proposed for the detection of human DILI, human primary hepatocytes remain the gold standard for preclinical toxicological screening. However, their use is hindered by their limited availability, variability and phenotypic instability. In contrast, pluripotent stem cells, which include embryonic and induced pluripotent stem cells (iPSCs), proliferate extensively in vitro and can be differentiated into hepatocytes by the addition of soluble factors. This provides a stable source of hepatocytes for multiple applications, including early preclinical hepatotoxicity screening. In addition, iPSCs also have the potential to establish genotype-specific cells from different individuals, which would increase the predictivity of toxicity assays allowing more successful clinical trials. Therefore, the generation of human hepatocyte-like cells derived from pluripotent stem cells seems to be promising for overcoming limitations of hepatocyte preparations, and it is expected to have a substantial repercussion in preclinical hepatotoxicity risk assessment in early drug development stages.

  4. Sonographic assessment of petroleum-induced hepatotoxicity in Nigerians: does biochemical assessment underestimate liver damage?

    PubMed

    Anakwue, Angel-Mary; Anakwue, Raphael; Okeji, Mark; Idigo, Felicitas; Agwu, Kenneth; Nwogu, Uloma

    2017-03-01

    Exposure to petroleum products has been shown to have significant adverse effects on the liver which can manifest either as morphological or physiological changes. The aim of the study was to assess the effects of chronic exposure to some petroleum products on the liver of exposed workers using sonography and to determine whether biochemical assessments underestimated hepatotoxicity. Abdominal ultrasound was performed on 415 exposed workers in order to evaluate liver echogenicity and size. Also, biochemical assessment of the liver was done to evaluate its function. Statistically significant increase in the liver parenchymal echogenicity and the liver size was seen in the exposed workers compared with control (p ≤ 0.05). These increased as the exposure duration increased. It was also noted that out of 16.87% (N=70) exposed workers with abnormal liver echopattern, only 2.65% (N=11) had alanine aminotransferase above the reference range. The study revealed evidence of ultrasound detectable hepatotoxicity among the exposed subjects. Sonography appeared to detect petroleum products-induced hepatic toxicity more than biochemical assays suggesting that biochemical assessment may have underestimated toxicity.

  5. Hypericum perforatum-induced hepatotoxicity with possible association with copaiba (Copaifera langsdorffii Desf):case report

    PubMed Central

    Agollo, Marjorie Costa; Miszputen, Sender Jankiel; Diament, Jayme

    2014-01-01

    We report a case of liver damage in an elderly patient after the use of herbal products of Hypericum perforatum and copaiba (Copaifera langsdorffii Desf). Hepatotoxicity related to Hypericum perforatum is anecdotally known, but for copaiba, widely used as anti-inflammatory, there is just experimental data in the national literature. This report aimed to draw attention to the possible toxic effects of this association as well as to the clinical recovery of the patient after discontinuing their use. There is a tendency to suspect of the action of drugs to justify a non-viral acute liver injury, because of the large number of drugs responsible for hepatotoxicity. There are experiments and clinical reports in the literature describing some herbal products, including Hypericum perforatum, as the causative agents of this aggression, and are considered innocuous and used with no restrictions. We must remember that adverse reactions also occur with these substances; hence, they should be investigated when collecting the patient´s history, for leading to severe liver failure. PMID:25167337

  6. Strategies for In Vivo Screening and Mitigation of Hepatotoxicity Associated with Antisense Drugs.

    PubMed

    Kamola, Piotr J; Maratou, Klio; Wilson, Paul A; Rush, Kay; Mullaney, Tanya; McKevitt, Tom; Evans, Paula; Ridings, Jim; Chowdhury, Probash; Roulois, Aude; Fairchild, Ann; McCawley, Sean; Cartwright, Karen; Gooderham, Nigel J; Gant, Timothy W; Moores, Kitty; Hughes, Stephen A; Edbrooke, Mark R; Clark, Kenneth; Parry, Joel D

    2017-09-15

    Antisense oligonucleotide (ASO) gapmers downregulate gene expression by inducing enzyme-dependent degradation of targeted RNA and represent a promising therapeutic platform for addressing previously undruggable genes. Unfortunately, their therapeutic application, particularly that of the more potent chemistries (e.g., locked-nucleic-acid-containing gapmers), has been hampered by their frequent hepatoxicity, which could be driven by hybridization-mediated interactions. An early de-risking of this liability is a crucial component of developing safe, ASO-based drugs. To rank ASOs based on their effect on the liver, we have developed an acute screen in the mouse that can be applied early in the drug development cycle. A single-dose (3-day) screen with streamlined endpoints (i.e., plasma transaminase levels and liver weights) was observed to be predictive of ASO hepatotoxicity ranking established based on a repeat-dose (15 day) study. Furthermore, to study the underlying mechanisms of liver toxicity, we applied transcriptome profiling and pathway analyses and show that adverse in vivo liver phenotypes correlate with the number of potent, hybridization-mediated off-target effects (OTEs). We propose that a combination of in silico OTE predictions, streamlined in vivo hepatotoxicity screening, and a transcriptome-wide selectivity screen is a valid approach to identifying and progressing safer compounds. Copyright © 2017 GSK R&D. Published by Elsevier Inc. All rights reserved.

  7. Vitamin E and selenium treatment of monocrotaline induced hepatotoxicity in rats.

    PubMed

    Cuce, G; Canbaz, H T; Sozen, M E; Yerlikaya, F H; Kalkan, S

    2017-01-01

    Monocrotaline (MCT) is a hepatotoxic pyrrolizidine alkaloid that is derived from plants; exposure may occur by consumption of contaminated grains, herbal teas and medicines. MCT can cause liver damage. We investigated the antioxidant effects of selenium (Se) and vitamin E against the toxic effects of MCT. Female Wistar albino rats were divided into four groups: a control group, an MCT group, an MCT + Se group, and an MCT + vitamin E group. Liver tissues were harvested, fixed, processed to paraffin and sections were cut. Anti-von Willebrand factor (vWF) immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL), and hematoxylin and eosin staining were performed. Serum and liver tissue glutathione (GSH), catalase (CAT), and glutathione peroxidase (GPx) levels were measured. Histopathological and TUNEL data showed significantly increased liver damage in the MCT group compared to controls. Histopathological and TUNEL staining indicated significant improvements in the MCT + vitamin E and MCT + Se groups compared to the MCT group. MCT significantly reduced the serum GSH level and GPx activity, and liver GPx activity. Biochemical data indicated a significant improvement in serum GSH level in the MCT + vitamin E group compared to the MCT group. We suggest that vitamin E and Se afford limited protection against MCT hepatotoxicity.

  8. Influence of Moxifloxacin on Hepatic Redox Status and Plasma Biomarkers of Hepatotoxicity and Nephrotoxicity in Rat

    PubMed Central

    Olayinka, Ebenezer Tunde

    2015-01-01

    Moxifloxacin is a broad spectrum fluoroquinolone antibacterial agent. We examined the hepatic redox status and plasma biomarkers of nephrotoxicity and hepatotoxicity in rat following administration of moxifloxacin (MXF). Twenty-four Wistar rats, 180–200 g, were randomized into four groups (I–IV). Animals in group I (control) received 1 mL of distilled water, while animals in groups II, III, and IV received 1 mL each of MXF equivalent to 4 mg/kg b.w., 8 mg/kg b.w., and 16 mg/kg b.w., respectively. After seven days, plasma urea, bilirubin, and creatinine were significantly (P < 0.05) elevated in the MXF-treated animals. Activities of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase were significantly increased in the plasma of MXF-treated animals compared to control. Also plasma total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides increased significantly in the MXF-treated groups relative to control. Moreover, MXF triggered a significant decrease in hepatic catalase, superoxide dismutase, and glutathione-S transferase activities. Likewise, MXF caused a decrease in the hepatic levels of glutathione and vitamin C. A significant increase in hepatic MDA content was also observed in the MXF-treated animals relative to control. Overall, our data suggest that the half-therapeutic, therapeutic, and twice the therapeutic dose of MXF induced nephrotoxicity, hepatotoxicity, and altered hepatic redox balance in rats. PMID:26550491

  9. Severe hepatotoxicity following ingestion of Herbalife nutritional supplements contaminated with Bacillus subtilis.

    PubMed

    Stickel, Felix; Droz, Sara; Patsenker, Eleonora; Bögli-Stuber, Katja; Aebi, Beat; Leib, Stephen L

    2009-01-01

    Nutritional supplements are widely used. Recently, liver injury after consumption of Herbalife preparations was reported but the underlying pathogenesis remained cryptic. Two patients presented with cholestatic hepatitis and pruritus, and cirrhosis, respectively. Viral, alcoholic, metabolic, autoimmune, neoplastic, vascular liver diseases and synthetic drugs as the precipitating causes of liver injury were excluded. However, both patients reported long-term consumption of Herbalife products. All Herbalife products were tested for contamination with drugs, pesticides, heavy metals, and softeners, and examined for microbial contamination according to standard laboratory procedures. Bacteria isolated from the samples were identified as Bacillus subtilis by sequencing the 16S rRNA and gyrB genes. Causality between consumption of Herbalife products and disease according to CIOMS was scored "probable" in both cases. Histology showed cholestatic and lobular/portal hepatitis with cirrhosis in one patient, and biliary fibrosis with ductopenia in the other. No contamination with chemicals or heavy metals was detected, and immunological testing showed no drug hypersensitivity. However, samples of Herbalife products ingested by both patients showed growth of Bacillus subtilis of which culture supernatants showed dose- and time-dependent hepatotoxicity. Two novel incidents of severe hepatic injury following intake of Herbalife products contaminated with Bacillus subtilis emphasize its potential hepatotoxicity.

  10. Dietary protocatechuic acid ameliorates dextran sulphate sodium-induced ulcerative colitis and hepatotoxicity in rats.

    PubMed

    Farombi, Ebenezer O; Adedara, Isaac A; Awoyemi, Omolola V; Njoku, Chinonye R; Micah, Gabriel O; Esogwa, Cynthia U; Owumi, Solomon E; Olopade, James O

    2016-02-01

    The present study investigated the antioxidant and anti-inflammatory effects of dietary protocatechuic acid (PCA), a simple hydrophilic phenolic compound commonly found in many edible vegetables, on dextran sulphate sodium (DSS)-induced ulcerative colitis and its associated hepatotoxicity in rats. PCA was administered orally at 10 mg kg(-1) to dextran sulphate sodium exposed rats for five days. The result revealed that administration of PCA significantly (p < 0.05) prevented the incidence of diarrhea and bleeding, the decrease in the body weight gain, shortening of colon length and the increase in colon mass index in DSS-treated rats. Furthermore, PCA prevented the increase in the plasma levels of pro-inflammatory cytokines, markers of liver toxicity and markedly suppressed the DSS-mediated elevation in colonic nitric oxide concentration and myeloperoxidase activity in the treated rats. Administration of PCA significantly protected against colonic and hepatic oxidative damage by increasing the antioxidant status and concomitantly decreased hydrogen peroxide and lipid peroxidation levels in the DSS-treated rats. Moreover, histological examinations confirmed PCA chemoprotection against colon and liver damage. Immunohistochemical analysis showed that PCA significantly inhibited cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) protein expression in the colon of DSS-treated rats. In conclusion, the effective chemoprotective role of PCA in colitis and the associated hepatotoxicity is related to its intrinsic anti-inflammatory and anti-oxidative properties.

  11. Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions.

    PubMed

    Freyer, Nora; Greuel, Selina; Knöspel, Fanny; Gerstmann, Florian; Storch, Lisa; Damm, Georg; Seehofer, Daniel; Foster Harris, Jennifer; Iyer, Rashi; Schubert, Frank; Zeilinger, Katrin

    2018-03-15

    The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP ( p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP ( p < 0.0001), indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP ( p < 0.05), suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions.

  12. Microscale 3D Liver Bioreactor for In Vitro Hepatotoxicity Testing under Perfusion Conditions

    PubMed Central

    Freyer, Nora; Greuel, Selina; Knöspel, Fanny; Gerstmann, Florian; Storch, Lisa; Damm, Georg; Seehofer, Daniel; Foster Harris, Jennifer; Iyer, Rashi; Schubert, Frank; Zeilinger, Katrin

    2018-01-01

    The accurate prediction of hepatotoxicity demands validated human in vitro models that can close the gap between preclinical animal studies and clinical trials. In this study we investigated the response of primary human liver cells to toxic drug exposure in a perfused microscale 3D liver bioreactor. The cellularized bioreactors were treated with 5, 10, or 30 mM acetaminophen (APAP) used as a reference substance. Lactate production significantly decreased upon treatment with 30 mM APAP (p < 0.05) and ammonia release significantly increased in bioreactors treated with 10 or 30 mM APAP (p < 0.0001), indicating APAP-induced dose-dependent toxicity. The release of prostaglandin E2 showed a significant increase at 30 mM APAP (p < 0.05), suggesting an inflammatory reaction towards enhanced cellular stress. The expression of genes involved in drug metabolism, antioxidant reactions, urea synthesis, and apoptosis was differentially influenced by APAP exposure. Histological examinations revealed that primary human liver cells in untreated control bioreactors were reorganized in tissue-like cell aggregates. These aggregates were partly disintegrated upon APAP treatment, lacking expression of hepatocyte-specific proteins and transporters. In conclusion, our results validate the suitability of the microscale 3D liver bioreactor to detect hepatotoxic effects of drugs in vitro under perfusion conditions. PMID:29543727

  13. 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.

  14. Hepatoprotective activity of Leptadenia reticulata stems against carbon tetrachloride-induced hepatotoxicity in rats

    PubMed Central

    Nema, Amit Kumar; Agarwal, Abhinav; Kashaw, Varsha

    2011-01-01

    Objective: To evaluate the hepatoprotective activity of ethanolic and aqueous extract of stems of Leptadenia reticulata (Retz.) Wight. and Arn. in carbon tetrachloride (CCl4)-induced hepatotoxicity in rats. Materials and Methods: The toxicant CCl4 was used to induce hepatotoxicity at a dose of 1.25 ml/kg as 1 : 1 mixture with olive oil. Ethanolic and aqueous extracts of L. reticulata stems were administered in the doses of 250 and 500 mg/kg/day orally for 7 days. Silymarin (50 mg/kg) was used as standard drug. The hepatoprotective effect of these extracts was evaluated by the assessment of biochemical parameters such as serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, total bilirubin, serum protein, and histopathological studies of the liver. Results: Treatment of animals with ethanolic and aqueous extracts significantly reduced the liver damage and the symptoms of liver injury by restoration of architecture of liver as indicated by lower levels of serum bilirubin and protein as compared with the normal and silymarin-treated groups. Histology of the liver sections confirmed that the extracts prevented hepatic damage induced by CCl4 showing the presence of normal hepatic cords, absence of necrosis, and fatty infiltration. Conclusion: The ethanolic and aqueous extracts of stems of L. reticulata showed significant hepatoprotective activity. The ethanolic extract is more potent in hepatoprotection in CCl4-indiced liver injury model as compared with aqueous extract. PMID:21713086

  15. Gemfibrozil disrupts lysophosphatidylcholine and bile acid homeostasis via PPARα and its relevance to hepatotoxicity.

    PubMed

    Liu, Aiming; Krausz, Kristopher W; Fang, Zhong-Ze; Brocker, Chad; Qu, Aijuan; Gonzalez, Frank J

    2014-04-01

    Gemfibrozil, a ligand of peroxisome proliferator-activated receptor α (PPARα), is one of the most widely prescribed anti-dyslipidemia fibrate drugs. Among the adverse reactions observed with gemfibrozil are alterations in liver function, cholestatic jaundice, and cholelithiasis. However, the mechanisms underlying these toxicities are poorly understood. In this study, wild-type and Ppara-null mice were dosed with a gemfibrozil-containing diet for 14 days. Ultra-performance chromatography electrospray ionization quadrupole time-of-flight mass spectrometry-based metabolomics and traditional approaches were used to assess the mechanism of gemfibrozil-induced hepatotoxicity. Unsupervised multivariate data analysis revealed four lysophosphatidylcholine components in wild-type mice that varied more dramatically than those in Ppara-null mice. Targeted metabolomics revealed taurocholic acid and tauro-α-muricholic acid/tauro-β-muricholic acid were significantly increased in wild-type mice, but not in Ppara-null mice. In addition to the above perturbations in metabolite homeostasis, phenotypic alterations in the liver were identified. Hepatic genes involved in metabolism and transportation of lysophosphatidylcholine and bile acid compounds were differentially regulated between wild-type and Ppara-null mice, in agreement with the observed downstream metabolic alterations. These data suggest that PPARα mediates gemfibrozil-induced hepatotoxicity in part by disrupting phospholipid and bile acid homeostasis.

  16. Ameliorative Influence of Green Tea Extract on Copper Nanoparticle-Induced Hepatotoxicity in Rats

    NASA Astrophysics Data System (ADS)

    Ibrahim, Marwa A.; Khalaf, A. A.; Galal, Mona K.; Ogaly, Hanan A.; H. M. Hassan, Azza

    2015-09-01

    The potential toxicity of copper nanoparticles (CNPs) to the human health and environment remains a critical issue. In the present study, we investigated the protective influence of an aqueous extract of green tea leaves (GTE) against CNPs-induced (20-30 nm) hepatotoxicity. Four different groups of rats were used: group I was the control, group II received CNPs (40 mg/kg BW), group III received CNPs plus GTE, and group IV received GTE alone. We highlighted the hepatoprotective effect of GTE against CNPs toxicity through monitoring the alteration of liver enzyme activity, antioxidant defense mechanism, histopathological alterations, and DNA damage evaluation. The rats that were given CNPs only had a highly significant elevation in liver enzymes, alteration in oxidant-antioxidant balance, and severe pathological changes. In addition, we detected a significant elevation of DNA fragmentation percentage, marked DNA laddering, and significance over expression of both caspase-3 and Bax proteins. The findings for group III clarify the efficacy of GTE as a hepatoprotectant on CNPs through improving the liver enzyme activity, antioxidant status, as well as suppressing DNA fragmentation and the expression of the caspase-3 and Bax proteins. In conclusion, GTE was proved to be a potential hepatoprotective additive as it significantly ameliorates the hepatotoxicity and apoptosis induced by CNPs.

  17. [Individualized clinical treatment from the prospective of hepatotoxicity of non-toxic traditional Chinese medicine].

    PubMed

    Yang, Nan; Chen, Juan; Hou, Xue-Feng; Song, Jie; Feng, Liang; Jia, Xiao-Bin

    2017-04-01

    Traditional Chinese medicine has a long history in clinical application, and been proved to be safe and effective. In recent years, the toxicity and side-effects caused by the western medicine have been attracted much attention. As a result, increasing people have shifted their attention to traditional Chinese medicine. Nonetheless, due to the natural origin of traditional Chinese medicine and the lack of basic knowledge about them, many people mistakenly consider the absolute safety of traditional Chinese medicine, except for well-known toxic ones, such as arsenic. However, according to the clinical practices and recent studies, great importance shall be attached to the toxicity of non-toxic traditional Chinese medicine, in particular the hepatotoxicity. Relevant studies indicated that the toxicity of non-toxic traditional Chinese medicine is closely correlated with individual gene polymorphism and constitution. By discussing the causes and mechanisms of the hepatotoxicity induced by non-toxic traditional Chinese medicine in clinical practices, we wrote this article with the aim to provide new ideas for individualized clinical therapy of traditional Chinese medicine and give guidance for rational and safe use of traditional Chinese medicine. Copyright© by the Chinese Pharmaceutical Association.

  18. Protective Effects of Caffeic Acid Phenethyl Ester on Fluoxetine-Induced Hepatotoxicity: An Experimental Study.

    PubMed

    Yılmaz, Ahmet; Elbey, Bilal; Yazgan, Ümit Can; Dönder, Ahmet; Arslan, Necmi; Arslan, Serkan; Alabalık, Ulaş; Aslanhan, Hamza

    2016-01-01

    Background. The aim of the study was to analyse the effect of caffeic acid phenethyl ester (CAPE) on fluoxetine-induced hepatotoxicity in rats. Materials and Methods. Group I served as control. Group II received CAPE intraperitoneally. Group III received fluoxetine per orally. Group IV received fluoxetine and CAPE. The total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI), and liver enzymes including paraoxonase-1 (PON-1), aspartate transaminase, and alanine transaminase levels were measured. Liver tissues were processed histopathologically for evaluation of liver injury and to validate the serum enzyme levels. Results. An increase in TOS and OSI and a decrease in TAC and PON-1 levels in serum and liver tissues of Group III were observed compared to Groups I and II. After treatment with CAPE, the level of TOS and OSI decreased while TAC and PON-1 increased in serum and liver in Group IV. Histopathological examination of the liver revealed hepatic injury after fluoxetine treatment and reduction of injury with CAPE treatment. Conclusion. Our results suggested that CAPE treatment provided protection against fluoxetine toxicity. Following CAPE treatment with fluoxetine-induced hepatotoxicity, TOS and OSI levels decreased, whereas PON-1 and TAC increased in the serum and liver.

  19. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats.

    PubMed

    El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

    2015-12-01

    Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. The treatment with Arctium lappa extract reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in the acetaminophen group when compared with the control group. DNA fragments in the acetaminophen-injected group were also significantly increased (P < 0.05). The comet assay revealed increased detaching tail length and DNA concentration during the hepatic toxicity in the acetaminophen group. The malondialdehyde content was inhibited by Arctium lappa treatment (12.97±0.89 nmol/mg) when compared with the acetaminophen-treated-only group (12.97±0.89 nmol/mg). Histopathologic examination revealed that acetaminophen administration produced hepatic cell necrosis, infiltrate of lymphocytes, and vacuolation that were associated with the acetaminophen-treated animal group, but the degree of acetaminophen-induced hepatotoxicity was mediated by treatment with Arctium lappa extract. Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats.

  20. Use of Arctium lappa Extract Against Acetaminophen-Induced Hepatotoxicity in Rats

    PubMed Central

    El-Kott, Attalla Farag; Bin-Meferij, Mashael Mohammed

    2015-01-01

    Background Severe destructive hepatic injuries can be induced by acetaminophen overdose and may lead to acute hepatic failure. Objective To investigate the ameliorative effects of Arctium lappa root extract on acetaminophen-induced hepatotoxicity. Methods Rats were divided into 4 groups: normal control group, Arctium lappa extract group, acetaminophen-injected group, and acetaminophen treated with Arctium lappa extract group. Results The treatment with Arctium lappa extract reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase in the acetaminophen group when compared with the control group. DNA fragments in the acetaminophen-injected group were also significantly increased (P < 0.05). The comet assay revealed increased detaching tail length and DNA concentration during the hepatic toxicity in the acetaminophen group. The malondialdehyde content was inhibited by Arctium lappa treatment (12.97±0.89 nmol/mg) when compared with the acetaminophen-treated-only group (12.97±0.89 nmol/mg). Histopathologic examination revealed that acetaminophen administration produced hepatic cell necrosis, infiltrate of lymphocytes, and vacuolation that were associated with the acetaminophen-treated animal group, but the degree of acetaminophen-induced hepatotoxicity was mediated by treatment with Arctium lappa extract. Conclusions Arctium lappa can prevent most of the hepatic tissue damage caused by acetaminophen overdose in rats. PMID:26543508

  1. Colour cyclic code for Brillouin distributed sensors

    NASA Astrophysics Data System (ADS)

    Le Floch, Sébastien; Sauser, Florian; Llera, Miguel; Rochat, Etienne

    2015-09-01

    For the first time, a colour cyclic coding (CCC) is theoretically and experimentally demonstrated for Brillouin optical time-domain analysis (BOTDA) distributed sensors. Compared to traditional intensity-modulated cyclic codes, the code presents an additional gain of √2 while keeping the same number of sequences as for a colour coding. A comparison with a standard BOTDA sensor is realized and validates the theoretical coding gain.

  2. Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice

    PubMed Central

    Sheweita, Salah A.; El-Hosseiny, Lobna S.; Nashashibi, Munther A.

    2016-01-01

    Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn’t change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared

  3. Protective Effects of Essential Oils as Natural Antioxidants against Hepatotoxicity Induced by Cyclophosphamide in Mice.

    PubMed

    Sheweita, Salah A; El-Hosseiny, Lobna S; Nashashibi, Munther A

    2016-01-01

    Clinical application of cyclophosphamide (CP) as an anticancer drug is often limited due to its toxicity. CP is metabolized mainly in the liver by cytochrome P450 system into acrolein which is the proximate toxic metabolite. Many different natural antioxidants were found to alleviate the toxic effects of various toxic agents via different mechanisms. Therefore, the present study aimed at investigating the role of essential oils extracted from fennel, cumin and clove as natural antioxidants in the alleviation of hepatotoxicity induced by CP through assessment of hepatotoxicity biomarkers (AST, ALT, ALP), histopathology of liver tissues as well as other biochemical parameters involved in the metabolism of CP. The data of the present study showed that treatment of male mice with cyclophosphamide (2.5 mg/Kg BW) as repeated dose for 28 consecutive days was found to induce hepatotoxicity through the elevation in the activities of AST, ALT, and ALP. Combined administration of any of these oils with CP to mice partially normalized the altered hepatic biochemical markers caused by CP, whereas administration of fennel, clove or cumin essential oils alone couldn't change liver function indices. Moreover, CP caused histological changes in livers of mice including swelling and dilation in sinusoidal space, inflammation in portal tract and hepatocytes, as well as, hyperplasia in Kuppfer cells. However, co-administration of any of the essential oils with CP alleviated to some extent the changes caused by CP but not as the normal liver. CP was also found to induce free radical levels (measured as thiobarbituric acid reactive substances) and inhibited the activities of superoxide dismutase, glutathione reductase, and catalase as well as activities and protein expressions of both glutathione S-transferase (GSTπ) and glutathione peroxidase. Essential oils restored changes in activities of antioxidant enzymes (SOD, CAT, GR, GST, and GPx) caused by CP to their normal levels compared

  4. Modulatory effects of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity and oxidative stress in rats.

    PubMed

    Ademiluyi, Adedayo O; Oboh, Ganiyu; Owoloye, Tosin R; Agbebi, Oluwaseun J

    2013-06-01

    To investigate the ameliorative effect of dietary inclusion of garlic (Allium sativum) on gentamycin-induced hepatotoxicity in rats. Adult male rats were randomly divided into four groups with six animals in each group. Groups 1 and 2 were fed basal diet while Groups 3 and 4 were fed diets containing 2% and 4% garlic respectively for 27 d prior to gentamycin administration. Hepatotoxicity was induced by the intraperitoneal administration of gentamycin (100 mg/kg body weight) for 3 d. The liver and plasma were studied for hepatotoxicity and antioxidant indices. Gentamycin induces hepatic damage as revealed by significant (P<0.05) elevation of liver damage marker enzymes (aspartate transaminase and alanine aminotransferase) and reduction in plasma albumin level. Gentamycin also caused a significant (P<0.05) alteration in plasma and liver enzymatic (catalase, glutathione and super oxygen dehydrogenises) and non-enzymatic (glutathione and vitamin C) antioxidant indices with concomitant increase in the malondialdehyde content; however, there was a significant (P<0.05) restoration of the antioxidant status coupled with significant (P<0.05) decrease in the tissues' malondialdehyde content, following consumption of diets containing garlic. These results suggest that dietary inclusion of garlic powder could protect against gentamycin-induced hepatotoxicity, improve antioxidant status and modulate oxidative stress; a function attributed to their phenolic constituents.

  5. THE DIFFERENTIAL HEPATOTOXICITY AND CYTOCHROME P450 RESPONSE OF F344 RATS TO THE THREE ISOMERS OF DICHLOROBENZENE

    EPA Science Inventory

    The acute hepatotoxicity and response of hepatic cytochrome P450 to treatment with the three isomers of dichlorobenzene (DCB) have been investigated. The objectives were to estimate toxic thresholds and to further e1ucidate the role of cytochrome P450 in the metabolism and toxici...

  6. Protective effects of phenolics rich extract of ginger against Aflatoxin B1-induced oxidative stress and hepatotoxicity.

    PubMed

    A V, Vipin; K, Raksha Rao; Kurrey, Nawneet Kumar; K A, Anu Appaiah; G, Venkateswaran

    2017-07-01

    Aflatoxin B 1 (AFB 1 ) is one of the predominant mycotoxin contaminant in food and feed, causing oxidative stress and hepatotoxicity. Ginger phenolics have been reported for its antioxidant potential and hepatoprotective activity. The present study investigated the protective effects of phenolics rich ginger extract (GE) against AFB 1 induced oxidative stress and hepatotoxicity, in vitro and in vivo. The phenolic acid profiles of GE showed 6-gingerol and 6-shogaol as predominant components. Pretreatment of HepG2 cells with GE significantly inhibited the production of intracellular reactive oxygen species (ROS), DNA strand break, and cytotoxicity induced by AFB 1 . A comparable effect was observed in in vivo. Male Wistar rats were orally treated with GE (100 and 250mg/kg) daily, with the administration of AFB 1 (200μg/kg) every alternative day for 28days. Treatment with GE significantly reduced AFB 1 induced toxicity on the serum markers of liver damage. In addition, GE also showed significant hepatoprotective effect by reducing the lipid peroxidation and by enhancing the antioxidant enzymes activities. These results combined with liver histopathological observations indicated that GE has potential protective effect against AFB 1 induced hepatotoxicity. Additionally, administration of GE up-regulated Nrf2/HO-1 pathway, which further proved the efficiency of GE to inhibit AFB 1 induced hepatotoxicity. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  7. Use of the HepaRG Cell Line to Assess Potential Human Hepatotoxicity of ToxCast™ Chemicals

    EPA Science Inventory

    The HepaRG cell line is a promising model system for predicting human hepatotoxicity in part because of the greater capacity to metabolize chemicals than other cell models. We hypothesized that this cell line would be a relevant model for toxicity testing of industrial chemicals....

  8. Hesperidin protects against cyclophosphamide-induced hepatotoxicity by upregulation of PPARγ and abrogation of oxidative stress and inflammation.

    PubMed

    Mahmoud, Ayman M

    2014-09-01

    The most important reason for the non-approval and withdrawal of drugs by the Food and Drug Administration is hepatotoxicity. Therefore, this study was undertaken to evaluate the protective effects of hesperidin against cyclophosphamide (CYP)-induced hepatotoxicity in Wistar rats. The rats received a single intraperitoneal dose of CYP of 200 mg/kg body mass, followed by treatment with hesperidin, orally, at doses of 25 and 50 mg/kg for 11 consecutive days. CYP induced hepatic damage, as evidenced by the significantly elevated levels of serum pro-inflammatory cytokines, serum transaminases, liver lipid peroxidation, and nitric oxide. As a consequence, there was reduced glutathione content, and the activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, were markedly reduced. In addition, CYP administration induced a considerable downregulation of peroxisome proliferator activated receptor gamma (PPARγ) and upregulation of nuclear factor-kappa B (NF-κB) and inducible nitric oxide synthase (iNOS) mRNA expression. Hesperidin, in a dose-dependent manner, rejuvenated the altered markers to an almost normal state. In conclusion, hesperidin showed a potent protective effect against CYP-induced oxidative stress and inflammation leading to hepatotoxicity. The study suggests that hesperidin exerts its protective effect against CYP-induced hepatotoxicity through upregulation of hepatic PPARγ expression and abrogation of inflammation and oxidative stress.

  9. Histological and immunohistochemical effects of Curcuma longa on activation of rat hepatic stellate cells after cadmium induced hepatotoxicity.

    PubMed

    El-Mansy, A A; Mazroa, S A; Hamed, W S; Yaseen, A H; El-Mohandes, E A

    2016-01-01

    The liver is a target for toxic chemicals such as cadmium (Cd). When the liver is damaged, hepatic stellate cells (HSC) are activated and transformed into myofibroblast-like cells, which are responsible for liver fibrosis. Curcuma longa has been reported to exert a hepato-protective effect under various pathological conditions. We investigated the effects of C. longa administration on HSC activation in response to Cd induced hepatotoxicity. Forty adult male albino rats were divided into: group 1 (control), group 2 (Cd treated), group 3 (C. longa treated) and group 4 (Cd and C. longa treated). After 6 weeks, liver specimens were prepared for light and electron microscopy examination of histological changes and immunohistochemical localization of alpha smooth muscle actin (αSMA) as a specific marker for activated HSC. Activated HSC with a positive αSMA immune reaction were not detected in groups 1 and 3. Large numbers of activated HSC with αSMA immune reactions were observed in group 2 in addition to Cd induced hepatotoxic changes including excess collagen deposition in thickened portal triads, interlobular septa with hepatic lobulation, inflammatory cell infiltration, a significant increase in Kupffer cells and degenerated hepatocytes. In group 4, we observed a significant decrease in HSC that expressed αSMA with amelioration of the hepatotoxic changes. C. longa administration decreased HSC activation and ameliorated hepatotoxic changes caused by Cd in adult rats.

  10. Upgrading cytochrome P450 activity in HepG2 cells co-transfected with adenoviral vectors for drug hepatotoxicity assessment.

    PubMed

    Tolosa, Laia; Donato, M Teresa; Pérez-Cataldo, Gabriela; Castell, José Vicente; Gómez-Lechón, M José

    2012-12-01

    In a number of adverse drug reactions leading to hepatotoxicity, drug metabolism is thought to be involved by the generation of reactive metabolites from non-toxic drugs. The use of hepatoma cell lines, such as HepG2 cell line, for the evaluation of drug-induced hepatotoxicity is hampered by their low cytochrome P450 expression which makes impossible the study of the toxicity produced by bioactivable compounds. Genetically manipulated cells constitute promising tools for hepatotoxicity applications. HepG2 cells were simultaneously transfected with recombinant adenoviruses encoding CYP1A2, CYP2C9 and CYP3A4 to confer them drug-metabolic competence. Upgraded cells (Adv-HepG2) were highly able to metabolize the toxin studied in contrast to the reduced metabolic capacity of HepG2 cells. Aflatoxin B1-induced hepatotoxicity was studied as a proof of concept in metabolically competent and non-competent HepG2 cells by using high content screening technology. Significant differences in mitochondrial membrane potential, intracellular calcium concentration, nuclear morphology and cell viability after treatment with aflatoxin B1 were observed in Adv-HepG2 when compared to HepG2 cells. Rotenone (non bioactivable) and citrate (non hepatotoxic) were analysed as negative controls. This cell model showed to be a suitable hepatic model to test hepatotoxicity of bioactivable drugs and constitutes a valuable alternative for hepatotoxicity testing. Copyright © 2011 Elsevier Ltd. All rights reserved.

  11. Measuring Cyclic Error in Laser Heterodyne Interferometers

    NASA Technical Reports Server (NTRS)

    Ryan, Daniel; Abramovici, Alexander; Zhao, Feng; Dekens, Frank; An, Xin; Azizi, Alireza; Chapsky, Jacob; Halverson, Peter

    2010-01-01

    An improved method and apparatus have been devised for measuring cyclic errors in the readouts of laser heterodyne interferometers that are configured and operated as displacement gauges. The cyclic errors arise as a consequence of mixing of spurious optical and electrical signals in beam launchers that are subsystems of such interferometers. The conventional approach to measurement of cyclic error involves phase measurements and yields values precise to within about 10 pm over air optical paths at laser wavelengths in the visible and near infrared. The present approach, which involves amplitude measurements instead of phase measurements, yields values precise to about .0.1 microns . about 100 times the precision of the conventional approach. In a displacement gauge of the type of interest here, the laser heterodyne interferometer is used to measure any change in distance along an optical axis between two corner-cube retroreflectors. One of the corner-cube retroreflectors is mounted on a piezoelectric transducer (see figure), which is used to introduce a low-frequency periodic displacement that can be measured by the gauges. The transducer is excited at a frequency of 9 Hz by a triangular waveform to generate a 9-Hz triangular-wave displacement having an amplitude of 25 microns. The displacement gives rise to both amplitude and phase modulation of the heterodyne signals in the gauges. The modulation includes cyclic error components, and the magnitude of the cyclic-error component of the phase modulation is what one needs to measure in order to determine the magnitude of the cyclic displacement error. The precision attainable in the conventional (phase measurement) approach to measuring cyclic error is limited because the phase measurements are af-

  12. Mechanism Profiling of Hepatotoxicity Caused by Oxidative Stress Using Antioxidant Response Element Reporter Gene Assay Models and Big Data

    PubMed Central

    Kim, Marlene Thai; Huang, Ruili; Sedykh, Alexander; Wang, Wenyi; Xia, Menghang; Zhu, Hao

    2015-01-01

    Background: Hepatotoxicity accounts for a substantial number of drugs being withdrawn from the market. Using traditional animal models to detect hepatotoxicity is expensive and time-consuming. Alternative in vitro methods, in particular cell-based high-throughput screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the antioxidant response element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. Objective: The ARE-bla computational model and HTS data from a big data source (PubChem) were used to profile environmental and pharmaceutical compounds with hepatotoxicity data. Methods: Quantitative structure–activity relationship (QSAR) models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when no ARE-bla data were available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the in vitro–in vivo correlations (IVIVCs), the most relevant bioassay(s) related to hepatotoxicity were identified. Results: The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVCs. Conclusion: Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources. Citation: Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H. 2016. Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and

  13. Mechanism Profiling of Hepatotoxicity Caused by Oxidative Stress Using Antioxidant Response Element Reporter Gene Assay Models and Big Data.

    PubMed

    Kim, Marlene Thai; Huang, Ruili; Sedykh, Alexander; Wang, Wenyi; Xia, Menghang; Zhu, Hao

    2016-05-01

    Hepatotoxicity accounts for a substantial number of drugs being withdrawn from the market. Using traditional animal models to detect hepatotoxicity is expensive and time-consuming. Alternative in vitro methods, in particular cell-based high-throughput screening (HTS) studies, have provided the research community with a large amount of data from toxicity assays. Among the various assays used to screen potential toxicants is the antioxidant response element beta lactamase reporter gene assay (ARE-bla), which identifies chemicals that have the potential to induce oxidative stress and was used to test > 10,000 compounds from the Tox21 program. The ARE-bla computational model and HTS data from a big data source (PubChem) were used to profile environmental and pharmaceutical compounds with hepatotoxicity data. Quantitative structure-activity relationship (QSAR) models were developed based on ARE-bla data. The models predicted the potential oxidative stress response for known liver toxicants when no ARE-bla data were available. Liver toxicants were used as probe compounds to search PubChem Bioassay and generate a response profile, which contained thousands of bioassays (> 10 million data points). By ranking the in vitro-in vivo correlations (IVIVCs), the most relevant bioassay(s) related to hepatotoxicity were identified. The liver toxicants profile contained the ARE-bla and relevant PubChem assays. Potential toxicophores for well-known toxicants were created by identifying chemical features that existed only in compounds with high IVIVCs. Profiling chemical IVIVCs created an opportunity to fully explore the source-to-outcome continuum of modern experimental toxicology using cheminformatics approaches and big data sources. Kim MT, Huang R, Sedykh A, Wang W, Xia M, Zhu H. 2016. Mechanism profiling of hepatotoxicity caused by oxidative stress using antioxidant response element reporter gene assay models and big data. Environ Health Perspect 124:634-641;

  14. NMR-based metabonomic analysis of the hepatotoxicity induced by combined exposure to PCBs and TCDD in rats

    SciT

    Lu Chunfeng; Department of Pharmacology, Basic Medical College, Jiamusi University, Jiamusi 154007; Wang Yimei

    2010-11-01

    A metabonomic approach using {sup 1}H NMR spectroscopy was adopted to investigate the metabonomic pattern of rat urine after oral administration of environmental endocrine disruptors (EDs) polychlorinated biphenyls (PCBs) and 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD) alone or in combination and to explore the possible hepatotoxic mechanisms of combined exposure to PCBs and TCDD. {sup 1}H NMR spectra of urines collected 24 h before and after exposure were analyzed via pattern recognition by using principal component analysis (PCA). Serum biochemistry and liver histopathology indicated significant hepatotoxicity in the rats of the combined group. The PCA scores plots of urinary {sup 1}H NMR datamore » showed that all the treatment groups could be easily distinguished from the control group, so could the PCBs or TCDD group and the combined group. The loadings plots of the PCA revealed remarkable increases in the levels of lactate, glucose, taurine, creatine, and 2-hydroxy-isovaleric acid and reductions in the levels of 2-oxoglutarate, citrate, succinate, hippurate, and trimethylamine-N-oxide in rat urine after exposure. These changes were more striking in the combined group. The changed metabolites may be considered possible biomarker for the hepatotoxicity. The present study demonstrates that combined exposure to PCBs and TCDD induced significant hepatotoxicity in rats, and mitochondrial dysfunction and fatty acid metabolism perturbations might contribute to the hepatotoxicity. There was good conformity between changes in the urine metabonomic pattern and those in serum biochemistry and liver histopathology. These results showed that the NMR-based metabonomic approach may provide a promising technique for the evaluation of the combined toxicity of EDs.« less

  15. Quercetin attenuates toosendanin-induced hepatotoxicity through inducing the Nrf2/GCL/GSH antioxidant signaling pathway.

    PubMed

    Jin, Yao; Huang, Zhen-Lin; Li, Li; Yang, Yang; Wang, Chang-Hong; Wang, Zheng-Tao; Ji, Li-Li

    2018-06-19

    Toosendanin (TSN) is the main active compound in Toosendan Fructus and Meliae Cortex, two commonly used traditional Chinese medicines. TSN has been reported to induce hepatotoxicity, but its mechanism remains unclear. In this study, we demonstrated the critical role of nuclear factor erythroid 2-related factor 2 (Nrf2) in protecting against TSN-induced hepatotoxicity in mice and human normal liver L-02 cells. In mice, administration of TSN (10 mg/kg)-induced acute liver injury evidenced by increased serum alanine/aspartate aminotransferase (ALT/AST) and alkaline phosphatase (ALP) activities, and total bilirubin (TBiL) content as well as the histological changes. Furthermore, TSN markedly increased liver reactive oxygen species (ROS) and malondialdehyde (MDA) levels, and decreased liver glutathione (GSH) content and Nrf2 expression. In L-02 cells, TSN (2 μM) time-dependently reduced glutamate-cysteine ligase (GCL) activity and cellular expression of the catalytic/modify subunit of GCL (GCLC/GCLM). Moreover, TSN reduced cellular GSH content and the increased ROS formation, and time-dependently decreased Nrf2 expression and increased the expression of the Nrf2 inhibitor protein kelch-like ECH-associated protein-1 (Keap1). Pre-administration of quercetin (40, 80 mg/kg) effectively inhibited TSN-induced liver oxidative injury and reversed the decreased expression of Nrf2 and GCLC/GCLM in vivo and in vitro. In addition, the quercetin-provided protection against TSN-induced hepatotoxicity was diminished in Nrf2 knock-out mice. In conclusion, TSN decreases cellular GSH content by reducing Nrf2-mediated GCLC/GCLM expression via decreasing Nrf2 expression. Quercetin attenuates TSN-induced hepatotoxicity by inducing the Nrf2/GCL/GSH antioxidant signaling pathway. This study implies that inducing Nrf2 activation may be an effective strategy to prevent TSN-induced hepatotoxicity.

  16. Protective effect of ALDH2 against cyclophosphamide-induced acute hepatotoxicity via attenuating oxidative stress and reactive aldehydes.

    PubMed

    Zhai, Xiaoxuan; Zhang, Zhenxiao; Liu, Wenwen; Liu, Baoshan; Zhang, Rui; Wang, Wenjun; Zheng, Wen; Xu, Feng; Wang, Jiali; Chen, Yuguo

    2018-04-30

    Cyclophosphamide (CY) is a widely used chemotherapeutic agent that is associated with severe side effects, such as hepatotoxicity and nephrotoxicity. However, the extent, mechanisms and potential prevention and treatment strategies of CY-induced acute hepatotoxicity and nephrotoxicity are largely unknown. In this study, we determined the existence and extent of CY-induced acute hepatotoxicity and nephrotoxicity, and demonstrated the effect of ALDH2 on CY-induced acute tissue toxicity and related mechanisms. Adult male C57BL/6J (wide-type, WT) and ALDH2 -/- (KO) mice were divided into four groups: WT, WT + CY, KO + CY and WT + CY + Alda-1. Biochemical analysis showed that plasma ALT was increased by 35.8% in KO + CY group and decreased by 21.1% in WT + CY + Alda-1 group compared to WT + CY group (P < 0.05, respectively). However, there was no significant difference among WT, WT + CY and KO + CY groups regarding plasma renal marker enzymes, including blood urea nitrogen (BUN), creatinine and cystatin C (CysC). Levels of reactive oxygen species (ROS) and toxic aldehydes (acrolein, 4-hydroxynonenol and malondialdehyde) were increased significantly in KO + CY group and decreased significantly in WT + CY + Alda-1 group compared to WT + CY group (P < 0.05, respectively). These findings demonstrate that CY could induce acute hepatotoxicity without nephrotoxicity, and ALDH2 plays a protective role in CY-induced acute hepatotoxicity. The underlying mechanisms are associated with attenuating oxidative stress and detoxifying reactive aldehydes. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Effect of goat milk on hepatotoxicity induced by antitubercular drugs in rats.

    PubMed

    Miglani, Sonam; Patyar, Rakesh Raman; Patyar, Sazal; Reshi, Mohammad Rafi

    2016-10-01

    Aim of the present study was to assess the hepatoprotective activity of goat milk on antitubercular drug-induced hepatotoxicity in rats. Hepatotoxicity was induced in rats using a combination of isoniazid, rifampicin, and pyrazinamide given orally as a suspension for 30 days. Treatment groups received goat milk along with antitubercular drugs. Liver damage was assessed using biochemical and histological parameters. Administration of goat milk (20 mL/kg) along with antitubercular drugs (Group III) reversed the levels of serum alanine aminotransferase (82 ± 25.1 vs. 128.8 ± 8.9 units/L) and aspartate aminotransferase (174.7 ± 31.5 vs. 296.4 ± 56.4 units/L, p<0.01) compared with antitubercular drug treatment Group II. There was a significant decrease in serum alanine aminotransferase (41.8 ± 4.1 vs. 128.8 ± 8.9 ​ units/L, p<0.01) and aspartate aminotransferase (128.8 ± 8.54 vs. 296.4 ± 56.4 units/L, p<0.001) levels in Group IV (goat milk 40 mL/kg) compared with antitubercular drug treatment Group II. Goat milk (20 mL/kg and 40 mL/kg) was effective in reversing the rise in malondialdehyde level compared with the antitubercular drug suspension groups (58.5 ± 2 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p<0.001 and 69.7 ± 0.78 vs. 89.88 ± 2.42 μmol/mL of tissue homogenate, p<0.001, respectively). Similarly, both doses of milk significantly prevented a fall in superoxide dismutase level (6.23 ± 0.29 vs. 3.1 ± 0.288 units/mL, p<0.001 and 7.8 ± 0.392 vs. 3.1 ± 0.288 units/mL, p<0.001) compared with the group receiving antitubercular drugs alone. Histological examination indicated that goat milk reduced inflammation and necrotic changes in hepatocytes in the treatment groups. The results indicated that goat milk prevented the antitubercular drug-induced hepatotoxicity and is an effective hepatoprotective agent. Copyright © 2016. Published by Elsevier B.V.

  18. Influence of caffeine on allyl alcohol-induced hepatotoxicity in rats. I. In vivo study.

    PubMed

    Karas, M; Chakrabarti, S K

    2001-01-01

    Cotreatment of rats with a low hepatotoxic dose (30.7 mg/kg, i.p.) of allyl alcohol (AA) and a higher, but nontoxic, dose (150 mg/kg, oral) of caffeine (CF) potentiated the hepatotoxicity of AA. This was verified by significantly higher levels of plasma alanine aminotransferase (ALT) activity and histopathologically greater severity of lesions in the periportal hepatocytes than those due to AA alone. Treatment of rats with 4-methylpyrazole (4-MP) (0.5 mmol/kg, i.p.) (an inhibitor liver alcohol dehydrogenase) for 30 minutes, followed by similar cotreatment with AA and CF, completely prevented the elevation of plasma levels of ALT and histological damage induced by cotreatment with CF and AA 24 hours following their administration. Severe liver damage induced by cotreatment with CF and AA was further, markedly enhanced by phenobarbital pretreatment (80 mg/kg, i.p., 3 days). Thus, extensive necrosis of periportal hepatocytes was noted, as well as edema and accumulation of inflammatory cells in the necrotic foci caused by such pretreatment. The depression of hepatic nonprotein sulfhydryls resulting from CF plus AA was much more severe than that caused by AA or CF alone and appeared as early as 30 minutes after administration. However, much less marked depletion of protein thiols was observed following similar treatments. Significant increase in lipid peroxidation (as measured by melondialdehyde [MDA] formation) was also observed in rat liver but only 24 hours after administration. The production ofMDA in the rat liver was significantly higher after administration of AA plus CF than after administration of AA alone. Pretreatment of rats with phenobarbital further significantly enhanced the formation of 2,4-dinitrophenylhydrazine (DNP)-reactive metabolite(s) (measured as DNP-acrolein adduct equivalents) in rat liver induced by AA (30.7 mg/kg) plus CF (150 mg/kg) within 1 hour following such treatment. Cotreatment with AA and a higher dose of CF resulted in significantly

  19. Hepatotoxic mycotoxins

    Aflatoxins are produced by Aspergillus species including A. flavus and A. parasiticus. Fumonisins are produced by Fusarium species, mainly F. verticillioides and F. parasiticus. These mycotoxins are common contaminants of commodities and have been shown to co-contaminate corn. Aflatoxins are know...

  20. Down-regulation of angiotensin II receptor subtypes and desensitization of cyclic GMP production in neuroblastoma N1E-115 cells.

    PubMed

    Reagan, L P; Ye, X; Maretzski, C H; Fluharty, S J

    1993-01-01

    Murine neuroblastoma N1E-115 cells possess membranous receptors for the octapeptide angiotensin II (AngII) whose density is substantially increased by in vitro differentiation. Incubation of differentiated N1E-115 cells with AngII produced a rapid decrease in receptor density, but did not alter the affinity of these receptors for either 125I-AngII or the high-affinity antagonist 125I-[Sarc1,Ile8]-AngII. This apparent down-regulation was dose related with an ED50 of 1 nM, and maximal decreases of approximately 90% were obtained with 100 nM AngII. Receptor loss from differentiated cell membranes was unaffected by incubations of membranes obtained from agonist-exposed cells with non-hydrolyzable analogues of GTP for 60 min at 37 degrees C to ensure dissociation of the ligand. Partial loss of AngII receptors was apparent within 5 min of agonist exposure, whereas maximal declines were not observed until 30 min. This temporal pattern resulted from a preferential decrease in the AT1 receptor subtype during the first 5 min, followed by a decline in both AT1 and AT2 receptors with longer periods of agonist exposure. The loss of membranous receptors was reversible with partial recovery observed after 4 h, and with nearly full recovery observed 18 h after exposure of the cells to AngII. However, the long-term recovery of receptor density was blocked by the protein synthesis inhibitor, cycloheximide. The heptapeptide angiotensin III produced a similar down-regulation of receptors, and the high-affinity antagonist [Sarc1,Thr8]-AngII blocked agonist-induced down-regulation. Finally, the apparent loss of cell surface AngII receptors decreased the ability of AngII to stimulate cyclic GMP production within intact N1E-115 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Halothane hepatotoxicity and the reduced derivative, 1,1,1-trifluoro-2-chloroethane.

    PubMed Central

    Brown, B R; Sipes, I G; Baker, R K

    1977-01-01

    Halothane (1,1,1-trifluoro-2-bromo-2-chloroethane) is a safe, clinically useful inhalation anesthetic. Rare, unpredictable cases of liver necrosis have been reported following its use. Although the mechanism of this reaction in man is unknown the most plausible is biotransformation to reactive intermediates compounds. The oxidative metabolism of halothane appears to be benign. There is early evidence that reductive (nonoxygen dependent) may be harmful. Since the bromine atom of halothane appears to possess weak bond energy, the reduced, debrominated derivative of halothane, 1,1,1-trifluoro-2-chloroethane, was synthesized and tested for hepatotoxicity in the rat. The derivative is unstable and thus was prepared anaerobically and trapped in propylene glycol solvent. Injection of small amounts of this compound into the portal vein of rats produces extensive liver necrosis. It is postulated that biotransformation of halothane via a reductive pathway could produce this reactive intermediate metabolite. Images FIGURE 1. PMID:612444

  2. Circulating microRNA profiles in human patients with acetaminophen hepatotoxicity or ischemic hepatitis.

    PubMed

    Ward, Jeanine; Kanchagar, Chitra; Veksler-Lublinsky, Isana; Lee, Rosalind C; McGill, Mitchell R; Jaeschke, Hartmut; Curry, Steven C; Ambros, Victor R

    2014-08-19

    We have identified, by quantitative real-time PCR, hundreds of miRNAs that are dramatically elevated in the plasma or serum of acetaminophen (APAP) overdose patients. Most of these circulating microRNAs decrease toward normal levels during treatment with N-acetyl cysteine (NAC). We identified a set of 11 miRNAs whose profiles and dynamics in the circulation during NAC treatment can discriminate APAP hepatotoxicity from ischemic hepatitis. The elevation of certain miRNAs can precede the dramatic rise in the standard biomarker, alanine aminotransferase (ALT), and these miRNAs also respond more rapidly than ALT to successful treatment. Our results suggest that miRNAs can serve as sensitive diagnostic and prognostic clinical tools for severe liver injury and could be useful for monitoring drug-induced liver injury during drug discovery.

  3. Recent Updates on Acetaminophen Hepatotoxicity: The Role of Nrf2 in Hepatoprotection

    PubMed Central

    Gum, Sang Il

    2013-01-01

    Acetaminophen (APAP) known as paracetamol is the main ingredient in Tylenol, which has analgesic and anti-pyretic properties. Inappropriate use of APAP causes major morbidity and mortality secondary to hepatic failure. Overdose of APAP depletes the hepatic glutathione (GSH) rapidly, and the metabolic intermediate leads to hepatocellular death. This article reviews the mechanisms of hepatotoxicity and provides an overview of current research studies. Pharmacokinetics including metabolism (activation and detoxification), subsequent transport (efflux)-facilitating excretion, and some other aspects related to toxicity are discussed. Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated gene battery plays a critical role in the multiple steps associated with the mitigation of APAP toxicity. The role of Nrf2 as a protective target is described, and potential natural products inhibiting APAP toxicity are outlined. This review provides an update on the mechanism of APAP toxicity and highlights the beneficial role of Nrf2 and specific natural products in hepatoprotection. PMID:24386516

  4. Cyclic and low temperature effects on microcircuits

    NASA Technical Reports Server (NTRS)

    Weissflug, V. A.; Sisul, E. V.

    1977-01-01

    Cyclic temperature and low temperature operating life tests, and pre-/post-life device evaluations were used to determine the degrading effects of thermal environments on microcircuit reliability. Low power transistor-transistor-logic gates and linear devices were included in each test group. Device metallization systems included aluminum metallization/aluminum wire, aluminum metallization/gold wire, and gold metallization/gold wire. Fewer than 2% electrical failures were observed during the cyclic and low temperature life tests and the post-life evaluations revealed approximately 2% bond pull failures. Reconstruction of aluminum die metallization was observed in all devices and the severity of the reconstruction appeared to be directly related to the magnitude of the temperature excursion. All types of bonds except the gold/gold bonds were weakened by exposure to repeated cyclic temperature stress.

  5. Evaluation of homogeneous electrocatalysts by cyclic voltammetry.

    PubMed

    Rountree, Eric S; McCarthy, Brian D; Eisenhart, Thomas T; Dempsey, Jillian L

    2014-10-06

    The pursuit of solar fuels has motivated extensive research on molecular electrocatalysts capable of evolving hydrogen from protic solutions, reducing CO2, and oxidizing water. Determining accurate figures of merit for these catalysts requires the careful and appropriate application of electroanalytical techniques. This Viewpoint first briefly presents the fundamentals of cyclic voltammetry and highlights practical experimental considerations before focusing on the application of cyclic voltammetry for the characterization of electrocatalysts. Key metrics for comparing catalysts, including the overpotential (η), potential for catalysis (E(cat)), observed rate constant (k(obs)), and potential-dependent turnover frequency, are discussed. The cyclic voltammetric responses for a general electrocatalytic one-electron reduction of a substrate are presented along with methods to extract figures of merit from these data. The extension of this analysis to more complex electrocatalytic schemes, such as those responsible for H2 evolution and CO2 reduction, is then discussed.

  6. Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats

    PubMed Central

    El-Hosseiny, L. S.; Alqurashy, N. N.; Sheweita, S. A.

    2016-01-01

    Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats’ liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes’ activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition. PMID:27493593

  7. Deltamethrin-Induced Hepatotoxicity and Virgin Olive Oil Consumption: An Experimental Study.

    PubMed

    Khalatbary, Ali Reza; Ghabaee, Davood Nasiry Zarrin; Ahmadvand, Hassan; Amiri, Fereshteh Talebpour; Lehi, Somaieh Tadayoni

    2017-11-01

    Deltamethrin (DM) is a synthetic pyrethroid insecticide which can lead to pathological effects in mammals through oxidative stress. On the other hand, virgin olive oil (VOO) is a rich source of phenolic compounds with antioxidants. The aim of the present study was to determine the protective effects of VOO against DM-induced hepatotoxicity. Thirty-six mice were randomly separated into 4 groups: vehicle group, VOO group, DM group, and DM plus VOO group. Immunohistochemistry of PARP, COX-2, and caspase-3 with the biochemical analysis of malondialdehyde and total antioxidant capacity levels were performed in the liver samples 5 weeks after gavaging. Statistical analysis was performed using SPSS, version 15. The data were compared between the groups using the Tukey multiple comparison tests and the analysis of the variance. A P value <0.05 was considered significant. The malondialdehyde level in the liver was increased in the DM group (71.18±0.01), whereas it was significantly (P=0.001) decreased after VOO administration in the DM plus VOO group (39.59±2.43). While the total antioxidant capacity level in the liver was decreased in the DM group (3.05±0.05), it was significantly increased (P=0.03) after VOO administration in the DM plus VOO group (3.95±0.04). A greater expression of caspase-3 (P=0.008), COX-2 (P =0.004), and PARP (P 0.006) could be detected in the DM group, while it was significantly (P=0.009) attenuated in the DM plus VOO group. Also, the degeneration of hepatocytes, which was detected in the DM group, was attenuated after VOO consumption. VOO exerted protective effects against DM-induced hepatotoxicity, which might be associated with its anti-apoptotic, anti-inflammatory, and antioxidative properties.

  8. Characterizing the mechanism of thiazolidinedione-induced hepatotoxicity: An in vitro model in mitochondria

    SciT

    Hu, Dan; Wu, Chun-qi; Li, Ze-jun

    Objective: To characterize the mechanism of action of thiazolidinedione (TZD)-induced liver mitochondrial toxicity caused by troglitazone, rosiglitazone, and pioglitazone in HepaRG cells. Methods: Human hepatoma cells (HepaRG) were treated with troglitazone, rosiglitazone, or pioglitazone (12.5, 25, and 50 μM) for 48 h. The Seahorse Biosciences XF24 Flux Analyzer was used to measure mitochondrial oxygen consumption. The effect of TZDs on reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected by flow cytometry. The mitochondrial ultrastructure of HepaRG cells was observed under a transmission electrical microscope (TEM). mtDNA content was evaluated by real-time PCR, and ATP content and mitochondrialmore » respiratory chain (MRC) complex I, II, III, IV activity were measured via chemiluminescence. Results were considered statistically significant at p < 0.05. Results: Among the three drugs, troglitazone exhibited the highest potency, followed by rosiglitazone, and then pioglitazone. The TZDs caused varying degrees of mitochondrial respiratory function disorders including decreases in oxygen consumption, MRC activity, and ATP level, and an elevation in ROS level. TZD treatment resulted in mtDNA content decline, reduction in MMP, and alterations of mitochondrial structure. Conclusion: All investigated TZDs show a certain degree of mitochondrial toxicity, with troglitazone exhibiting the highest potency. The underlying mechanism of TZD-induced hepatotoxicity may be associated with alterations in mitochondrial respiratory function disorders, oxidative stress, and changes in membrane permeability. These parameters may be used early in drug development to further optimize risk:benefit profiles. - Highlights: • We compared three TZD mitochondrial toxicity characteristics in HepaRG cells. • TZD induced respiratory disorders and mitochondrial structural damage. • Mitochondrial toxicity evaluation presents guidance value for

  9. Urate synthesis and oxidative stress in phenytoin hepatotoxicity: the role of antioxidant vitamins.

    PubMed

    Ekaidem, Itemobong S; Usoh, Itoro F; Akpanabiatu, Monday I; Uboh, Friday E; Akpan, Henry D

    2014-11-01

    Phenytoin is known to induce microsomal enzymes including xanthine oxidase which catalyzes uric acid synthesis with superoxides as byproducts, thus contributing to the oxidative stress of phenytoin hepatotoxicity. To investigate the role of antioxidant vitamins in ameliorating phenytoin induced hepatic changes through possible actions on xanthine oxidase activities as measured by urate concentration. Growing albino rats of Wistar strain were randomly divided into 8 groups of 7 rats each. Group 2, 3, 4, 5, 6, 7 and 8 were treated with phenytoin alone, phenytoin + folic acid, phenytoin + vitamin E, phenytoin + vitamin E + vitamin C, phenytoin + vitamin C, phenytoin + folic acid + vitamin E and phenytoin + vitamin E + vitamin C + folic acid respectively while animals in group 1 were given normal saline to serve as control. Serum concentrations of uric acid, albumin, total protein and the activities of aspartate and alanine aminotransferases (AST and ALT) and catalase were measured spectrophotometrically using appropriate commercial reagent kits. Result showed that administration of phenytoin alone caused significant (p < 0.05) increase in serum levels of globulin, uric acid, AST and ALT activities while the levels of albumin and catalase were reduced significantly (p < 0.05). Supplementation of phenytoin treatment with vitamins resulted in various degrees of protection. However, the elevated level of uric acid in serum was not significantly (p < 0.05) affected by any of the vitamins used and there was no significant correlation between the activities of aminotransferases and uric acid concentration in the vitamin treated animals as was observed between aminotransferases and catalase. The findings in this study suggest that antioxidant vitamins were able to ameliorate phenytoin hepatotoxic effects by improving oxidant radicals removal in the animals but would not inhibit further generation of the superoxides by xanthine oxidase activity and that xanthine oxidase may

  10. Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ - Hawaii, 2013.

    PubMed

    Johnston, David I; Chang, Arthur; Viray, Melissa; Chatham-Stephens, Kevin; He, Hua; Taylor, Ethel; Wong, Linda L; Schier, Joshua; Martin, Colleen; Fabricant, Daniel; Salter, Monique; Lewis, Lauren; Park, Sarah Y

    2016-01-01

    Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro™ (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases' medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and traceback, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

  11. Protective Effect of Propolis in Proteinuria, Crystaluria, Nephrotoxicity and Hepatotoxicity Induced by Ethylene Glycol Ingestion.

    PubMed

    El Menyiy, Nawal; Al Waili, Noori; Bakour, Meryem; Al-Waili, Hamza; Lyoussi, Badiaa

    2016-10-01

    Propolis is a natural honeybee product with wide biological activities and potential therapeutic properties. The aim of the study is to evaluate the protective effect of propolis extract on nephrotoxicity and hepatotoxicity induced by ethylene glycol in rats. Five groups of rats were used. Group 1 received drinking water, group 2 received 0.75% ethylene-glycol in drinking water, group 3 received 0.75% ethylene-glycol in drinking water along with cystone 500 mg/kg/body weight (bw) daily, group 4 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 100 mg/kg/bw daily, and group 5 received 0.75% ethylene-glycol in drinking water along with propolis extract at a dose of 250 mg/kg/bw daily. The treatment continued for a total of 30 d. Urinalyses for pH, crystals, protein, creatinine, uric acid and electrolytes, and renal and liver function tests were performed. Ethylene-glycol increased urinary pH, urinary volume, and urinary calcium, phosphorus, uric acid and protein excretion. It decreased creatinine clearance and magnesium and caused crystaluria. Treatment with propolis extract or cystone normalized the level of magnesium, creatinine, sodium, potassium and chloride. Propolis is more potent than cystone. Propolis extract alleviates urinary protein excretion and ameliorates the deterioration of liver and kidney function caused by ethylene glycol. Propolis extract has a potential protective effect against ethylene glycol induced hepatotoxicity and nephrotoxicity and has a potential to treat and prevent urinary calculus, crystaluria and proteinuria. Copyright © 2016 IMSS. Published by Elsevier Inc. All rights reserved.

  12. Pregnane X Receptor-Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity.

    PubMed

    Spruiell, Krisstonia; Gyamfi, Afua A; Yeyeodu, Susan T; Richardson, Ricardo M; Gonzalez, Frank J; Gyamfi, Maxwell A

    2015-09-01

    Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXR-humanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor α, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females. U.S. Government work not protected by U.S. copyright.

  13. Hepatotoxicity associated with the dietary supplement OxyELITE Pro™ — Hawaii, 2013

    PubMed Central

    Johnston, David I.; Chang, Arthur; Viray, Melissa; Chatham-Stephens, Kevin; He, Hua; Taylor, Ethel; Wong, Linda L.; Schier, Joshua; Martin, Colleen; Fabricant, Daniel; Salter, Monique; Lewis, Lauren; Park, Sarah Y.

    2015-01-01

    Dietary supplements are increasingly marketed to and consumed by the American public for a variety of purported health benefits. On 9 September 2013, the Hawaii Department of Health (HDOH) was notified of a cluster of acute hepatitis and fulminant hepatic failure among individuals with exposure to the dietary supplement OxyELITE Pro™ (OEP). HDOH conducted an outbreak investigation in collaboration with federal partners. Physicians were asked to report cases, defined as individuals with acute onset hepatitis of unknown etiology on or after 1 April 2013, a history of weight-loss/muscle-building dietary supplement use during the 60 days before illness onset, and residence in Hawaii during the period of exposure. Reported cases’ medical records were reviewed, questionnaires were administered, and a product investigation, including chemical analyses and trace back, was conducted. Of 76 reports, 44 (58%) met case definition; of these, 36 (82%) reported OEP exposure during the two months before illness. No other common supplements or exposures were observed. Within the OEP-exposed subset, two patients required liver transplantation, and a third patient died. Excessive product dosing was not reported. No unique lot numbers were identified; there were multiple mainland distribution points, and lot numbers common to cases in Hawaii were also identified in continental states. Product analysis found consumed products were consistent with labeled ingredients; the mechanism of hepatotoxicity was not identified. We report one of the largest statewide outbreaks of dietary supplement-associated hepatotoxicity. The implicated product was OEP. The increasing popularity of dietary supplements raises the potential for additional clusters of dietary supplement-related adverse events. PMID:26538199

  14. Hepatotoxicity of kaurene glycosides from Xanthium strumarium L. fruits in mice.

    PubMed

    Wang, Yang; Han, Ting; Xue, Li-Ming; Han, Ping; Zhang, Qiao-Yan; Huang, Bao-Kang; Zhang, Hong; Ming, Qian-Liang; Peng, Wei; Qin, Lu-Ping

    2011-06-01

    The fruit of Xanthium strumarium L. (Cang-Er-Zi) is a traditional Chinese medicine that is used in curing nasal diseases and headache according to the Chinese Pharmacopoeia. However, clinical utilization of Xanthium strumarium is relatively limited because of its toxicity. The present investigation was carried out to evaluate the toxic effects on acute liver injury in mice of the two kaurene glycosides (atractyloside and carbxyatractyloside), which are main toxic constituents isolated from Fructus Xanthii on acute liver injury in mice. Histopathological examinations revealed that there were not obviously visible injury in lungs, heart, spleen, and the central nervous system in the mice by intraperitoneal injection of atractyloside (ATR, at the doses 50,125 and 200 mg/kg) and carbxyatractyloside (CATR, at the doses 50,100 and 150 mg/kg) for 5 days. However, it revealed extensive liver injuries compared with the normal group. In the determination of enzyme levels in serum, intraperitoneal injection of ATR and CATR resulted in significantly elevated serum alanine aminotransferase (ALT), asparate aminotransferase (AST), alkaline phosphatase (ALP) activities compared to controls. In the hepatic oxidative stress level, antioxidant-related enzyme activity assays showed that ATR and CATR administration significantly increased hepatic malondialdehyde (MDA) concentration, as well as decreased superoxide dismutase (SOD), catalase (CAT) activities and glutathione (GSH) concentration, and this was in good agreement with the results of serum aminotransferase activity and histopathological examinations. Taken together, our results demonstrate that kaurene glycosides induce hepatotoxicity in mice by way of its induction of oxidative stress as lipid peroxidation in liver, which merited further studies. Therefore, these toxic constituents explain, at least in part, the hepatotoxicity of X. strumarium L. in traditional medicine.

  15. Chloroform ingestion causing severe gastrointestinal injury, hepatotoxicity and dermatitis confirmed with plasma chloroform concentrations.

    PubMed

    Jayaweera, Dushan; Islam, Shawkat; Gunja, Naren; Cowie, Chris; Broska, James; Poojara, Latesh; Roberts, Michael S; Isbister, Geoffrey K

    2017-02-01

    Poisoning due to chloroform ingestion is rare. The classic features of acute chloroform toxicity include central nervous system (CNS) and respiratory depression, and delayed hepatotoxicity. A 30-year-old female ingested 20-30 mL of 99% chloroform solution, which caused rapid loss of consciousness, transient hypotension and severe respiratory depression requiring endotracheal intubation and ventilation. She was alert by 12 h and extubated 16 h post-overdose. At 38-h post-ingestion, her liver function tests started to rise and she was commenced on intravenous acetylcysteine. Her alanine transaminase (1283 U/L), aspartate transaminase (734 U/L) and international normalized ratio (2.3) peaked 67- to 72-h post-ingestion. She also developed severe abdominal pain, vomiting and diarrhoea. An abdominal CT scan was consistent with severe enterocolitis, and an upper gastrointestinal endoscopy showed erosive oesophagitis, severe erosive gastritis and ulceration. She was treated with opioid analgesia, proton pump inhibitors, sucralfate and total parenteral nutrition. Secretions caused a contact dermatitis of her face and back. Nine days post-ingestion she was able to tolerate food. Her liver function tests normalized and the dermatitis resolved. Chloroform was measured using headspace gas chromatograph mass spectrometry, with a peak concentration of 2.00 μg/mL, 4 h 20 min post-ingestion. The concentration-time data fitted a 1-compartment model with elimination half-life 6.5 h. In addition to early CNS depression and delayed hepatotoxicity, we report severe gastrointestinal injury and dermatitis with chloroform ingestion. Recovery occurred with good supportive care, acetylcysteine and management of gastrointestinal complications.

  16. Oxidative Stress Alleviation by Sage Essential Oil in Co-amoxiclav induced Hepatotoxicity in Rats.

    PubMed

    El-Hosseiny, L S; Alqurashy, N N; Sheweita, S A

    2016-06-01

    Clinical studies have shown that several classes of antibiotics are evidenced in drug induced liver injury. The combination of amoxicillin with clavulanic acid is commonly cited in such cases. Accordingly, the present study investigated the potential hepatoprotective and in vivo antioxidant efficacy of sage essential oil in Co-amoxiclav induced hepatotoxicity in rats. Sage essential oil was hydrodistilled from the aerial parts of Salvia officinalis L. and its compositional analysis was characterized by Gas chromatography-Mass spectroscopy. Rats were treated singly or concomitantly with Co-amoxiclav and sage essential oil for a period of seven days. The major components of sage oil as identified by GC-MS were 1,8-cineole, β-pinene, camphor, β-caryophyllene, α-pinene and α-caryophyllene comprising 26.3%, 14.4%, 10.9%, 7.8%, 6% and 2.5% respectively. The in vivo exposure of rats to Co-amoxiclav resulted in hepatotoxicity biochemically evidenced by the significant elevation of serum AST, ALT, ALP, γ-GT, total bilirubin and histologically conveyed by hydropic, inflammatory and cholestatic changes in rats' liver. Oxidative stress mediated the hepatic injury as indicated by the significant escalation in lipid peroxidation, as well as, the significant depletion of both glutathione level and glutathione dependent enzymes' activities. The concomitant administration of sage essential oil with Co-amoxiclav exerted a hepatoprotective effect via inducing an in vivo antioxidant defense response eventually regressing, to some extent, the hepatoarchitectural changes induced by Co-amoxiclav. Results suggest that sage essential oil is a potential candidate for counteracting hepatic injury associating Co-amoxiclav and this effect is in part related to the complexity of its chemical composition.

  17. Modulatory Effect of Methanol Extract of Piper guineense in CCl₄-Induced Hepatotoxicity in Male Rats.

    PubMed

    Oyinloye, Babatunji Emmanuel; Osunsanmi, Foluso Oluwagbemiga; Ajiboye, Basiru Olaitan; Ojo, Oluwafemi Adeleke; Kappo, Abidemi Paul

    2017-08-24

    This study seeks to investigate the possible protective role of the methanol extract of Piper guineense seeds against CCl₄-induced hepatotoxicity in an animal model. Hepatotoxicity was induced by administering oral doses of CCl₄ (1.2 g/kg bw) three times a week for three weeks. Group 1 (Control) and Group 2 (CCl₄) were left untreated; Piper guineense (PG; 400 mg/kg bw) was administered to Group 3 (T₁) by oral gavage for 14 days prior to the administration of CCl₄ and simultaneously with CCl₄; PG (400 mg/kg bw) was administered simultaneously with CCl₄ in Group 4 (T₂); and Livolin forte (20 mg/kg bw) was administered simultaneously with CCl₄ in Group 5 (T₃), the standard drug group. The administration of CCl₄ induces histopathological alteration in the liver, with concomitant increased activities of serum hepatic marker enzymes associated with increased levels of lipid peroxidation. Similarly, there was decrease in non-enzymatic (reduced glutathione) and enzymatic antioxidants (glutathione S-transferase), superoxide dismutase, and catalase. An elevation in serum triglyceride and total cholesterol levels was noticed along with decreased levels of serum total protein. Treatment with PG 400 mg/kg bw exhibited excellent modulatory activity with respect to the different parameters studied by reversing all the above-mentioned biochemical changes significantly in the experimental animals. These results suggest that PG offered protection comparable to that of Livolin forte with better efficacy when pre-treated with 400 mg/kg bw 14 days prior to CCl₄-exposure.

  18. The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats.

    PubMed

    Gelen, Volkan; Şengül, Emin; Yıldırım, Serkan; Atila, Gözde

    2018-04-01

    5-fluorouracil-induced (5-FU), an anticarcinogenic agent, is reported to have side-effects that include hepatotoxicity and nephrotoxicity. The study objective was to investigate the protective effects of naringin on 5-FU-induced hepatotoxicity and nephrotoxicity. Thirty rodents were assigned to three groups. The control group received 1 ml of intragastric distilled water for 14 days. The 5-FU group received 1 ml of distilled water for 14 days as a placebo. On day 9, this same group received a 20 mg/kg dose of 5-FU administered intraperitoneally(IP) for a further five days. The naringin+5-FU group received a 100 mg/kg dose of naringin (IP) for 14 days. On day 9, 20 mg/kg of 5-FU was administered (IP) to this group for a further five days. On day 15, the rats were decapitated, and blood and renal and hepatic tissues were taken. It was determined that serum creatinine, BUN, AST, ALT, ALP, and LDH levels, as well as cytokine levels in the liver and kidney tissues were significantly elevated in the 5-FU group, compared to the control group. The comparative values were similar in the control and naringin+5-FU groups. When the liver tissue was examined histopathologically, in the control group it was found to be normal in structure. However, necrosis was observed in the hepatocytes of the pericentric region in the 5-FU group. 8-OHdG cell density was significantly elevated in the 5-FU group, compared to the control and naringin+5-FU groups. Naringin was observed to have a protective effect on 5-FU-induced liver and kidney damage.

  19. The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats

    PubMed Central

    Gelen, Volkan; Şengül, Emin; Yıldırım, Serkan; Atila, Gözde

    2018-01-01

    Objective(s): 5-fluorouracil-induced (5-FU), an anticarcinogenic agent, is reported to have side-effects that include hepatotoxicity and nephrotoxicity. The study objective was to investigate the protective effects of naringin on 5-FU-induced hepatotoxicity and nephrotoxicity. Materials and Methods: Thirty rodents were assigned to three groups. The control group received 1 ml of intragastric distilled water for 14 days. The 5-FU group received 1 ml of distilled water for 14 days as a placebo. On day 9, this same group received a 20 mg/kg dose of 5-FU administered intraperitoneally(IP) for a further five days. The naringin+5-FU group received a 100 mg/kg dose of naringin (IP) for 14 days. On day 9, 20 mg/kg of 5-FU was administered (IP) to this group for a further five days. On day 15, the rats were decapitated, and blood and renal and hepatic tissues were taken. Results: It was determined that serum creatinine, BUN, AST, ALT, ALP, and LDH levels, as well as cytokine levels in the liver and kidney tissues were significantly elevated in the 5-FU group, compared to the control group. The comparative values were similar in the control and naringin+5-FU groups. When the liver tissue was examined histopathologically, in the control group it was found to be normal in structure. However, necrosis was observed in the hepatocytes of the pericentric region in the 5-FU group. 8-OHdG cell density was significantly elevated in the 5-FU group, compared to the control and naringin+5-FU groups. Conclusion: Naringin was observed to have a protective effect on 5-FU-induced liver and kidney damage. PMID:29796225

  20. Nephrotoxicity and hepatotoxicity evaluation of Crocus sativus stigmas in neonates of nursing mice

    PubMed Central

    Bahmani, Mahmoud; Rafieian, Mortaza; Baradaran, Azar; Rafieian, Samira; Rafieian-kopaei, Mahmoud

    2014-01-01

    Background: Crocus sativus, known as saffron crocus, is best known for the spice saffron. Saffron use spans more than 3500 years, however, its toxicity on neonates during lactation has not yet evaluated. Objectives: This study was aimed to examine the acute toxicity of saffron on adult mice and its nephrotoxicity and hepatotoxicity on neonates of lactating mothers that used saffron during lactation. Materials and Methods: In this experimental study, following acute toxicity evaluation, 32 pregnant mice were randomly designated into four equal groups. Following delivery, the mothers of groups 1 to 4 were administered orally (by gavage) normal saline (control group), 500, 1000 or 2000 mg/kg/day of saffron for three weeks, respectively. The newborn’s kidney and liver parameters were assessed at the end of the study for possible nephrotoxicity and hepatotoxicity evaluation. The kidney and liver tissue samples of newborns were histopathologically studied after staining with Hematoxylin & Eosin. Data were analyzed using ANOVA and Scheffe’s tests Results: The LD50 value of saffron was calculated to be 4120±556 mg/kg in mice. To evaluate lactating toxicity, saffron was administered orally to the mothers once daily for 21 days, after delivery, during lactating period. Saffron increased serum urea nitrogen (p< 0.05). Histological studies indicated that saffron did not have any toxic effect on liver, however, histopathology changes were seen in the kidney of neonates. Conclusions: From the results of present study, it might be concluded that saffron is a nearly safe spice, however, nursing mothers should avoid high doses of this spice. PMID:24772401

  1. Protective effect of Selenium nanoparticle against cyclophosphamide induced hepatotoxicity and genotoxicity in Swiss albino mice.

    PubMed

    Bhattacharjee, Arin; Basu, Abhishek; Ghosh, Prosenjit; Biswas, Jaydip; Bhattacharya, Sudin

    2014-08-01

    Cyclophosphamide (CP) is the most commonly used chemotherapeutic drug for various types of cancer. However, its use causes severe cytotoxicity to normal cells in human. It is well known that the undesirable side effects are caused due to the formation of reactive oxygen species. Selenium is an essential micronutrient for both animals and humans and has antioxidant and membrane stabilizing property, but selenium is also toxic above certain level. Nano selenium has been well proved to be less toxic than inorganic selenium as well as certain organoselenium compounds. The objective of the study is to evaluate the protective role of Nano-Se against CP-induced hepatotoxicity and genotoxicity in Swiss albino mice. CP was administered intraperitoneally (25 mg/kg b.w.) and Nano-Se was given by oral gavages (2 mg Se/kg b.w.) in concomitant and pretreatment scheme. Intraperitoneal administration of CP induced hepatic damage as indicated by the serum marker enzymes aspartate and alanine transaminases and increased the malonaldehyde level, depleted the glutathione content and antioxidant enzyme activity (glutathione peroxidase, glutathione-s-transferase, superoxide dismutase and catalase), and induced DNA damage and chromosomal aberration. Oral administration of Nano-Se caused a significant reduction in malonaldehyde, ROS level and glutathione levels, restoration of antioxidant enzyme activity, reduction in chromosomal aberration in bone marrow, and DNA damage in lymphocytes and also in bone marrow. Moreover, the chemoprotective efficiency of Nano-Se against CP induced toxicity was confirmed by histopathological evaluation. The results support the protective effect of Nano-Se against CP-induced hepatotoxicity and genotoxicity. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  2. Tropical green leafy vegetables prevent garlic-induced hepatotoxicity in the rat.

    PubMed

    Oboh, Ganiyu

    2006-01-01

    Garlic (Allium sativum) is popularly consumed because of its role in the treatment and management of several diseases. However, unregulated and chronic intake of garlic can cause damage to cells through the production of free radicals. This study was carried out in order to assess the ability of some tropical green leafy vegetables (Telfairia occidentalis, Solanum macrocapon, Corchorus olitorius, Baselia alba, Cnidoscolus acontifolus, Amarantus cruentus, and Ocimum gratissimum) to prevent garlic-induced hepatotoxicity in rats. Wistar strain albino rats were fed diet containing 4% garlic along with or without 40% green leafy vegetable supplement for 14 days. Thereafter, the feeding trial was terminated, the serum of the blood was prepared, and the liver, spleen, intestine, and organ were isolated for gross pathological investigation. The results of the study revealed that there was a significant increase (P < .05) in serum glutamate-oxaloacetate transaminase (SGOT) and glutamate-pyruvate transaminase (SGPT) of the albino rats fed diet containing 4% garlic supplement when compared with the rats fed the basal diet without garlic and vegetable (40%) supplement. However, there was a significant decrease (P < .05) in the serum total protein and albumin levels in those rats. Conversely, there was a consistent significant decrease (P < .05) in the SGOT and SGPT of the rats fed diet containing garlic (4%) and T. occidentalis (40%) and C. acontifolus (40%) supplement compared with those rats fed diet containing garlic (4%) supplement, while there were no consistent significant decrease in those rats fed diet with garlic (4%) alongside with 40% of other leafy vegetables (S. macrocanum, C. olitorius, B. alba, A. cruentus, and O. gratissimum). An increase in serum level of total protein and albumin was also observed in the rats fed T. occidentalis and C. acontifolus. Thus, T. occidentalis and C. acontifolus proved to be better vegetables in preventing garlic

  3. Diet Restriction Inhibits Apoptosis and HMGB1 Oxidation and Promotes Inflammatory Cell Recruitment during Acetaminophen Hepatotoxicity

    PubMed Central

    Antoine, Daniel James; Williams, Dominic P; Kipar, Anja; Laverty, Hugh; Park, B Kevin

    2010-01-01

    Acetaminophen (APAP) overdose is a major cause of acute liver failure and serves as a paradigm to elucidate mechanisms, predisposing factors and therapeutic interventions. The roles of apoptosis and inflammation during APAP hepatotoxicity remain controversial. We investigated whether fasting of mice for 24 h can inhibit APAP-induced caspase activation and apoptosis through the depletion of basal ATP. We also investigated in fasted mice the critical role played by inhibition of caspase-dependent cysteine 106 oxidation within high mobility group box-1 protein (HMGB1) released by ATP depletion in dying cells as a mechanism of immune activation. In fed mice treated with APAP, necrosis was the dominant form of hepatocyte death. However, apoptosis was also observed, indicated by K18 cleavage, DNA laddering and procaspase-3 processing. In fasted mice treated with APAP, only necrosis was observed. Inflammatory cell recruitment as a consequence of hepatocyte death was observed only in fasted mice treated with APAP or fed mice cotreated with a caspase inhibitor. Hepatic inflammation was also associated with loss in detection of serum oxidized-HMGB1. A significant role of HMGB1 in the induction of inflammation was confirmed with an HMGB1-neutralizing antibody. The differential response between fasted and fed mice was a consequence of a significant reduction in basal hepatic ATP, which prevented caspase processing, rather than glutathione depletion or altered APAP metabolism. Thus, the inhibition of caspase-driven apoptosis and HMGB1 oxidation by ATP depletion from fasting promotes an inflammatory response during drug-induced hepatotoxicity/liver pathology. PMID:20811657

  4. Blockade of store-operated calcium entry alleviates ethanol-induced hepatotoxicity via inhibiting apoptosis

    SciT

    Cui, Ruibing; Yan, Lihui; Luo, Zheng

    2015-08-15

    Extracellular Ca{sup 2+} influx has been suggested to play a role in ethanol-induced hepatocyte apoptosis and necrosis. Previous studies indicated that store-operated Ca{sup 2+} entry (SOCE) was involved in liver injury induced by ethanol in HepG2 cells. However, the mechanisms underlying liver injury caused by SOCE remain unclear. We aimed to investigate the effects and mechanism of SOCE inhibition on liver injury induced by ethanol in BRL cells and Sprague–Dawley rats. Our data demonstrated that ethanol (0–400 mM) dose-dependently increased hepatocyte injury and 100 mM ethanol significantly upregulated the mRNA and protein expression of SOC for at least 72 hmore » in BRL cells. Blockade of SOCE by pharmacological inhibitors and sh-RNA knockdown of STIM1 and Orai1 attenuated intracellular Ca{sup 2+} overload, restored the mitochondrial membrane potential (MMP), decreased cytochrome C release and inhibited ethanol-induced apoptosis. STIM1 and Orai1 expression was greater in ethanol-treated than control rats, and the SOCE inhibitor corosolic acid ameliorated the histopathological findings and alanine transaminase and aspartate transaminase activity as well as decreased cytochrome C release and inhibited alcohol-induced cell apoptosis. These findings suggest that SOCE blockade could alleviate alcohol-induced hepatotoxicity via inhibiting apoptosis. SOCE might be a useful therapeutic target in alcoholic liver diseases. - Highlights: • Blockade of SOCE alleviated overload of Ca{sup 2+} and hepatotoxicity after ethanol application. • Blockade of SOCE inhibited mitochondrial apoptosis after ethanol application. • SOCE might be a useful therapeutic target in alcoholic liver diseases.« less

  5. Hibiscus vitifolius (Linn.) root extracts shows potent protective action against anti-tubercular drug induced hepatotoxicity.

    PubMed

    Samuel, Anbu Jeba Sunilson John; Mohan, Syam; Chellappan, Dinesh Kumar; Kalusalingam, Anandarajagopal; Ariamuthu, Saraswathi

    2012-05-07

    The roots of Hibiscus vitifolius Linn. (Malvaceae) is used for the treatment of jaundice in the folklore system of medicine in India. This study is an attempt to evaluate the hepatoprotective activity of the roots of Hibiscus vitifolius against anti-tubercular drug induced hepatotoxicity. Hepatotoxicity was induced in albino rats of either sex by oral administration of a combination of three anti-tubercular drugs. Petroleum ether, chloroform, methanol and aqueous extracts of roots of Hibiscus vitifolius (400mg/kg/day) were evaluated for their possible hepatoprotective potential. All the extracts were found to be safe up to a dose of 2000mg/kg. Among the four extracts studied, oral administration of methanol extract of Hibiscus vitifolius at 400mg/kg showed significant difference in all the parameters when compared to control. There was a significant (P<0.001) reduction in the levels of serum aspartate amino transaminase, alanine amino transferase, alkaline phosphatase, lactate dehydrogenase, total and direct bilirubin, where as an increase was found in the levels of total cholesterol, total protein and albumin. Liver homogenate studies showed a significant increase in the levels of total protein, phospholipids and glycogen, and a reduction in the levels of total lipids, triglycerides, and cholesterol against control animals. In the tissue anti-oxidant studies, we found a significant increase in the levels of catalase and superoxide dismutase, whereas there was marked reduction in the levels of thiobarbituric acid reactive substances, as compared to control. Histology of liver sections of the animals treated with the extracts showed significant reduction of necrosis and fatty formation when compared with control specimens. These findings suggest that the root extracts of Hibiscus vitifolius have potent hepatoprotective activity, thereby justifying its ethnopharmacological claim. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  6. Utility of human hepatocyte spheroids without feeder cells for evaluation of hepatotoxicity.

    PubMed

    Ogihara, Takuo; Arakawa, Hiroshi; Jomura, Tomoko; Idota, Yoko; Koyama, Satoshi; Yano, Kentaro; Kojima, Hajime

    2017-01-01

    We investigated the utility of three-dimensionally cultured hepatocytes (spheroids) without feeder cells (Sph(f-)) for the prediction of drug-induced liver injury (DILI) in humans. Sph(f-) and spheroids cultured on feeder cells (Sph(f+)) were exposed to the hepatotoxic drugs flutamide, diclofenac, isoniazid and chlorpromazine at various concentrations for 14 days, and albumin secretion and cumulative leakages of toxicity marker enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and γ-glutamyl transpeptidase (γ-GTP), were measured. The cumulative AST, LDH or γ-GTP leakages from Sph(f-) were similar to or greater than those from Sph(f+) for all drugs tested, although ALT leakages showed no consistent difference between Sph(f+) and Sph(f-). In the case of Sph(f-), significant correlations among all the toxicity markers except for γ-GTP were observed. As regards the drug concentrations causing 1.2-fold elevation of enzyme leakage (F 1.2 ), no consistent difference between Sph(f+) and Sph(f-) was found, although several F 1.2 values were undetermined, especially in Sph(f+). The IC 50 of albumin secretion and F 1.2 of AST leakage from Sph(f-) were equal to or lower than those of Sph(f+) for all the tested drugs. These results indicate that feeder cells might contribute to resistance to hepatotoxicity, suggesting DILI could be evaluated more accurately by using Sph(f-). We suggest that long-term exposure of Sph(f-) to drugs might be a versatile method to predict and reproduce clinical chronic toxicity, especially in response to repeated drug administration.

  7. Amelioration of acetaminophen induced hepatotoxicity by methanolic extract of pomegranate peels in rats.

    PubMed

    Ahmad, Nadia; Tahir, Mohammad; Lone, Khalid Perwez

    2016-07-01

    To observe the ameliorating effect by methanolic extract of pomegranate peel in acetaminophen-induced hepatotoxicity. The randomised controlled study was conducted from July 2013 to June 2014 at the University of Health Sciences, Lahore, Pakistan, and comprised rats that were randomly divided into three equal groups. Control group A was given normal saline (5ml/kg), whereas group B and C were given 750mg/kg acetaminophen intraperitoneally dissolved in normal saline (5ml/kg) on 1st day of experiment. From Day 2 till day 14, group A and B were given distilled water (5ml/kg), while group C was given 50mg/kg methanolic extract of pomegranate peel dissolved in distilled water (5ml/kg) orally. On day 15, blood was collected through cardiac puncture, and livers were removed and processed for histological examination. There were 24 rats weighing 175±25gm each. Each group had 8(33.3%) rats. Mean liver aspartate aminotransferase at the end of the experiment in groups A, B and C were 97.88±19.45, 148.25±16.48 and 96.13±17.95U/L, while alanine transaminase levels were 51.50±15.38, 96.75±10.91 and 49.63±12.08 U/L (p<0.05 each) On histological examination of group B, the normal hepatic architecture was distorted with loss of classically arranged hepatic cords. Vascular congestion was present with centrilobular necrosis, marked by pyknotic nuclei and vacuoles. Acetaminophen is hepatotoxic and methanolic extract of pomegranate peel ameliorated the hepatic picture probably because of its antioxidant properties.

  8. Severe congenital cyclic neutropenia: A case report

    PubMed Central

    Patil, Vidyavathi H; Hugar, Shivayogi M; Balikai, Girish; Patil, Sudha

    2016-01-01

    Congenital cyclic neutropenia syndrome is a constitutional genetic disorder which is characterized by very low number of neutrophils (neutropenia). Patients suffering from this disorder clinically present with neutropenia at early age, history of recurrent fever, ulcerations in the oral cavity, gingivitis, and other recurrent infections. This paper describes a case report of a child with recurrent mouth ulcers, fever, and later diagnosed with severe congenital cyclic neutropenia. This also emphasizes the importance of identification of rare causes of immunosuppressive conditions in children presenting with recurrent oral ulcers and poor dental hygiene, to prevent long-term complications of oral cavity and also morbidity and mortality secondary to neutropenic sepsis. PMID:27857902

  9. Holographic entanglement entropy and cyclic cosmology

    NASA Astrophysics Data System (ADS)

    Frampton, Paul H.

    2018-06-01

    We discuss a cyclic cosmology in which the visible universe, or introverse, is all that is accessible to an observer while the extroverse represents the total spacetime originating from the time when the dark energy began to dominate. It is argued that entanglement entropy of the introverse is the more appropriate quantity to render infinitely cyclic, rather than the entropy of the total universe. Since vanishing entanglement entropy implies disconnected spacetimes, at the turnaround when the introverse entropy is zero the disconnected extroverse can be jettisoned with impunity.

  10. Hepatotoxicity associated with 6-methyl mercaptopurine formation during azathioprine and 6-mercaptopurine therapy does not occur on the short-term during 6-thioguanine therapy in IBD treatment.

    PubMed

    van Asseldonk, Dirk P; Seinen, Margien L; de Boer, Nanne K H; van Bodegraven, Ad A; Mulder, Chris J

    2012-02-01

    High concentrations of methylated thiopurine metabolites, such as 6-methyl mercaptopurine, are associated with hepatotoxicity during administration of the conventional thiopurines azathioprine or 6-mercaptopurine in IBD patients. Metabolization of the non-conventional thiopurine 6-thioguanine does not generate 6-methyl mercaptopurine. Hence, the aim of our study was to evaluate hepatotoxicity during 6-thioguanine in IBD patients who previously failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. A retrospective single center intercept cohort study was performed of IBD patients using 6-thioguanine between January 2006 and July 2010 after failing conventional thiopurine therapy due to 6-methyl mercaptopurine associated hepatotoxicity. The primary outcome was the occurrence of 6-thioguanine induced hepatotoxicity, scaled according to the Common Terminology Criteria for Adverse Events. Nineteen patients were included. Median duration of 6-thioguanine therapy (median daily dosage 21 mg (9-24)) was 23 weeks (6-96). Hepatotoxicity did not reoccur in 15 out of 19, whereas grade 1 toxicity persisted in 4 patients (p<0.001). Median aspartate aminotransferase and alanine aminotransferase concentrations decreased from 34 U/l (20-59) and 64 U/l (15-175) to 23 U/l (18-40; p=0.003) and 20 U/l (14-48; p=0.019), respectively. Hepatotoxicity does not reoccur during 6-thioguanine treatment in most IBD patients who failed conventional thiopurines due to 6-methyl mercaptopurine associated hepatotoxicity. Hence, at least at short-term, 6-thioguanine appears a justifiable alternative thiopurine for these IBD patients. Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  11. Synergistic drug-cytokine induction of hepatocellular death as an in vitro approach for the study of inflammation-associated idiosyncratic drug hepatotoxicity

    SciT

    Cosgrove, Benjamin D.; Cell Decision Processes Center, Massachusetts Institute of Technology, Cambridge, MA; Biotechnology Process Engineering Center, Massachusetts Institute of Technology, Cambridge, MA

    Idiosyncratic drug hepatotoxicity represents a major problem in drug development due to inadequacy of current preclinical screening assays, but recently established rodent models utilizing bacterial LPS co-administration to induce an inflammatory background have successfully reproduced idiosyncratic hepatotoxicity signatures for certain drugs. However, the low-throughput nature of these models renders them problematic for employment as preclinical screening assays. Here, we present an analogous, but high-throughput, in vitro approach in which drugs are administered to a variety of cell types (primary human and rat hepatocytes and the human HepG2 cell line) across a landscape of inflammatory contexts containing LPS and cytokines TNF,more » IFN{gamma}, IL-1{alpha}, and IL-6. Using this assay, we observed drug-cytokine hepatotoxicity synergies for multiple idiosyncratic hepatotoxicants (ranitidine, trovafloxacin, nefazodone, nimesulide, clarithromycin, and telithromycin) but not for their corresponding non-toxic control compounds (famotidine, levofloxacin, buspirone, and aspirin). A larger compendium of drug-cytokine mix hepatotoxicity data demonstrated that hepatotoxicity synergies were largely potentiated by TNF, IL-1{alpha}, and LPS within the context of multi-cytokine mixes. Then, we screened 90 drugs for cytokine synergy in human hepatocytes and found that a significantly larger fraction of the idiosyncratic hepatotoxicants (19%) synergized with a single cytokine mix than did the non-hepatotoxic drugs (3%). Finally, we used an information theoretic approach to ascertain especially informative subsets of cytokine treatments for most highly effective construction of regression models for drug- and cytokine mix-induced hepatotoxicities across these cell systems. Our results suggest that this drug-cytokine co-treatment approach could provide a useful preclinical tool for investigating inflammation-associated idiosyncratic drug hepatotoxicity.« less

  12. Acute Exposure to Tris(1,3-dichloro-2-propyl) Phosphate (TDCIPP) Causes Hepatic Inflammation and Leads to Hepatotoxicity in Zebrafish

    NASA Astrophysics Data System (ADS)

    Liu, Chunsheng; Su, Guanyong; Giesy, John P.; Letcher, Robert J.; Li, Guangyu; Agrawal, Ira; Li, Jing; Yu, Liqin; Wang, Jianghua; Gong, Zhiyuan

    2016-01-01

    Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) has been frequently detected in environmental media and has adverse health effect on wildlife and humans. It has been implicated to have hepatotoxicity, but its molecular mechanisms remain unclear. In the present study, adult male zebrafish were exposed to TDCIPP and global hepatic gene expression was examined by RNA-Seq and RT-qPCR in order to understand the molecular mechanisms of TDCIPP-induced hepatotoxicity. Our results indicated that TDCIPP exposure significantly up-regulated the expression of genes involved in endoplasmic reticulum stress and Toll-like receptor (TLR) pathway, implying an inflammatory response, which was supported by up-regulation of inflammation-related biomaker genes. Hepatic inflammation was further confirmed by histological observation of increase of infiltrated neutrophils and direct observation of liver recruitment of neutrophils labeled with Ds-Red fluorescent protein of Tg(lysC:DsRed) zebrafish upon TDCIPP exposure. To further characterize the hepatotoxicity of TDCIPP, the expression of hepatotoxicity biomarker genes, liver histopathology and morphology were examined. The exposure to TDCIPP significantly up-regulated the expression of several biomarker genes for hepatotoxicity (gck, gsr and nqo1) and caused hepatic vacuolization and apoptosis as well as increase of the liver size. Collectively, our results suggest that exposure to TDCIPP induces hepatic inflammation and leads to hepatotoxicity in zebrafish.

  13. Strain controlled cyclic tests on miniaturized specimens

    NASA Astrophysics Data System (ADS)

    Procházka, R.; Džugan, J.

    2017-02-01

    The paper is dealing with strain controlled cyclic tests using a non-contact strain measurement based on digital image correlation techniques on proportional sizes of conventional specimens. The cyclic behaviour of 34CrNiMo6 high-strength steel was investigated on miniaturized round specimens with diameter of 2mm that were compared with specimens in accordance with ASTM E606 standards. The cycle asymmetry coefficient was R= -1. This application is intended to be used for life time assessment of in service components in future work which enables to carried out a group of mechanical tests from a limited amount of the experimental material. The attention was paid to confirm the suitability of the proposed size miniaturization geometry, testing set up and procedure. The test results obtained enabled to construct Manson-Coffin curves and assess fatigue parameters. The purpose of this study is to present differences between cyclic curves and cyclic parameters which have been evaluated based on conventional and miniaturized specimens.

  14. A Cyclical Plan for Using Study Strategies.

    ERIC Educational Resources Information Center

    Hayes, David A.; Alvermann, Donna E.

    1984-01-01

    A cyclical plan for studying that takes into account information processing strategies and their effective management by students consists of (1) specifying study purposes, (2) previewing the materials, (3) proceeding through the task incrementally, and (4) connecting the content to be learned to other knowledge about the material studied. Setting…

  15. Cyclic Cratonic Carbonates and Phanerozoic Calcite Seas.

    ERIC Educational Resources Information Center

    Wilkinson, Bruce H.

    1982-01-01

    Discusses causes of cyclicity in cratonic carbonate sequences and evidence for and potential significance of postulated primary calcite sediment components in past Paleozoic seas, outlining problems, focusing on models explaining existing data, and identifying background. Future sedimentary geologists will need to address these and related areas…

  16. Unexpected paracetamol (acetaminophen) hepatotoxicity at standard dosage in two older patients: time to rethink 1 g four times daily?

    PubMed

    Ging, Patricia; Mikulich, Olga; O'Reilly, Katherine M A

    2016-07-01

    We present two cases of acute hepatotoxicity associated with elevated paracetamol (acetaminophen) levels in older patients. Both patients were receiving a standard European dose of oral paracetamol (2 × 500 mg QDS) with no risk factors for slowed metabolism (weight <50 kg, interacting medications, hepatic enzyme inducers, history of liver disease). Significantly, both patients had recently had a dose escalation from 'as needed' dosing to 4 g daily, and the medication was being administered by nursing staff. Our experience shows that even when prescribed appropriately at the usual therapeutic dosage, paracetamol can be hepatotoxic. © The Author 2016. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  17. Development of tacrine-bifendate conjugates with improved cholinesterase inhibitory and pro-cognitive efficacy and reduced hepatotoxicity.

    PubMed

    Cen, Juan; Guo, Huiyan; Hong, Chen; Lv, Jianwu; Yang, Yacheng; Wang, Ting; Fang, Dong; Luo, Wen; Wang, Chaojie

    2018-01-20

    A novel series of tacrine-bifendate (THA-DDB) conjugates (7a-e) were synthesized and evaluated as potential anti-Alzheimer's agents. These compounds showed potent cholinesterase and self-induced β-amyloid (Aβ) aggregation inhibitory activities. A Lineweaver-Burk plot and molecular modeling study showed that these compounds can target both catalytic active site (CAS) and peripheral anionic site (PAS) of acetylcholinesterase (AChE). The cytotoxicity of the conjugate 7d against PC12 and HepG2 cells and hepatotoxicity against human hepatocyte cell line (HL-7702) were found to be considerably less compared to THA. Moreover, treatment with 7d did not exhibit significant hepatotoxicity in mice. Finally, in vivo studies confirmed that 7d significantly ameliorates the cognitive performances of scopolamine-treated ICR mice. Therefore, 7d has high potential for the treatment of Alzheimer's disease and warrants further investigation. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  18. Trifluoperazine inhibits acetaminophen-induced hepatotoxicity and hepatic reactive nitrogen formation in mice and in freshly isolated hepatocytes.

    PubMed

    Banerjee, Sudip; Melnyk, Stepan B; Krager, Kimberly J; Aykin-Burns, Nukhet; McCullough, Sandra S; James, Laura P; Hinson, Jack A

    2017-01-01

    The hepatotoxicity of acetaminophen (APAP) occurs by initial metabolism to N-acetyl-p-benzoquinone imine which depletes GSH and forms APAP-protein adducts. Subsequently, the reactive nitrogen species peroxynitrite is formed from nitric oxide (NO) and superoxide leading to 3-nitrotyrosine in proteins. Toxicity occurs with inhibited mitochondrial function. We previously reported that in hepatocytes the nNOS (NOS1) inhibitor NANT inhibited APAP toxicity, reactive nitrogen and oxygen species formation, and mitochondrial dysfunction. In this work we examined the effect of trifluoperazine (TFP), a calmodulin antagonist that inhibits calcium induced nNOS activation, on APAP hepatotoxicity and reactive nitrogen formation in murine hepatocytes and in vivo . In freshly isolated hepatocytes TFP inhibited APAP induced toxicity, reactive nitrogen formation (NO, GSNO, and 3-nitrotyrosine in protein), reactive oxygen formation (superoxide), loss of mitochondrial membrane potential, decreased ATP production, decreased oxygen consumption rate, and increased NADH accumulation. TFP did not alter APAP induced GSH depletion in the hepatocytes or the formation of APAP protein adducts which indicated that reactive metabolite formation was not inhibited. Since we previously reported that TFP inhibits the hepatotoxicity of APAP in mice without altering hepatic APAP-protein adduct formation, we examined the APAP treated mouse livers for evidence of reactive nitrogen formation. 3-Nitrotyrosine in hepatic proteins and GSNO were significantly increased in APAP treated mouse livers and decreased in the livers of mice treated with APAP plus TFP. These data are consistent with a hypothesis that APAP hepatotoxicity occurs with altered calcium metabolism, activation of nNOS leading to increased reactive nitrogen formation, and mitochondrial dysfunction.

  19. Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits

    PubMed Central

    Zubairi, Maysaa B.; Ahmed, Jawad H.; Al-Haroon, Sawsan S.

    2014-01-01

    Objectives: To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity. Materials and Methods: Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally), group 3, 4,5 and 6 were treated at a dose in (mg/kg/day) of the following: Carvedilol (10 mg), prazosin (0.5 mg), metoprolol (10 mg), and a combination of metoprolol (10 mg) and prazosin (0.5 mg) respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA) and glutathione (GSH) in serum and liver homogenates were estimated. Histopathological examinations of liver were performed. Results: Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments. Conclusion: Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection. PMID:25538338

  20. Effect of adrenergic blockers, carvedilol, prazosin, metoprolol and combination of prazosin and metoprolol on paracetamol-induced hepatotoxicity in rabbits.

    PubMed

    Zubairi, Maysaa B; Ahmed, Jawad H; Al-Haroon, Sawsan S

    2014-01-01

    To evaluate hepatoprotective potential of carvedilol, prazosin, metoprolol and prazosin plus metoprolol in paracetamol-induced hepatotoxicity. Thirty-six male rabbits were divided into six groups, six in each, group 1 received distilled water, group 2 were treated with paracetamol (1 g/kg/day, orally), group 3, 4,5 and 6 were treated at a dose in (mg/kg/day) of the following: Carvedilol (10 mg), prazosin (0.5 mg), metoprolol (10 mg), and a combination of metoprolol (10 mg) and prazosin (0.5 mg) respectively 1 h before paracetamol treatment. All treatments were given for 9 days; animals were sacrificed at day 10. Liver function tests, malondialdehyde (MDA) and glutathione (GSH) in serum and liver homogenates were estimated. Histopathological examinations of liver were performed. Histopathological changes of hepatotoxicity were found in all paracetamol-treated rabbits. The histopathological findings of paracetamol toxicity disappeared in five rabbits on prazosin, very mild in one. In carvedilol group paracetamol toxicity completely disappeared in three, while mild in three rabbits. Paracetamol hepatotoxicity was not changed by metoprolol. In metoprolol plus prazosin treated rabbits, moderate histopathological changes were observed. Serum liver function tests and MDA in serum and in liver homogenate were elevated; GSH was depleted after paracetamol treatment and returned back to the control value on prior treatment with prazosin. MDA in serum and liver homogenate, alkaline phosphatase, total bilirubin were significantly decreased after carvedilol and prazosin plus metoprolol treatments. Carvedilol and prazosin are hepatoprotective in paracetamol hepatotoxicity, combination of prazosin and metoprolol have moderate, and metoprolol has a little hepatoprotection.

  1. High Dose Atorvastatin Associated with Increased Risk of Significant Hepatotoxicity in Comparison to Simvastatin in UK GPRD Cohort

    PubMed Central

    Clarke, Alan T.; Johnson, Paul C. D.; Hall, Gillian C.; Ford, Ian; Mills, Peter R.

    2016-01-01

    Background & Aims Occasional risk of serious liver dysfunction and autoimmune hepatitis during atorvastatin therapy has been reported. We compared the risk of hepatotoxicity in atorvastatin relative to simvastatin treatment. Methods The UK GPRD identified patients with a first prescription for simvastatin [164,407] or atorvastatin [76,411] between 1997 and 2006, but with no prior record of liver disease, alcohol-related diagnosis, or liver dysfunction. Incident liver dysfunction in the following six months was identified by biochemical value and compared between statin groups by Cox regression model adjusting for age, sex, year treatment started, dose, alcohol consumption, smoking, body mass index and comorbid conditions. Results Moderate to severe hepatotoxicity [bilirubin >60μmol/L, AST or ALT >200U/L or alkaline phosphatase >1200U/L] developed in 71 patients on atorvastatin versus 101 on simvastatin. Adjusted hazard ratio [AHR] for all atorvastatin relative to simvastatin was 1.9 [95% confidence interval 1.4–2.6]. High dose was classified as 40–80mg daily and low dose 10–20mg daily. Hepatotoxicity occurred in 0.44% of 4075 patients on high dose atorvastatin [HDA], 0.07% of 72,336 on low dose atorvastatin [LDA], 0.09% of 44,675 on high dose simvastatin [HDS] and 0.05% of 119,732 on low dose simvastatin [LDS]. AHRs compared to LDS were 7.3 [4.2–12.7] for HDA, 1.4 [0.9–2.0] for LDA and 1.5 [1.0–2.2] for HDS. Conclusions The risk of hepatotoxicity was increased in the first six months of atorvastatin compared to simvastatin treatment, with the greatest difference between high dose atorvastatin and low dose simvastatin. The numbers of events in the analyses were small. PMID:26983033

  2. Liver steatosis is a risk factor for hepatotoxicity in patients with inflammatory bowel disease under immunosuppressive treatment.

    PubMed

    Schröder, Torsten; Schmidt, Klaus J; Olsen, Vera; Möller, Steffen; Mackenroth, Tilo; Sina, Christian; Lehnert, Hendrik; Fellermann, Klaus; Büning, Jürgen

    2015-06-01

    In inflammatory bowel disease (IBD), hepatic disorders are frequently due to nonalcoholic fatty liver disease and drug-induced hepatotoxicity. Immunosuppressive treatment is known to exert hepatotoxic side effects by a still unknown mode. The relevance of liver steatosis for the development of drug-related hepatotoxicity in IBD is unknown. The charts of 259 patients with IBD under immunosuppression with either azathioprine, 6-mercaptopurine, or methotrexate were reviewed. The prevalence of liver steatosis was assessed by means of ultrasound reports. Aspartate transaminase and alanine transaminase above the normal range were used to indicate liver abnormalities. Liver steatosis on the basis of ultrasound criteria was observed in 73 patients (28.2%). In patients with liver steatosis, the presence of elevated liver enzymes (ELE) was found to be significantly more prevalent (28.8 vs. 14.5%, P=0.0095). The finding of liver steatosis was associated with higher age (44.1 vs. 34.5 years, P<0.0001) and body weight (BMI 26.7 vs. 23.4 kg/m, P<0.0001). Development of ELE under immunosuppression was seen in 50 patients (19.3%). Of the patients who developed ELE, 44.0% (vs. 24.4%, P=0.0095) showed liver steatosis. Logistic regression analysis revealed that male individuals showed an increased likelihood of developing ELE associated with steatosis (P=0.0118, odds ratio=3.93) and that patients who received steroids less often developed ELE in association with liver steatosis (P=0.0414, odds ratio=0.31). This study suggests that fatty liver represents a risk factor for hepatotoxicity in patients with IBD under immunosuppressive treatment and should be routinely considered in treatment strategies.

  3. Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPAR{alpha} with clofibrate

    SciT

    Donthamsetty, Shashikiran; Bhave, Vishakha S.; Mitra, Mayurranjan S.

    2008-08-01

    The objective was to investigate if the hepatotoxic sensitivity in nonalcoholic steatohepatitic mice to acetaminophen (APAP) is due to downregulation of nuclear receptor PPAR{alpha} via lower cell division and tissue repair. Male Swiss Webster mice fed methionine and choline deficient diet for 31 days exhibited NASH. On the 32nd day, a marginally toxic dose of APAP (360 mg/kg, ip) yielded 70% mortality in steatohepatitic mice, while all non steatohepatitic mice receiving the same dose survived. {sup 14}C-APAP covalent binding, CYP2E1 protein, and enzyme activity did not differ from the controls, obviating increased APAP bioactivation as the cause of amplified APAPmore » hepatotoxicity. Liver injury progressed only in steatohepatitic livers between 6 and 24 h. Cell division and tissue repair assessed by {sup 3}H-thymidine incorporation and PCNA were inhibited only in the steatohepatitic mice given APAP suggesting that higher sensitivity of NASH liver to APAP-induced hepatotoxicity was due to lower tissue repair. The hypothesis that impeded liver tissue repair in steatohepatitic mice was due to downregulation of PPAR{alpha} was tested. PPAR{alpha} was downregulated in NASH. To investigate whether downregulation of PPAR{alpha} in NASH is the critical mechanism of compromised liver tissue repair, PPAR{alpha} was induced in steatohepatitic mice with clofibrate (250 mg/kg for 3 days, ip) before injecting APAP. All clofibrate pretreated steatohepatitic mice receiving APAP exhibited lower liver injury, which did not progress and the mice survived. The protection was not due to lower bioactivation of APAP but due to higher liver tissue repair. These findings suggest that inadequate PPAR{alpha} expression in steatohepatitic mice sensitizes them to APAP hepatotoxicity.« less

  4. Rhodium-Catalyzed Dehydrogenative Borylation of Cyclic Alkenes

    PubMed Central

    Kondoh, Azusa; Jamison, Timothy F.

    2010-01-01

    A rhodium-catalyzed dehydrogenative borylation of cyclic alkenes is described. This reaction provides direct access to cyclic 1-alkenylboronic acid pinacol esters, useful intermediates in organic synthesis. Suzuki-Miyaura cross-coupling applications are also presented. PMID:20107646

  5. Compressed sensing with cyclic-S Hadamard matrix for terahertz imaging applications

    NASA Astrophysics Data System (ADS)

    Ermeydan, Esra Şengün; ćankaya, Ilyas

    2018-01-01

    Compressed Sensing (CS) with Cyclic-S Hadamard matrix is proposed for single pixel imaging applications in this study. In single pixel imaging scheme, N = r . c samples should be taken for r×c pixel image where . denotes multiplication. CS is a popular technique claiming that the sparse signals can be reconstructed with samples under Nyquist rate. Therefore to solve the slow data acquisition problem in Terahertz (THz) single pixel imaging, CS is a good candidate. However, changing mask for each measurement is a challenging problem since there is no commercial Spatial Light Modulators (SLM) for THz band yet, therefore circular masks are suggested so that for each measurement one or two column shifting will be enough to change the mask. The CS masks are designed using cyclic-S matrices based on Hadamard transform for 9 × 7 and 15 × 17 pixel images within the framework of this study. The %50 compressed images are reconstructed using total variation based TVAL3 algorithm. Matlab simulations demonstrates that cyclic-S matrices can be used for single pixel imaging based on CS. The circular masks have the advantage to reduce the mechanical SLMs to a single sliding strip, whereas the CS helps to reduce acquisition time and energy since it allows to reconstruct the image from fewer samples.

  6. A retrospective review of methotrexate-induced hepatotoxicity among patients with psoriasis in a tertiary dermatology center in Malaysia.

    PubMed

    Ng, Lim Chui; Lee, Yin Yin; Lee, Chew Kek; Wong, Su-Ming

    2013-01-01

    Methotrexate (MTX) is a common and efficacious systemic agent used for the treatment of moderate to severe psoriasis. Nevertheless, its use is associated with the risk of hepatotoxicity. This study was performed to study the association of MTX dose with regards to hepatotoxicity as evidenced by deranged transaminases. This was a retrospective review of patients with psoriasis on MTX from 2000 to 2009 at the outpatient dermatology clinic, University Malaya Medical Centre (UMMC). We analyzed patients' demography, serial laboratory investigations, liver ultrasounds, and liver biopsies of patients on MTX. Sixty-six of 710 (9.30%) patients with psoriasis were prescribed MTX throughout the 10-year period. Among them 57.6% developed deranged transaminases, with six requiring MTX withdrawal due to hepatotoxicity. The mean cumulative dose of MTX at the detection of liver enzyme derangement was 552.3 ± 596.1 mg. A high proportion of patients on MTX had deranged transaminases. However, the number of serious events was low. We concluded from this study that the use of MTX is relatively safe in patients with moderate to severe psoriasis. © 2013 The International Society of Dermatology.

  7. In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System.

    PubMed

    Knöspel, Fanny; Jacobs, Frank; Freyer, Nora; Damm, Georg; De Bondt, An; van den Wyngaert, Ilse; Snoeys, Jan; Monshouwer, Mario; Richter, Marco; Strahl, Nadja; Seehofer, Daniel; Zeilinger, Katrin

    2016-04-16

    Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro.

  8. In Vitro Model for Hepatotoxicity Studies Based on Primary Human Hepatocyte Cultivation in a Perfused 3D Bioreactor System

    PubMed Central

    Knöspel, Fanny; Jacobs, Frank; Freyer, Nora; Damm, Georg; De Bondt, An; van den Wyngaert, Ilse; Snoeys, Jan; Monshouwer, Mario; Richter, Marco; Strahl, Nadja; Seehofer, Daniel; Zeilinger, Katrin

    2016-01-01

    Accurate prediction of the potential hepatotoxic nature of new pharmaceuticals remains highly challenging. Therefore, novel in vitro models with improved external validity are needed to investigate hepatic metabolism and timely identify any toxicity of drugs in humans. In this study, we examined the effects of diclofenac, as a model substance with a known risk of hepatotoxicity in vivo, in a dynamic multi-compartment bioreactor using primary human liver cells. Biotransformation pathways of the drug and possible effects on metabolic activities, morphology and cell transcriptome were evaluated. Formation rates of diclofenac metabolites were relatively stable over the application period of seven days in bioreactors exposed to 300 µM diclofenac (300 µM bioreactors (300 µM BR)), while in bioreactors exposed to 1000 µM diclofenac (1000 µM BR) metabolite concentrations declined drastically. The biochemical data showed a significant decrease in lactate production and for the higher dose a significant increase in ammonia secretion, indicating a dose-dependent effect of diclofenac application. The microarray analyses performed revealed a stable hepatic phenotype of the cells over time and the observed transcriptional changes were in line with functional readouts of the system. In conclusion, the data highlight the suitability of the bioreactor technology for studying the hepatotoxicity of drugs in vitro. PMID:27092500

  9. Upgrading HepG2 cells with adenoviral vectors that encode drug-metabolizing enzymes: application for drug hepatotoxicity testing.

    PubMed

    Gómez-Lechón, M José; Tolosa, Laia; Donato, M Teresa

    2017-02-01

    Drug attrition rates due to hepatotoxicity are an important safety issue considered in drug development. The HepG2 hepatoma cell line is currently being used for drug-induced hepatotoxicity evaluations, but its expression of drug-metabolizing enzymes is poor compared with hepatocytes. Different approaches have been proposed to upgrade HepG2 cells for more reliable drug-induced liver injury predictions. Areas covered: We describe the advantages and limitations of HepG2 cells transduced with adenoviral vectors that encode drug-metabolizing enzymes for safety risk assessments of bioactivable compounds. Adenoviral transduction facilitates efficient and controlled delivery of multiple drug-metabolizing activities to HepG2 cells at comparable levels to primary human hepatocytes by generating an 'artificial hepatocyte'. Furthermore, adenoviral transduction enables the design of tailored cells expressing particular metabolic capacities. Expert opinion: Upgraded HepG2 cells that recreate known inter-individual variations in hepatic CYP and conjugating activities due to both genetic (e.g., polymorphisms) or environmental (e.g., induction, inhibition) factors seems a suitable model to identify bioactivable drug and conduct hepatotoxicity risk assessments. This strategy should enable the generation of customized cells by reproducing human pheno- and genotypic CYP variability to represent a valuable human hepatic cell model to develop new safer drugs and to improve existing predictive toxicity assays.

  10. Hemizygosity of transsulfuration genes confers increased vulnerability against acetaminophen-induced hepatotoxicity in mice

    SciT

    Hagiya, Yoshifumi; Kamata, Shotaro; Mitsuoka, Saya

    2015-01-15

    The key mechanism for acetaminophen hepatotoxicity is cytochrome P450 (CYP)-dependent formation of N-acetyl-p-benzoquinone imine, a potent electrophile that forms protein adducts. Previous studies revealed the fundamental role of glutathione, which binds to and detoxifies N-acetyl-p-benzoquinone imine. Glutathione is synthesized from cysteine in the liver, and N-acetylcysteine is used as a sole antidote for acetaminophen poisoning. Here, we evaluated the potential roles of transsulfuration enzymes essential for cysteine biosynthesis, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), in acetaminophen hepatotoxicity using hemizygous (Cbs{sup +/−} or Cth{sup +/−}) and homozygous (Cth{sup −/−}) knockout mice. At 4 h after intraperitoneal acetaminophen injection, serum alaninemore » aminotransferase levels were highly elevated in Cth{sup −/−} mice at 150 mg/kg dose, and also in Cbs{sup +/−} or Cth{sup +/−} mice at 250 mg/kg dose, which was associated with characteristic centrilobular hepatocyte oncosis. Hepatic glutathione was depleted while serum malondialdehyde accumulated in acetaminophen-injected Cth{sup −/−} mice but not wild-type mice, although glutamate–cysteine ligase (composed of catalytic [GCLC] and modifier [GCLM] subunits) became more activated in the livers of Cth{sup −/−} mice with lower K{sub m} values for Cys and Glu. Proteome analysis using fluorescent two-dimensional difference gel electrophoresis revealed 47 differentially expressed proteins after injection of 150 mg acetaminophen/kg into Cth{sup −/−} mice; the profiles were similar to 1000 mg acetaminophen/kg-treated wild-type mice. The prevalence of Cbs or Cth hemizygosity is estimated to be 1:200–300 population; therefore, the deletion or polymorphism of either transsulfuration gene may underlie idiosyncratic acetaminophen vulnerability along with the differences in Cyp, Gclc, and Gclm gene activities. - Highlights: • Cbs{sup +/−}, Cth{sup +/

  11. HLA alleles influence the clinical signature of amoxicillin-clavulanate hepatotoxicity.

    PubMed

    Stephens, Camilla; López-Nevot, Miguel-Ángel; Ruiz-Cabello, Francisco; Ulzurrun, Eugenia; Soriano, Germán; Romero-Gómez, Manuel; Moreno-Casares, Antonia; Lucena, M Isabel; Andrade, Raúl J

    2013-01-01

    The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

  12. HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity

    PubMed Central

    Stephens, Camilla; López-Nevot, Miguel-Ángel; Ruiz-Cabello, Francisco; Ulzurrun, Eugenia; Soriano, Germán; Romero-Gómez, Manuel; Moreno-Casares, Antonia; Lucena, M. Isabel; Andrade, Raúl J.

    2013-01-01

    Background and Aim The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. Methods High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. Results The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy’s Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). Conclusions HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients. PMID:23874514

  13. Separation of isotopes by cyclical processes

    DOEpatents

    Hamrin, Jr., Charles E.; Weaver, Kenny

    1976-11-02

    Various isotopes of hydrogen are separated by a cyclic sorption process in which a gas stream containing the isotopes is periodically passed through a high pressure column containing a palladium sorbent. A portion of the product from the high pressure column is passed through a second column at lower pressure to act as a purge. Before the sorbent in the high pressure column becomes saturated, the sequence is reversed with the stream flowing through the former low-pressure column now at high pressure, and a portion of the product purging the former high pressure column now at low pressure. The sequence is continued in cyclic manner with the product being enriched in a particular isotope.

  14. On the energy efficiency of cyclic mechanisms

    NASA Astrophysics Data System (ADS)

    Briskin, E. S.; Kalinin, Ya. V.; Maloletov, A. V.; Chernyshev, V. V.

    2014-01-01

    We consider cyclic mechanisms with one degree of freedom driven by engines of various types such as alternating and direct current motors, internal combustion engines, etc. We pose the problem of modifying the mechanism structure by joining additional links or by varying the parameters or operation mode of the original mechanism so as to minimize the thermal losses in the driving motor. The solution is based on the minimization of the functional determining the irreversible power losses. We show that, for the engines considered, all cyclic mechanisms with one degree of freedom should satisfy a fundamental condition ensuring the minimum of losses. We consider two examples, one of which corresponds to actually existing mechanisms.

  15. Cyclic debonding of adhesively bonded composites

    NASA Technical Reports Server (NTRS)

    Mall, S.; Johnson, W. S.; Everett, R. A., Jr.

    1982-01-01

    The fatigue behavior of a simple composite to composite bonded joint was analyzed. The cracked lap shear specimen subjected to constant amplitude cyclic loading was studied. Two specimen geometries were tested for each bonded system: (1) a strap adherend of 16 plies bonded to a lap adherend of 8 plies; and (2) a strap adherend of 8 plies bonded to a lap adherend of 16 plies. In all specimens the fatigue failure was in the form of cyclic debonding with some 0 deg fiber pull off from the strap adherend. The debond always grew in the region of adhesive that had the highest mode (peel) loading and that region was close to the adhesive strap interface.

  16. Factors associated with anti-TB drug-induced hepatotoxicity and genetic polymorphisms in indigenous and non-indigenous populations in Brazil.

    PubMed

    Heinrich, Melissa M; Zembrzuski, Verônica M; Ota, Marcos M; Sacchi, Flavia P; Teixeira, Raquel L F; Cabello Acero, Pedro H; Cunha, Geraldo Marcelo; Souza-Santos, Reinaldo; Croda, Julio; Basta, Paulo C

    2016-12-01

    Anti-tuberculosis (TB) drugs are responsible for the occurrence of several adverse drug reactions (ADRs), including hepatotoxicity. The aim was to estimate the incidence of hepatotoxicity and its association with genetic polymorphisms and clinical-epidemiological factors by comparing indigenous and non-indigenous TB patients. We investigated clinical-epidemiological variables, serum levels of liver enzymes and NAT2, CYP2E1 and GSTM1 polymorphisms. A non-conditional logistic regression was used to identify the factors associated with hepatotoxicity. Odds ratios were used as the association measures. The incidence of hepatotoxicity was 19.7% for all patients. The risk of hepatotoxicity was almost four times higher in indigenous patients, comparing to non-indigenous. We identified a new nonsynonymous single nucleotide polymorphism of NAT2 in indigenous patients. In total, 54.6% of the patients expressed a slow acetylation phenotype profile. The frequency of the null genotype of GSTM1 was higher in non-indigenous patients (p = 0.002), whereas no significant differences in relation to polymorphisms of CYP2E1 were observed between the groups. Hepatotoxicity was associated with patients older than 60 and indigenous (OR = 26.0; 95%CI:3.1-217.6; OR = 3.8; 95%CI:1.3-11.1, respectively). Furthermore, hepatotoxicity was associated with a slow acetylation profile in indigenous patients (OR = 10.7; 95%CI:1.2-97.2). Our findings suggest that there are distinct acetylation profiles in the Brazilian population, emphasizing the importance of pharmacogenetic analyses for achieving personalized therapeutic schemes and better outcomes. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Optimum Cyclic Redundancy Codes for Noisy Channels

    NASA Technical Reports Server (NTRS)

    Posner, E. C.; Merkey, P.

    1986-01-01

    Capabilities and limitations of cyclic redundancy codes (CRC's) for detecting transmission errors in data sent over relatively noisy channels (e.g., voice-grade telephone lines or very-high-density storage media) discussed in 16-page report. Due to prevalent use of bytes in multiples of 8 bits data transmission, report primarily concerned with cases in which both block length and number of redundant bits (check bits for use in error detection) included in each block are multiples of 8 bits.

  18. Visual search of cyclic spatio-temporal events

    NASA Astrophysics Data System (ADS)

    Gautier, Jacques; Davoine, Paule-Annick; Cunty, Claire

    2018-05-01

    The analysis of spatio-temporal events, and especially of relationships between their different dimensions (space-time-thematic attributes), can be done with geovisualization interfaces. But few geovisualization tools integrate the cyclic dimension of spatio-temporal event series (natural events or social events). Time Coil and Time Wave diagrams represent both the linear time and the cyclic time. By introducing a cyclic temporal scale, these diagrams may highlight the cyclic characteristics of spatio-temporal events. However, the settable cyclic temporal scales are limited to usual durations like days or months. Because of that, these diagrams cannot be used to visualize cyclic events, which reappear with an unusual period, and don't allow to make a visual search of cyclic events. Also, they don't give the possibility to identify the relationships between the cyclic behavior of the events and their spatial features, and more especially to identify localised cyclic events. The lack of possibilities to represent the cyclic time, outside of the temporal diagram of multi-view geovisualization interfaces, limits the analysis of relationships between the cyclic reappearance of events and their other dimensions. In this paper, we propose a method and a geovisualization tool, based on the extension of Time Coil and Time Wave, to provide a visual search of cyclic events, by allowing to set any possible duration to the diagram's cyclic temporal scale. We also propose a symbology approach to push the representation of the cyclic time into the map, in order to improve the analysis of relationships between space and the cyclic behavior of events.

  19. Cyclic steaming in heavy oil diatomite

    SciT

    Kumar, M.; Beatty, F.D.

    1995-12-31

    Chevron currently uses cyclic steaming as a recovery method to produce economically its heavy oil diatomite resource in the Cymric field, San Joaquin Valley, California. A highly instrumented, cyclically steaming well from this field was simulated in this study to delineate important production mechanisms, to optimize operations, and to improve reservoir management. The model was constrained, as much as possible, by the available measured data. Results show that fluid flow from the well to the reservoir is primarily through the hydraulic fracture induced by the injected steam. Parameters with unique importance to modeling cyclic steaming in diatomites are: (1) inducedmore » fracture dimension (length and height), (2) matrix permeability, (3) oil/water capillary pressure, (4) grid size perpendicular to fracture face, and (5) producing bottomhole pressures. Additionally, parameters important for conventional steam injection processes, such as relative permeabilities and injected steam volume, quality, and rate, are important for diatomites also. Oil production rates and steam/oil ratios calculated by this model compare reasonably with field data.« less

  20. Cyclic dominance in evolutionary games: a review

    PubMed Central

    Szolnoki, Attila; Mobilia, Mauro; Jiang, Luo-Luo; Szczesny, Bartosz; Rucklidge, Alastair M.; Perc, Matjaž

    2014-01-01

    Rock is wrapped by paper, paper is cut by scissors and scissors are crushed by rock. This simple game is popular among children and adults to decide on trivial disputes that have no obvious winner, but cyclic dominance is also at the heart of predator–prey interactions, the mating strategy of side-blotched lizards, the overgrowth of marine sessile organisms and competition in microbial populations. Cyclical interactions also emerge spontaneously in evolutionary games entailing volunteering, reward, punishment, and in fact are common when the competing strategies are three or more, regardless of the particularities of the game. Here, we review recent advances on the rock–paper–scissors (RPS) and related evolutionary games, focusing, in particular, on pattern formation, the impact of mobility and the spontaneous emergence of cyclic dominance. We also review mean-field and zero-dimensional RPS models and the application of the complex Ginzburg–Landau equation, and we highlight the importance and usefulness of statistical physics for the successful study of large-scale ecological systems. Directions for future research, related, for example, to dynamical effects of coevolutionary rules and invasion reversals owing to multi-point interactions, are also outlined. PMID:25232048

  1. Cyclic degassing of Erebus volcano, Antarctica

    NASA Astrophysics Data System (ADS)

    Ilanko, Tehnuka; Oppenheimer, Clive; Burgisser, Alain; Kyle, Philip

    2015-06-01

    Field observations have previously identified rapid cyclic changes in the behaviour of the lava lake of Erebus volcano. In order to understand more fully the nature and origins of these cycles, we present here a wavelet-based frequency analysis of time series measurements of gas emissions from the lava lake, obtained by open-path Fourier transform infrared spectroscopy. This reveals (i) a cyclic change in total gas column amount, a likely proxy for gas flux, with a period of about 10 min, and (ii) a similarly phased cyclic change in proportions of volcanic gases, which can be explained in terms of chemical equilibria and pressure-dependent solubilities. Notably, the wavelet analysis shows a persistent periodicity in the CO2/CO ratio and strong periodicity in H2O and SO2 degassing. The `peaks' of the cycles, defined by maxima in H2O and SO2 column amounts, coincide with high CO2/CO ratios and proportionally smaller increases in column amounts of CO2, CO, and OCS. We interpret the cycles to arise from recharge of the lake by intermittent pulses of magma from shallow depths, which degas H2O at low pressure, combined with a background gas flux that is decoupled from this very shallow magma degassing.

  2. Cyclic dominance in evolutionary games: a review.

    PubMed

    Szolnoki, Attila; Mobilia, Mauro; Jiang, Luo-Luo; Szczesny, Bartosz; Rucklidge, Alastair M; Perc, Matjaž

    2014-11-06

    Rock is wrapped by paper, paper is cut by scissors and scissors are crushed by rock. This simple game is popular among children and adults to decide on trivial disputes that have no obvious winner, but cyclic dominance is also at the heart of predator-prey interactions, the mating strategy of side-blotched lizards, the overgrowth of marine sessile organisms and competition in microbial populations. Cyclical interactions also emerge spontaneously in evolutionary games entailing volunteering, reward, punishment, and in fact are common when the competing strategies are three or more, regardless of the particularities of the game. Here, we review recent advances on the rock-paper-scissors (RPS) and related evolutionary games, focusing, in particular, on pattern formation, the impact of mobility and the spontaneous emergence of cyclic dominance. We also review mean-field and zero-dimensional RPS models and the application of the complex Ginzburg-Landau equation, and we highlight the importance and usefulness of statistical physics for the successful study of large-scale ecological systems. Directions for future research, related, for example, to dynamical effects of coevolutionary rules and invasion reversals owing to multi-point interactions, are also outlined. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

  3. Scale factor duality for conformal cyclic cosmologies

    NASA Astrophysics Data System (ADS)

    Camara da Silva, U.; Alves Lima, A. L.; Sotkov, G. M.

    2016-11-01

    The scale factor duality is a symmetry of dilaton gravity which is known to lead to pre-big-bang cosmologies. A conformal time version of the scale factor duality (SFD) was recently implemented as a UV/IR symmetry between decelerated and accelerated phases of the post-big-bang evolution within Einstein gravity coupled to a scalar field. The problem investigated in the present paper concerns the employment of the conformal time SFD methods to the construction of pre-big-bang and cyclic extensions of these models. We demonstrate that each big-bang model gives rise to two qualitatively different pre-big-bang evolutions: a contraction/expansion SFD model and Penrose's Conformal Cyclic Cosmology (CCC). A few examples of SFD symmetric cyclic universes involving certain gauged Kähler sigma models minimally coupled to Einstein gravity are studied. We also describe the specific SFD features of the thermodynamics and the conditions for validity of the generalized second law in the case of Gauss-Bonnet (GB) extension of these selected CCC models.

  4. METABOLISM AND DISPOSITION OF ACETAMINOPHEN: RECENT ADVANCES IN RELATION TO HEPATOTOXICITY AND DIAGNOSIS

    PubMed Central

    McGill, Mitchell R.; Jaeschke, Hartmut

    2013-01-01

    Acetaminophen (APAP) is one of the most widely used drugs. Though safe at therapeutic doses, overdose causes mitochondrial dysfunction and centrilobular necrosis in the liver. The first studies of APAP metabolism and activation were published more than forty years ago. Most of the drug is eliminated by glucuronidation and sulfation. These reactions are catalyzed by UDP-glucuronosyltransferases (UGT1A1 and 1A6) and sulfotransferases (SULT1A1, 1A3/4, and 1E1), respectively. However, some is converted by CYP2E1 and other cytochrome P450 enzymes to a reactive intermediate that can bind to sulfhydryl groups. The metabolite can deplete liver glutathione (GSH) and modify cellular proteins. GSH binding occurs spontaneously, but may also involve GSH-S-transferases. Protein binding leads to oxidative stress and mitochondrial damage. The glucuronide, sulfate, and GSH conjugates are excreted by transporters in the canalicular (Mrp2 and Bcrp) and basolateral (Mrp3 and Mrp4) hepatocyte membranes. Conditions that interfere with metabolism and metabolic activation can alter the hepatotoxicity of the drug. Recent data providing novel insights into these processes, particularly in humans, are reviewed in the context of earlier work, and the effects of altered metabolism and reactive metabolite formation are discussed. Recent advances in the diagnostic use of serum adducts are covered. PMID:23462933

  5. Amelioration of lead-induced hepatotoxicity by Allium sativum extracts in Swiss albino mice

    PubMed Central

    Sharma, Arti; Sharma, Veena; Kansal, Leena

    2010-01-01

    Lead is a blue–gray and highly toxic divalent metal that occurs naturally in the earth's crust and is spread throughout the environment by various human activities. The efficacy of garlic (Allium sativum) to reduce hepatotoxicity induced by lead nitrate was evaluated experimentally in male mice. Oral treatment with lead nitrate at a dose of 50 mg/kg body weight daily for 40 days (1/45 of LD50) induced a significant increase in the levels of hepatic aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, acid phosphatase, cholesterol, lipid peroxidation, and lead nitrate. In parallel, hepatic protein levels in lead-exposed mice were significantly depleted. Lead nitrate exposure also produced detrimental effects on the redox status of the liver indicated by a significant decline in the levels of liver antioxidants such as superoxide dismutase, catalase, and glutathione. After exposure to lead nitrate (50 mg/kg body weight for 10 days), the animals received aqueous garlic extract (250 mg/kg body weight and 500 mg/kg body weight) and ethanolic garlic extract (100 mg/kg body weight and 250 mg/kg body weight), and partially restored the deranged parameters significantly. Histological examination of the liver also revealed pathophysiological changes in lead nitrate-exposed group and treatment with garlic improved liver histology. Our data suggest that garlic is a phytoantioxidant that can counteract the deleterious effects of lead nitrate. PMID:21483544

  6. Hepatotoxicity of Herbal Supplements Mediated by Modulation of Cytochrome P450

    PubMed Central

    Chen, Taosheng

    2017-01-01

    Herbal supplements are a significant source of drug-drug interactions (DDIs), herb-drug interactions, and hepatotoxicity. Cytochrome P450 (CYP450) enzymes metabolize a large number of FDA-approved pharmaceuticals and herbal supplements. This metabolism of pharmaceuticals and supplements can be augmented by concomitant use of either pharmaceuticals or supplements. The xenobiotic receptors constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) can respond to xenobiotics by increasing the expression of a large number of genes that are involved in the metabolism of xenobiotics, including CYP450s. Conversely, but not exclusively, many xenobiotics can inhibit the activity of CYP450s. Induction of the expression or inhibition of the activity of CYP450s can result in DDIs and toxicity. Currently, the United States (US) Food and Drug Administration does not require the investigation of the interactions of herbal supplements and CYP450s. This review provides a summary of herbal supplements that inhibit CYP450s, induce the expression of CYP450s, and/or whose toxicity is mediated by CYP450s. PMID:29117101

  7. Carbon Tetrachloride at Hepatotoxic Levels Blocks Reversibly Gap Junctions between Rat Hepatocytes

    NASA Astrophysics Data System (ADS)

    Saez, J. C.; Bennett, M. V. L.; Spray, D. C.

    1987-05-01

    Electrical coupling and dye coupling between pairs of rat hepatocytes were reversibly reduced by brief exposure to halogenated methanes (CBrCl3, CCl4, and CHCl3). The potency of different halomethanes in uncoupling hepatocytes was comparable to their hepatotoxicity in vivo, and the rank order was the same as that of their tendency to form free radicals. The effect of carbon tetrachloride (CCl4) on hepatocytes was substantially reduced by prior treatment with SKF 525A, an inhibitor of cytochrome P-450, and by exposure to the reducing reagent β -mercaptoethanol. Halomethane uncoupling occurred with or without extracellular calcium and did not change intracellular concentrations of calcium and hydrogen ions or the phosphorylation state of the main gap-junctional protein. Thus the uncoupling appears to depend on cytochrome P-450 oxidative metabolism in which free radicals are generated and may result from oxidation of the gap-junctional protein or of a regulatory molecule that leads to closure of gap-junctional channels. Decreases in junctional conductance may be a rapid cellular response to injury that protects healthy cells by uncoupling them from unhealthy ones.

  8. Attenuation of N-nitrosodimethylamine induced hepatotoxicity by Operculina turpethum in Swiss Albino mice

    PubMed Central

    Sharma, Veena; Singh, Manu

    2014-01-01

    Objective(s): To appraise the antihepatotoxic efficacy of ethanolic extract of Operculum turpethum root on the liver of Swiss albino mice. Materials and Methods: Hepatic fibrosis was induced in adult male albino mice through intraperitoneal administrations of N-nitrosodimethylamine (NDMA) at the concentration of 10 mg/kg body weight. The liver toxicity and therapeutic effect of the plant ethanolic extract was assessed by the analysis of liver marker enzymes and antioxidant enzymes and liver histopathological studies. Results: Hepatotoxicity was manifested by significantly decreased (P<0.01) levels of the activities of the enzymatic and non enzymatic antioxidants such as superoxide dismutase, catalase, GSH and increased levels of cholesterol, AST, ALT, ALP and lipid peroxidation. The plant extract significantly restored the antioxidant enzyme level in the liver and exhibited significant dose dependent curative effect against NDMA induced toxicity which was also supported by histopathological studies of the liver. Conclusion: O. turpethum manifested therapeutic effects by significantly restoring the enzymatic levels and reducing the hepatic damage in mice. This work intends to aid researchers in the study of natural products which could be useful in the treatment of liver diseases including cancer. PMID:24592311

  9. A Comparative Analysis of Drug-Induced Hepatotoxicity in Clinically Relevant Situations

    PubMed Central

    Thiel, Christoph; Cordes, Henrik; Fabbri, Lorenzo; Aschmann, Hélène Eloise; Baier, Vanessa; Atkinson, Francis; Blank, Lars Mathias; Kuepfer, Lars

    2017-01-01

    Drug-induced toxicity is a significant problem in clinical care. A key problem here is a general understanding of the molecular mechanisms accompanying the transition from desired drug effects to adverse events following administration of either therapeutic or toxic doses, in particular within a patient context. Here, a comparative toxicity analysis was performed for fifteen hepatotoxic drugs by evaluating toxic changes reflecting the transition from therapeutic drug responses to toxic reactions at the cellular level. By use of physiologically-based pharmacokinetic modeling, in vitro toxicity data were first contextualized to quantitatively describe time-resolved drug responses within a patient context. Comparatively studying toxic changes across the considered hepatotoxicants allowed the identification of subsets of drugs sharing similar perturbations on key cellular processes, functional classes of genes, and individual genes. The identified subsets of drugs were next analyzed with regard to drug-related characteristics and their physicochemical properties. Toxic changes were finally evaluated to predict both molecular biomarkers and potential drug-drug interactions. The results may facilitate the early diagnosis of adverse drug events in clinical application. PMID:28151932

  10. Replicative stress and alterations in cell cycle checkpoint controls following acetaminophen hepatotoxicity restrict liver regeneration.

    PubMed

    Viswanathan, Preeti; Sharma, Yogeshwar; Gupta, Priya; Gupta, Sanjeev

    2018-03-05

    Acetaminophen hepatotoxicity is a leading cause of hepatic failure with impairments in liver regeneration producing significant mortality. Multiple intracellular events, including oxidative stress, mitochondrial damage, inflammation, etc., signify acetaminophen toxicity, although how these may alter cell cycle controls has been unknown and was studied for its significance in liver regeneration. Assays were performed in HuH-7 human hepatocellular carcinoma cells, primary human hepatocytes and tissue samples from people with acetaminophen-induced acute liver failure. Cellular oxidative stress, DNA damage and cell proliferation events were investigated by mitochondrial membrane potential assays, flow cytometry, fluorescence staining, comet assays and spotted arrays for protein expression after acetaminophen exposures. In experimental groups with acetaminophen toxicity, impaired mitochondrial viability and substantial DNA damage were observed with rapid loss of cells in S and G2/M and cell cycle restrictions or even exit in the remainder. This resulted from altered expression of the DNA damage regulator, ATM and downstream transducers, which imposed G1/S checkpoint arrest, delayed entry into S and restricted G2 transit. Tissues from people with acute liver failure confirmed hepatic DNA damage and cell cycle-related lesions, including restrictions of hepatocytes in aneuploid states. Remarkably, treatment of cells with a cytoprotective cytokine reversed acetaminophen-induced restrictions to restore cycling. Cell cycle lesions following mitochondrial and DNA damage led to failure of hepatic regeneration in acetaminophen toxicity but their reversibility offers molecular targets for treating acute liver failure. © 2018 John Wiley & Sons Ltd.

  11. Biomonitoring of the Genotoxic and Hepatotoxic Effects and Oxidative Stress Potentials of Itraconazole in Pregnant Rats.

    PubMed

    El-Shershaby, Abdel-Fattah; Dakrory, Ahmed I; El-Dakdoky, Mai H; Ibrahim, Jehane; Kassem, Fatma

    2015-04-01

    Pregnant women are more susceptible to both vaginal colonization and infection by yeast. One hundred million fungal infected patients have been treated worldwide with itraconazole (Caputo, 2003. Itraconazole was administrated orally to pregnant rats at doses of 75, 100, or 150 mg/kg during gestational days (GD) 1 to 7 or GD 8 to 14 or GD 14 to 20. The genotoxicity and hepatotoxicity of the antifungal drug itraconazole were assessed during different periods of pregnancy using different methods. It was found that itraconazole was a genotoxic drug for both mothers and fetuses. This finding was observed via significant elevation in the estimated comet assay parameters (percentage of fragmented DNA, tail moment, and olive moment), percentage of fragmented DNA measured by diphenylamine assay and mixed smearing and laddering of DNA fragments of liver samples. In addition, itraconazole caused significant elevation in the level of hepatic malondialdehyde and depletion in the catalase activity and glutathione level. Furthermore, itraconazole induced histopathological alterations in the hepatic tissues of both mothers and fetuses. These findings indicate that itraconazole administration at doses of 75, 100, or 150 mg/kg during pregnancy induced maternal and fetal toxicity that could be induced by the genotoxicity and the oxidative damage. © 2015 Wiley Periodicals, Inc.

  12. Transcriptome profiling and pathway analysis of hepatotoxicity induced by tris (2-ethylhexyl) trimellitate (TOTM) in mice.

    PubMed

    Chen, Xian-Hua; Ma, Li; Hu, Yi-Xiang; Wang, Dan-Xian; Fang, Li; Li, Xue-Lai; Zhao, Jin-Chuan; Yu, Hai-Rong; Ying, Hua-Zhong; Yu, Chen-Huan

    2016-01-01

    Tris (2-ethylhexyl) trimellitate (TOTM) is commonly used as an alternative plasticizer for medical devices. But very little information was available on its biological effects. In this study, we investigated toxicity effects of TOTM on hepatic differential gene expression analyzed by using high-throughput sequencing analysis for over-represented functions and phenotypically anchored to complementary histopathologic, and biochemical data in the liver of mice. Among 1668 candidate genes, 694 genes were up-regulated and 974 genes were down-regulated after TOTM exposure. Using Gene Ontology analysis, TOTM affected three processes: the cell cycle, metabolic process and oxidative activity. Furthermore, 11 key genes involved in the above processes were validated by real time PCR. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that these genes were involved in the cell cycle pathway, lipid metabolism and oxidative process. It revealed the transcriptome gene expression response to TOTM exposure in mouse, and these data could contribute to provide a clearer understanding of the molecular mechanisms of TOTM-induced hepatotoxicity in human. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Genetic polymorphisms of N-acetyltransferase 2 & susceptibility to antituberculosis drug-induced hepatotoxicity.

    PubMed

    Sharma, Surendra K; Jha, Brajesh Kumar; Sharma, Abhishek; Sreenivas, V; Upadhyay, Vishwanath; Jaisinghani, Chandrita; Singla, Rohit; Mishra, Hemant Kumar; Soneja, Manish

    2016-12-01

    The N-acetyltransferase 2 (NAT2) gene encodes an enzyme which both activates and deactivates arylamine and other drugs and carcinogens. This study was aimed to investigate the role of NAT2 gene polymorphism in anti-tuberculosis drug-induced hepatotoxicity (DIH). In this prospective study, polymerase chain reaction-restriction fragment length polymorphism results for NAT2 gene were compared between 185 tuberculosis patients who did not develop DIH and 105 tuberculosis patients who developed DIH while on anti-tuberculosis drugs. Frequency of slow-acetylator genotype was commonly encountered and was not significantly different between DIH (82.8%) and non-DIH (77.2%) patients. However, the genotypic distribution of variant NAT2FNx015/FNx017 amongst slow-acetylator genotypes was significantly higher in DIH (56%) group as compared to non-DIH (39%) group (odds ratio 2.02; P=0.006). The present study demonstrated no association between NAT2 genotype and DIH in the north Indian patients with tuberculosis.

  14. Development and application of a comparative fatty acid analysis method to investigate voriconazole-induced hepatotoxicity.

    PubMed

    Chen, Guan-yuan; Chiu, Huai-hsuan; Lin, Shu-wen; Tseng, Yufeng Jane; Tsai, Sung-jeng; Kuo, Ching-hua

    2015-01-01

    As fatty acids play an important role in biological regulation, the profiling of fatty acid expression has been used to discover various disease markers and to understand disease mechanisms. This study developed an effective and accurate comparative fatty acid analysis method using differential labeling to speed up the metabolic profiling of fatty acids. Fatty acids were derivatized with unlabeled (D0) or deuterated (D3) methanol, followed by GC-MS analysis. The comparative fatty acid analysis method was validated using a series of samples with different ratios of D0/D3-labeled fatty acid standards and with mouse liver extracts. Using a lipopolysaccharide (LPS)-treated mouse model, we found that the fatty acid profiles after LPS treatment were similar between the conventional single-sample analysis approach and the proposed comparative approach, with a Pearson's correlation coefficient of approximately 0.96. We applied the comparative method to investigate voriconazole-induced hepatotoxicity and revealed the toxicity mechanism as well as the potential of using fatty acids as toxicity markers. In conclusion, the comparative fatty acid profiling technique was determined to be fast and accurate and allowed the discovery of potential fatty acid biomarkers in a more economical and efficient manner. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Protective effect of boric acid against carbon tetrachloride-induced hepatotoxicity in mice.

    PubMed

    Ince, Sinan; Keles, Hikmet; Erdogan, Metin; Hazman, Omer; Kucukkurt, Ismail

    2012-07-01

    The protective effect of boric acid against liver damage was evaluated by its attenuation of carbon tetrachloride (CCl(4))-induced hepatotoxicity in mice. Male albino mice were treated intraperitoneally (i.p.) with boric acid (50, 100, and 200 mg/kg) or silymarin daily for 7 days and received 0.2% CCl(4) in olive oil (10 mL/kg, i.p.) on day 7. Results showed that administration of boric acid significantly reduced the elevation in serum levels of aspartate aminotransferase, alkaline phosphatase, alanine aminotransferase, and the level of malondialdehyde in the liver that were induced by CCl(4) in mice. Boric acid treatment significantly increased glutathione content, as well as the activities of superoxide dismutase and catalase in the liver. Boric acid treatment improved the catalytic activity of cytochrome P450 2E1 and maintained activation of nuclear factor kappa light-chain enhancer of activated B cell gene expression, with no effect on inducible nitric oxide synthase gene expression in the livers of mice. Histopathologically, clear decreases in the severity of CCl(4)-induced lesions were observed, particularly at high boric acid concentrations. Results suggest that boric acid exhibits potent hepatoprotective effects on CCl(4)-induced liver damage in mice, likely the result of both the increase in antioxidant-defense system activity and the inhibition of lipid peroxidation.

  16. Protective effect of Spirulina platensis enriched in phenolic compounds against hepatotoxicity induced by CCl4.

    PubMed

    Kepekçi, Remziye Aysun; Polat, Sait; Çelik, Ahmet; Bayat, Nuray; Saygideger, Saadet Demirörs

    2013-12-01

    Phenolic compounds make up the major secondary metabolites with high pharmaceutical potential. Microalgae were reported to contain low amounts of phenolic compounds. The present study aimed to investigate the hepatoprotective potential of biomass of Spirulina platensis enriched in phenolic compounds. The protective effects of the biomass of S. platensis with low amounts of phenolics (SP1) and with high amounts of phenolics (SP2) against CCl4-induced acute hepatotoxicity were evaluated in rats. The increased levels of ALT, AST and MDA along with decreased activities of SOD and CAT were significantly (p<0.01) ameliorated by SP2. Histological examinations revealed that SP2 was more potent than SP1 in protecting the liver from toxic injury of CCl4 and preserving the hepatocyte ultrastructure. The lesions including necrosis, lymphocyte infiltration, ballooning degeneration and hepatocyte injury as irregular lamellar organisation, dilations in endoplasmic reticulums and the presence of great number of cytoplasmic vacuolization were healed by SP2. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Hepatoprotective influence of quercetin and ellagic acid on thioacetamide-induced hepatotoxicity in rats.

    PubMed

    Afifi, Nehal A; Ibrahim, Marwa A; Galal, Mona K

    2018-06-01

    Despite all the studies performed to date, therapy choices for liver injuries are very few. Therefore, the search for a new treatment that could safely and effectively block or reverse liver injuries remains a challenge. Quercetin (QR) and ellagic acid (EA) had potent antioxidant and anti-inflammatory activities. The current study aimed at evaluating the potential hepatoprotective influence of QR and EA against thioacetamide (TAA)-induced liver toxicity in rats and the underlying mechanism using silymarin as a reference drug. Fifty mature male rats were orally treated daily with EA and QR in separate groups for 45 consecutive days, and then were injected with TAA twice with 24 h intervals in the last 2 days of the experiment. Administration of TAA resulted in marked elevation of liver indices, alteration in oxidative stress parameters, and significant elevation in expression level of fibrosis-related genes (MMP9 and MMP2). Administration of QR and EA significantly attenuated the hepatic toxicity through reduction of liver biomarkers, improving the redox status of the tissue, as well as hampering the expression level of fibrosis-related genes. In this study, QR and EA were proved to attenuate the hepatotoxicity through their antioxidant, metal-chelating capacity, and anti-inflammatory effects.

  18. Drug-induced idiosyncratic hepatotoxicity: prevention strategy developed after the troglitazone case.

    PubMed

    Ikeda, Toshihiko

    2011-01-01

    Troglitazone induced an idiosyncratic, hepatocellular injury-type hepatotoxicity in humans. Statistically, double null genotype of glutathione S-transferase isoforms, GSTT1 and GSTM1, was a risk factor, indicating a low activity of the susceptible patients in scavenging chemically reactive metabolites. CYP3A4 and CYP2C8 were involved in the metabolic activation and CYP3A4 was inducible by repeated administrations of troglitazone. The genotype analysis, however, indicated that the metabolic idiosyncrasy resides in the degradation of but not in the production of the toxic metabolites of troglitazone. Antibody against hepatic aldolase B was detected in the case patients, suggesting involvement of immune reaction in the toxic mechanism. Troglitazone induced apoptotic cell death in human hepatocytes at a high concentration, and this property may have served as the immunological danger signal, which is thought to play an important role in activating immune reactions. Hypothesis is proposed in analogy to the virus-induced hepatitis. After the troglitazone-case, pharmaceutical companies implemented screening systems for chemically reactive metabolites at early stage of drug development, taking both the amount of covalent binding to the proteins in vitro and the assumed clinical dose level into consideration. At the post-marketing stage, gene analyses of the case patients, if any, to find pharmacogenetic biomarkers could be a powerful tool for contraindicating to the risky patients.

  19. Evaluation of Antitrypanosomal Dihydroquinolines for Hepatotoxicity, Mutagenicity, and Methemoglobin Formation In Vitro

    PubMed Central

    Werbovetz, Karl A.; Riccio, Edward S.; Furimsky, Anna; Richard, Julian V.; He, Shanshan; Iyer, Lalitha; Mirsalis, Jon

    2014-01-01

    N 1-benzylated dihydroquinolin-6-ols and their corresponding esters display exceptional activity against African trypanosomes in vitro, and administration of members of this class of compounds to trypanosome-infected mice results in cures in a first stage African trypanosomiasis model. Since a quinone imine intermediate has been implicated in the antiparasitic mechanism of action of these compounds, evaluation of the hepatotoxic, mutagenic, and methemoglobin-promoting effects of these agents was performed. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride (OSU-36.HCl) and 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate (OSU-40) showed outstanding in vitro selectivity for T. brucei compared to the HepG2, Hep3B, Huh7 and PLC5 hepatocyte cell lines. OSU-36.HCl and 1-(2-methoxybenzyl)-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate (OSU-75) were not mutagenic when screened in the Ames assay, with or without metabolic activation. The latter two compounds promoted time- and dose-dependent formation of methemoglobin when incubated in whole human blood, but such levels were below those typically required to produce symptoms of methemoglobinemia in humans. While compounds capable of quinone imine formation require careful evaluation, these in vitro studies indicate that antitrypanosomal dihydroquinolines merit further study as drug candidates against the neglected tropical disease human African trypanosomiasis. PMID:24819520

  20. Evaluation of Antitrypanosomal Dihydroquinolines for Hepatotoxicity, Mutagenicity, and Methemoglobin Formation In Vitro.

    PubMed

    Werbovetz, Karl A; Riccio, Edward S; Furimsky, Anna; Richard, Julian V; He, Shanshan; Iyer, Lalitha; Mirsalis, Jon

    2014-07-01

    N1-Benzylated dihydroquinolin-6-ols and their corresponding esters display exceptional activity against African trypanosomes in vitro, and administration of members of this class of compounds to trypanosome-infected mice results in cures in a first-stage African trypanosomiasis model. Since a quinone imine intermediate has been implicated in the antiparasitic mechanism of action of these compounds, evaluation of the hepatotoxic, mutagenic, and methemoglobin-promoting effects of these agents was performed. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate showed outstanding in vitro selectivity for Trypanosoma brucei compared to the HepG2, Hep3B, Huh7, and PLC5 hepatocyte cell lines. 1-Benzyl-1,2-dihydro-2,2,4-trimethylquinolin-6-ol hydrochloride and 1-(2-methoxybenzyl)-1,2-dihydro-2,2,4-trimethylquinolin-6-yl acetate were not mutagenic when screened in the Ames assay, with or without metabolic activation. The latter 2 compounds promoted time- and dose-dependent formation of methemoglobin when incubated in whole human blood, but such levels were below those typically required to produce symptoms of methemoglobinemia in humans. Although compounds capable of quinone imine formation require careful evaluation, these in vitro studies indicate that antitrypanosomal dihydroquinolines merit further study as drug candidates against the neglected tropical disease human African trypanosomiasis. © The Author(s) 2014.

  1. Protective effects of silymarin against bisphenol A-induced hepatotoxicity in mouse liver

    PubMed Central

    Zaulet, Mihaela; Kevorkian, Steliana Elvira Maria; Dinescu, Sorina; Cotoraci, Coralia; Suciu, Maria; Herman, Hildegard; Buburuzan, Laura; Badulescu, Liliana; Ardelean, Aurel; Hermenean, Anca

    2017-01-01

    Bisphenol A (BPA) is an endocrine-disrupting chemical released into the environment, with severe consequences for human health, including metabolic syndrome and associated pathological conditions. Due to limited information on BPA-induced hepatotoxicity, the present study focused on investigating the association between BPA-induced toxicity and inflammatory markers in the liver, and how these injuries may be alleviated using the natural agent silymarin, a flavonoid with antioxidant properties obtained from Silybum marianum. Administration of BPA to male CD-1 mice for 10 days caused a significant increase in the number of cells immunopositive for interleukin 6 and tumor necrosis factor-α, pro-inflammatory cytokines that mediate the hepatic inflammatory response. Treatment with 200 mg/kg of silymarin concurrently with BPA for 10 days resulted in a diminished level of pro-inflammatory cytokines and in significantly reduced ultrastructural injuries. Additionally, silymarin was able to restore the significantly decreased glycogen deposits observed following BPA exposure to normal levels, thus favoring hepatic glycogenesis. This study represents the first report of silymarin ability to reduce hepatic lesions and to counteract inflammation caused by BPA in mice. A dose of 200 mg/kg silymarin was sufficient to induce a protective effect against structural and ultrastructural injuries induced by BPA and to lower the levels of pro-inflammatory cytokines observed in murine liver tissue following exposure to BPA. PMID:28450905

  2. Cuscuta arvensis Beyr "Dodder": In Vivo Hepatoprotective Effects Against Acetaminophen-Induced Hepatotoxicity in Rats.

    PubMed

    Koca-Caliskan, Ufuk; Yilmaz, Ismet; Taslidere, Asli; Yalcin, Funda N; Aka, Ceylan; Sekeroglu, Nazim

    2018-05-02

    Cuscuta arvensis Beyr. is a parasitic plant, and commonly known as "dodder" in Europe, in the United States, and "tu si zi shu" in China. It is one of the preferred spices used in sweet and savory dishes. Also, it is used as a folk medicine for the treatment particularly of liver problems, knee pains, and physiological hepatitis, which occur notably in newborns and their mothers in the southeastern part of Turkey. The purpose of this study was to investigate the hepatoprotective effects and antioxidant activities of aqueous and methanolic extracts of C. arvensis Beyr. on acetaminophen (APAP)-induced acute hepatotoxicity in rats. The results were supported by subsequent histopathological studies. The hepatoprotective activity of both the aqueous and methanolic extracts at an oral dose of 125 and 250 mg/kg was investigated by observing the reduction levels or the activity of alkaline phosphatase, alkaline transaminase, aspartate aminotransferase, blood urine nitrogen, and total bilirubin content. In vivo antioxidant activity was determined by analyzing the serum superoxide dismutase, malondialdehyde, glutathione, and catalase levels. Chromatographic methods were used to isolate biologically active compounds from the extract, and spectroscopic methods were used for structure elucidation. Both the methanolic and aqueous extracts exerted noticable hepatoprotective and antioxidant effects supporting the folkloric usage of dodder. One of the bioactive compounds was kaempferol-3-O-rhamnoside, isolated and identified from the methanolic extract.

  3. Nanoparticles formulation of Cuscuta chinensis prevents acetaminophen-induced hepatotoxicity in rats.

    PubMed

    Yen, Feng-Lin; Wu, Tzu-Hui; Lin, Liang-Tzung; Cham, Thau-Ming; Lin, Chun-Ching

    2008-05-01

    Cuscuta chinensis is a commonly used traditional Chinese medicine to nourish the liver and kidney. Due to the poor water solubility of its major constituents such as flavonoids and lignans, its absorption upon oral administration could be limited. The purpose of the present study was to use the nanosuspension method to prepare C. chinensis nanoparticles (CN), and to compare the hepatoprotective and antioxidant effects of C. chinensis ethanolic extract (CE) and CN on acetaminophen-induced hepatotoxicity in rats. An oral dose of CE at 125 and 250 mg/kg and CN at 25 and 50mg/kg showed a significant hepatoprotective effect relatively to the same extent (P<0.05) by reducing levels of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. These biochemical assessments were supported by rat hepatic biopsy examinations. In addition, the antioxidant activities of CE and CN both significantly increased superoxide dismutase, catalase, glutathione peroxidase, and reduced malondialdehyde (P<0.05). Moreover, the results also indicated that the hepatoprotective and antioxidant effects of 50 mg/kg CN was effectively better than 125 mg/kg CE (P<0.05), and an oral dose of CN that is five times as less as CE could exhibit similar levels of outcomes. In conclusion, we suggest that the nanoparticles system can be applied to overcome other water poorly soluble herbal medicines and furthermore to decrease the treatment dosage.

  4. Immunization of Mice with Anthrax Protective Antigen Limits Cardiotoxicity but Not Hepatotoxicity Following Lethal Toxin Challenge.

    PubMed

    Devera, T Scott; Prusator, Dawn K; Joshi, Sunil K; Ballard, Jimmy D; Lang, Mark L

    2015-06-25

    Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. It is therefore important to determine to what extent anthrax vaccines and existing or candidate adjuvants can provide organ-specific protection against intoxication. We therefore compared the ability of Alum, CpG DNA and the CD1d ligand α-galactosylceramide (αGC) to enhance protective antigen-specific antibody titers, to protect mice against challenge with lethal toxin, and to block cardiotoxicity and hepatotoxicity. By measurement of serum cardiac Troponin I (cTnI), and hepatic alanine aminotransferase (ALT), and aspartate aminotransferase (AST), it was apparent that neither vaccine modality prevented hepatic intoxication, despite high Ab titers and ultimate survival of the subject. In contrast, cardiotoxicity was greatly diminished by prior immunization. This shows that a vaccine that confers survival following toxin exposure may still have an associated morbidity. We propose that organ-specific intoxication should be monitored routinely during research into new vaccine modalities.

  5. Cyclic steady state stress-strain behavior of UHMW polyethylene.

    PubMed

    Krzypow, D J; Rimnac, C M

    2000-10-01

    To increase the long-term performance of total joint replacements, finite element analyses of ultra high molecular weight polyethylene (UHMWPE) components have been conducted to predict the effect of load on the stress and strain distributions occurring on and within these components. Early models incorporated the monotonic behavior of UHMWPE without considering the unloading and cyclic loading behavior. However, UHMWPE components undergo cyclic loading during use and at least two wear damage modes (pitting and delamination) are thought to be associated with the fatigue fracture properties of UHMWPE. The objective of this study was to examine the fully reversed uniaxial tension/compression cyclic steady state stress-strain behavior of UHMWPE as a first step towards developing a cyclic constitutive relationship for UHMWPE. The hypothesis that cycling results in a permanent change in the stress-strain relationship, that is, that the cyclic steady state represents a new cyclically stabilized state, was examined. It was found that, like other ductile polymers, UHMWPE substantially cyclically softens under fully reversed uniaxial straining. More cyclic softening occurred in tension than in compression. Furthermore, cyclic steady state was attained, but not cyclic stability. It is suggested that it may be more appropriate to base a material constitutive relationship for UHMWPE for finite element analyses of components upon a cyclically modified stress-strain relationship.

  6. Multicenter study of trimethoprim/sulfamethoxazole-related hepatotoxicity: incidence and associated factors among HIV-infected patients treated for Pneumocystis jirovecii pneumonia.

    PubMed

    Yang, Jen-Jia; Huang, Chung-Hao; Liu, Chun-Eng; Tang, Hung-Jen; Yang, Chia-Jui; Lee, Yi-Chien; Lee, Kuan-Yeh; Tsai, Mao-Song; Lin, Shu-Wen; Chen, Yen-Hsu; Lu, Po-Liang; Hung, Chien-Ching

    2014-01-01

    The incidence of hepatotoxicity related to trimethoprim/sulfamethoxazole (TMP/SMX) administered at a therapeutic dose may vary among study populations of different ethnicities and hepatotoxic metabolites of TMP/SMX may be decreased by drug-drug interaction with fluconazole. We aimed to investigate the incidence of hepatotoxicity and the role of concomitant use of fluconazole in HIV-infected patients receiving TMP/SMX for Pneumocystis jirovecii pneumonia. We reviewed medical records to collect clinical characteristics and laboratory data of HIV-infected patients who received TMP/SMX for treatment of P. jirovecii pneumonia at 6 hospitals around Taiwan between September 2009 and February 2013. Hepatotoxicity was defined as 2-fold or greater increase of aminotransferase or total bilirubin level from baselines. Roussel UCLAF Causality Assessment Method (RUCAM) was used to analyze the causality of drug-induced liver injuries. NAT1 and NAT2 acetylator types were determined with the use of polymerase-chain-reaction (PCR) restriction fragment length polymorphism to differentiate common single-nucleotide polymorphisms (SNPs) predictive of the acetylator phenotypes in a subgroup of patients. During the study period, 286 courses of TMP/SMX treatment administered to 284 patients were analyzed. One hundred and fifty-two patients (53.1%) developed hepatotoxicity, and TMP/SMX was considered causative in 47 (16.4%) who had a RUCAM score of 6 or greater. In multivariate analysis, concomitant use of fluconazole for candidiasis was the only factor associated with reduced risk for hepatotoxicity (adjusted odds ratio, 0.372; 95% confidence interval, 0.145-0.957), while serostatus of hepatitis B or C virus, NAT1 and NAT2 acetylator types, or receipt of combination antiretroviral therapy was not. The incidence of hepatotoxicity decreased with an increasing daily dose of fluconazole up to 4.0 mg/kg. We conclude that the incidence of TMP/SMX-related hepatotoxicity was 16.4% in HIV

  7. Unusual Synchronous Methimazole-Induced Agranulocytosis and Severe Hepatotoxicity in Patient with Hyperthyroidism: A Case Report and Review of the Literature

    PubMed Central

    Yang, Jun; Zhang, Jun; Xu, Qin; Sheng, Guo-ping; Weng, Wan-wen; Dong, Meng-jie

    2015-01-01

    Context. To report a patient with hyperthyroidism who developed concurrent occurrence of agranulocytosis and severe hepatotoxicity after taking methimazole (MMI). Case. A 51-year-old Chinese male was diagnosed as hyperthyroidism with normal white blood count and liver function. After 4 weeks' treatment with MMI 20 mg/d, it developed to agranulocytosis and severe cholestatic hepatotoxicity. The patient's symptoms and laboratory abnormalities disappeared after the withdrawal of MMI; his white blood count and liver function recover to normal in 2 weeks and 5 weeks, respectively. 296 MBq dose of 131I was given to the patient 3 weeks after the withdrawal of MMI and his thyroid function was back to normal in 6 months. As we know through literature review, only 5 previous cases reported the synchronous ATD-induced agranulocytosis and severe hepatotoxicity in patients with hyperthyroidism. Methods. Review of the patient's clinical course. Literature review of cases of hyperthyroidism with agranulocytosis and severe hepatotoxicity demonstrated that these complications occurred after taking antithyroid drug (ATD). Conclusions. Patient with hyperthyroidism can have synchronous ATD-induced agranulocytosis and severe hepatotoxicity. This case is extremely rare, but the adverse effects with ATDs is clinically significant. The clinicians need to be careful about this and monitor biochemical of patients who take ATDs. PMID:26060496

  8. Statistical damage constitutive model for rocks subjected to cyclic stress and cyclic temperature

    NASA Astrophysics Data System (ADS)

    Zhou, Shu-Wei; Xia, Cai-Chu; Zhao, Hai-Bin; Mei, Song-Hua; Zhou, Yu

    2017-10-01

    A constitutive model of rocks subjected to cyclic stress-temperature was proposed. Based on statistical damage theory, the damage constitutive model with Weibull distribution was extended. Influence of model parameters on the stress-strain curve for rock reloading after stress-temperature cycling was then discussed. The proposed model was initially validated by rock tests for cyclic stress-temperature and only cyclic stress. Finally, the total damage evolution induced by stress-temperature cycling and reloading after cycling was explored and discussed. The proposed constitutive model is reasonable and applicable, describing well the stress-strain relationship during stress-temperature cycles and providing a good fit to the test results. Elastic modulus in the reference state and the damage induced by cycling affect the shape of reloading stress-strain curve. Total damage induced by cycling and reloading after cycling exhibits three stages: initial slow increase, mid-term accelerated increase, and final slow increase.

  9. Cyclic tensile strain and cyclic hydrostatic pressure differentially regulate expression of hypertrophic markers in primary chondrocytes.

    PubMed

    Wong, Marcy; Siegrist, Mark; Goodwin, Kelly

    2003-10-01

    Endochondral ossification is regulated by many factors, including mechanical stimuli, which can suppress or accelerate chondrocyte maturation. Mathematical models of endochondral ossification have suggested that tension (or shear stress) can accelerate the formation of endochondral bone, while hydrostatic stress preserves the cartilage phenotype. The goal of this study was to test this hypothesis by examining the expression of hypertrophic chondrocyte markers (transcription factor Cbfa1, MMP-13, type X collagen, VEGF, CTGF) and cartilage matrix proteins under cyclic tension and cyclic hydrostatic pressure. Chondrocyte-seeded alginate constructs were exposed to one of the two loading modes for a period of 3 h per day for 3 days. Gene expression was analyzed using real-time RT-PCR. Cyclic tension upregulated the expression of Cbfa1, MMP-13, CTGF, type X collagen and VEGF and downregulated the expression of TIMP-1. Cyclic tension also upregulated the expression of type 2 collagen, COMP and lubricin, but did not change the expression of SOX9 and aggrecan. Cyclic hydrostatic pressure downregulated the expression of MMP-13 and type I collagen and upregulated expression of TIMP-1 compared to the unloaded controls. Hydrostatic pressure may slow chondrocyte differentiation and have a chondroprotective, anti-angiogenic influence on cartilage tissue. Our results suggest that cyclic tension activates the Cbfa1/MMP-13 pathway and increases the expression of terminal differentiation hypertrophic markers. Mammalian chondrocytes appear to have evolved complex mechanoresponsive mechanisms, the effects of which can be observed in the histomorphologic establishment of the cartilaginous skeleton during development and maturation.

  10. Virtual screening using combinatorial cyclic peptide libraries reveals protein interfaces readily targetable by cyclic peptides.

    PubMed

    Duffy, Fergal J; O'Donovan, Darragh; Devocelle, Marc; Moran, Niamh; O'Connell, David J; Shields, Denis C

    2015-03-23

    Protein-protein and protein-peptide interactions are responsible for the vast majority of biological functions in vivo, but targeting these interactions with small molecules has historically been difficult. What is required are efficient combined computational and experimental screening methods to choose among a number of potential protein interfaces worthy of targeting lead macrocyclic compounds for further investigation. To achieve this, we have generated combinatorial 3D virtual libraries of short disulfide-bonded peptides and compared them to pharmacophore models of important protein-protein and protein-peptide structures, including short linear motifs (SLiMs), protein-binding peptides, and turn structures at protein-protein interfaces, built from 3D models available in the Protein Data Bank. We prepared a total of 372 reference pharmacophores, which were matched against 108,659 multiconformer cyclic peptides. After normalization to exclude nonspecific cyclic peptides, the top hits notably are enriched for mimetics of turn structures, including a turn at the interaction surface of human α thrombin, and also feature several protein-binding peptides. The top cyclic peptide hits also cover the critical "hot spot" interaction sites predicted from the interaction crystal structure. We have validated our method by testing cyclic peptides predicted to inhibit thrombin, a key protein in the blood coagulation pathway of important therapeutic interest, identifying a cyclic peptide inhibitor with lead-like activity. We conclude that protein interfaces most readily targetable by cyclic peptides and related macrocyclic drugs may be identified computationally among a set of candidate interfaces, accelerating the choice of interfaces against which lead compounds may be screened.

  11. Universal Behavior of a Cyclic Oxidation Model

    NASA Technical Reports Server (NTRS)

    Smialek, James L.

    2003-01-01

    A mathematical model has been generated to represent the iterative, discrete growth and spallation processes associated with cyclic oxidation. Parabolic growth kinetics (k(sub p)) over and a constant spall area (F(sub A)) were assumed, with spalling occurring interfacially at the thickest regions of the scale. Although most models require numerical techniques, the regularity and simplicity of this progression permitted an approximation by algebraic expressions. Normalization could now be performed to reflect all parametric effects, and a universal cyclic oxidation response was generated: W(sub u) = 1/2 {3J(sub u)(sup 1/2)+ J(sub u)(sup 3/2)} where W, is weight change normalized by the maximum and J(sub u) is the cycle number normalized by the number to reach maximum. Similarly, the total amount of metal consumed was represented by a single normalized curve. The factor [(S(sub c)-l)(raised dot)sqrt(F(sub A)k(sub p)DELTAt)] was identified as a general figure of merit, where S(sub c) is the mass ratio of oxide to oxygen and DELTAt is the cycle duration. A cyclic oxidation failure map was constructed, in normalized k(sub p)-F(sub A) space, as defined by the locus of points corresponding to a critical amount of metal consumption in a given time. All three constructions describe behavior for every value of growth rate, spall fraction, and cycle duration by means of single curves, but with two branches corresponding to the times before and after steady state is achieved.

  12. Quercus dilatata Lindl. ex Royle ameliorates BPA induced hepatotoxicity in Sprague Dawley rats.

    PubMed

    Kazmi, Syeda Tayyaba Batool; Majid, Muhammad; Maryam, Sonia; Rahat, Aymen; Ahmed, Madiha; Khan, Muhammad Rashid; Haq, Ihsan Ul

    2018-06-01

    Quercus dilatata Lindl. ex Royle was evaluated for in vitro polyphenol content and antioxidant potential as well as in vivo protective role against bisphenol A (BPA) induced hepatotoxicity. The distilled water-acetone (QDDAE) and methanol-ethyl acetate (QDMEtE) extracts were standardized and administered in high (300 mg/kg body weight (BW) and low (150 mg/kg BW) doses to Sprague Dawley rats, injected with BPA (25 mg/kg BW). Silymarin (50 mg/kg BW) was used as positive control. Subsequently, blood and liver homogenates were collected after four weeks of treatment, and the defensive effects of both extracts against oxidative damage and genotoxicity were assessed via hematological and biochemical investigations, determination of endogenous expression of enzymes as well as levels of free radicals and comet assay. Between the two extracts, maximum phenolics (213 ± 0.15 μg gallic acid equivalent/mg dry extract (DE) and flavonoids (55.6 ± 0.16 μg quercetin equivalent/mg DE) content, DPPH scavenging activity (IC 50 : 8.1 ± 0.5 μg/ml), antioxidant capacity (53.7 ± 0.98 μg ascorbic acid equivalent (AAE)/mg DE) and reducing potential (228.4 ± 2.4 μg AAE/mg DE) were observed in QDMEtE. In in vivo analysis, a dose dependent hepatoprotective activity was exhibited by both the extracts. QDDAE demonstrated maximum reduction in levels of alanine transaminase (49.77 ± 3.83 U/l), thiobarbituric acid reactant substances (33.46 ± 0.70 nM/min/mg protein), hydrogen peroxide (18.08 ± 0.01 ng/mg tissue) and nitrite (55.64 ± 1.79 μM/ml), along with decline in erythrocyte sedimentation rate (4.13 ± 0.072 mm/h), histopathological injuries and DNA damage in BPA intoxicated rats as compared with QDMEtE. Likewise, QDDAE also significantly restored activity levels of endogenous antioxidants, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (POD) and GSH with values of 6.46 ± 0.15

  13. Determinants of hepatotoxicity after repeated supratherapeutic paracetamol ingestion: systematic review of reported cases.

    PubMed

    Acheampong, Paul; Thomas, Simon H L

    2016-10-01

    To evaluate the role of reported daily dose, age and other risk factors, and to assess the value of quantifying serum transaminase activity and paracetamol (acetaminophen) concentration at initial assessment for identifying patients at risk of hepatotoxicity following repeated supratherapeutic paracetamol ingestion (RSPI). Systematic literature review with collation and analysis of individual-level data from reported cases of RSPI associated with liver damage. In 199 cases meeting the selection criteria, severe liver damage (ALT/AST ≥1000 IU l(-1) , liver failure or death) was reported in 186 (93%) cases including 77/78 (99%) children aged ≤6 years. Liver failure occurred in 127 (64%) cases; of these 49 (39%) died. Maximum ingested daily paracetamol doses were above UK recommendations in 143 (72%) patients. US-Australasian thresholds for repeated supratherapeutic ingestions requiring intervention were not met in 71 (36%) cases; of these 35 (49%) developed liver failure and 10 (14%) died. No cases developing liver damage had paracetamol concentration < 20 mg l(-1) and a normal ALT/AST on initial presentation or when RSPI was first suspected, but both of these values were only available for 79 (40%) cases. Severe liver damage is reported after RSPI in adults and children, sometimes involving reported doses below current thresholds for intervention. Paracetamol concentrations <20 mg l(-1) with normal serum ALT/AST activity on initial assessment suggests a low risk of subsequent liver damage. These findings are, however, limited by low patient numbers, publication bias and the accuracy of the histories in reported cases. © 2016 The British Pharmacological Society.

  14. Metabolic activation of hepatotoxic drug (benzbromarone) induced mitochondrial membrane permeability transition

    SciT

    Shirakawa, Maho; Sekine, Shuichi; Tanaka, Ayaka

    The risk of drug-induced liver injury (DILI) is of great concern to the pharmaceutical industry. It is well-known that metabolic activation of drugs to form toxic metabolites (TMs) is strongly associated with DILI onset. Drug-induced mitochondrial dysfunction is also strongly associated with increased risk of DILI. However, it is difficult to determine the target of TMs associated with exacerbation of DILI because of difficulties in identifying and purifying TMs. In this study, we propose a sequential in vitro assay system to assess TM formation and their ability to induce mitochondrial permeability transition (MPT) in a one-pot process. In this assaymore » system, freshly-isolated rat liver mitochondria were incubated with reaction solutions of 44 test drugs preincubated with liver microsomes in the presence or absence of NADPH; then, NADPH-dependent MPT pore opening was assessed as mitochondrial swelling. In this assay system, several hepatotoxic drugs, including benzbromarone (BBR), significantly induced MPT in a NADPH-dependent manner. We investigated the rationality of using BBR as a model drug, since it showed the most prominent MPT in our assay system. Both the production of a candidate toxic metabolite of BBR (1′,6-(OH){sub 2} BBR) and NADPH-dependent MPT were inhibited by several cytochrome P450 (CYP) inhibitors (clotrimazole and SKF-525A, 100 μM). In summary, this assay system can be used to evaluate comprehensive metabolite-dependent MPT without identification or purification of metabolites. - Highlights: • We constructed a sequential assay system for toxic metabolite induced MPT in one pot. • 14 drugs (e.g. benzbromarone (BBR)) induced toxic metabolite dependent MPT. • Both the production of toxic metabolite and MPT could be inhibited by CYP inhibitors. • This system could evaluate the comprehensive MPT without purification of metabolites.« less

  15. Glutamine Provides Effective Protection against Deltamethrin-Induced Acute Hepatotoxicity in Rats But Not Against Nephrotoxicity

    PubMed Central

    Gündüz, Ercan; Ülger, Burak Veli; İbiloğlu, İbrahim; Ekinci, Aysun; Dursun, Recep; Zengin, Yılmaz; İçer, Mustafa; Uslukaya, Ömer; Ekinci, Cenap; Güloğlu, Cahfer

    2015-01-01

    Background The aim of this study was to investigate the protective effects of L-glutamine (GLN) against liver and kidney injury caused by acute toxicity of deltamethrin (DLM). Material/Methods Thirty-two rats were indiscriminately separated into 4 groups with 8 rats each: control group (distilled water; 10 ml/kg, perorally [p.o.]), DLM group (35 mg/kg p.o. one dose.), GLN group (1.5 gr/kg, p.o. single dose.) and DLM (35 mg/kg p.o. one dose.) + GLN group (1.5 gr/kg, p.o. one dose after 4 hours.). Testing for total antioxidant status (TAS), total oxidant status (TOS), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) analyses were performed on tissue samples, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), urea, and creatinine were analyzed on serum samples. Liver and kidney samples were histopathologically analyzed. Results The TOS level in liver was significantly higher in the DLM group than in the control group, and the level in DLM+GLN group was considerably lower than in the DLM group. The TAS level in the DLM+GLN group was considerably higher than in the control and DLM groups. The TAS level in kidney tissues was considerably lower in the DLM group than in controls, but was similar to other groups. Histopathological analyses of liver tissues established a significant difference between DLM and DLM+GLN groups in terms of grade 2 hepatic injury. However, no significant difference was found between DLM and DLM+GLN groups in terms of kidney injury. Conclusions Glutamine leads to significant improvement in deltamethrin-induced acute hepatotoxicity in terms of histopathologic results, tissue oxidative stress parameters, and serum liver function marker enzymes. PMID:25890620

  16. Hepatoprotective effect of ethanol extract from Berchemia lineate against CCl4-induced acute hepatotoxicity in mice.

    PubMed

    Li, Cong; Yi, Li-Tao; Geng, Di; Han, Yuan-Yuan; Weng, Lian-Jin

    2015-05-01

    The roots of Berchemia lineate (L.) DC. (Rhamnaceae) have been long used as a remedy for the treatment of some diseases in Guangxi Province, China. The present study investigates the hepatoprotective effect of Berchemia lineate ethanol extract (BELE) on CCl4-induced acute liver damage in mice. Effect of BELE administrated for 7 consecutive days was evaluated in mice by the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin (TBIL), albulin (ALB), globulin (GLB), and total protein (TP) levels, as well as liver superoxide dismutase (SOD) activity and malondialdehyde (MDA) level. Moreover, histopathological examinations were also taken. Compared with the model group, administration of 400 mg/kg BELE for 7 d in mice significantly decreased the serum ALT (56.25 U/L), AST (297.67 U/L), ALP (188.20 U/L), and TBIL (17.90 mol/L), along with the elevation of TP (64.67 g/L). In addition, BELE (100, 200, and 400 mg/kg, i.g.) treated mice recorded a dose-dependent increment of SOD (291.17, 310.32, and 325.67 U/mg prot) and reduction of MDA (7.27, 6.77, and 5.33 nmol/mg prot) levels. Histopathological examinations also confirmed that BELE can ameliorate CCl4-induced liver injuries, characterized by extensive hepatocellular degeneration/necrosis, inflammatory cell infiltration, congestion, and sinusoidal dilatation. The results indicated that BELE possessed remarkable protective effect against acute hepatotoxicity and oxidative injuries induced by CCl4, and that the hepatoprotective effects of BELE may be due to both the inhibition of lipid peroxidation and the increase of antioxidant activity.

  17. Modeling Drug- and Chemical-Induced Hepatotoxicity with Systems Biology Approaches

    PubMed Central

    Bhattacharya, Sudin; Shoda, Lisl K.M.; Zhang, Qiang; Woods, Courtney G.; Howell, Brett A.; Siler, Scott Q.; Woodhead, Jeffrey L.; Yang, Yuching; McMullen, Patrick; Watkins, Paul B.; Andersen, Melvin E.

    2012-01-01

    We provide an overview of computational systems biology approaches as applied to the study of chemical- and drug-induced toxicity. The concept of “toxicity pathways” is described in the context of the 2007 US National Academies of Science report, “Toxicity testing in the 21st Century: A Vision and A Strategy.” Pathway mapping and modeling based on network biology concepts are a key component of the vision laid out in this report for a more biologically based analysis of dose-response behavior and the safety of chemicals and drugs. We focus on toxicity of the liver (hepatotoxicity) – a complex phenotypic response with contributions from a number of different cell types and biological processes. We describe three case studies of complementary multi-scale computational modeling approaches to understand perturbation of toxicity pathways in the human liver as a result of exposure to environmental contaminants and specific drugs. One approach involves development of a spatial, multicellular “virtual tissue” model of the liver lobule that combines molecular circuits in individual hepatocytes with cell–cell interactions and blood-mediated transport of toxicants through hepatic sinusoids, to enable quantitative, mechanistic prediction of hepatic dose-response for activation of the aryl hydrocarbon receptor toxicity pathway. Simultaneously, methods are being developing to extract quantitative maps of intracellular signaling and transcriptional regulatory networks perturbed by environmental contaminants, using a combination of gene expression and genome-wide protein-DNA interaction data. A predictive physiological model (DILIsym™) to understand drug-induced liver injury (DILI), the most common adverse event leading to termination of clinical development programs and regulatory actions on drugs, is also described. The model initially focuses on reactive metabolite-induced DILI in response to administration of acetaminophen, and spans multiple biological

  18. Assessment of mitochondrial dysfunction-related, drug-induced hepatotoxicity in primary rat hepatocytes

    SciT

    Liu, Cong; Sekine, Shuichi, E-mail: ssekine@facult

    Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and inmore » hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity. - Highlights: • Drug-induced mitochondrial toxicity was evaluated using primary rat hepatocytes. • Galactose and hyperoxia could activate OXPHOS in primary rat hepatocytes. • Cells with enhanced OXPHOS exhibit improved sensitivity to mitochondrial toxins. • Transferrin potentiate mitochondrial toxicity via increased ROS production.« less

  19. Functionally Enhanced Human Stem Cell Derived Hepatocytes in Galactosylated Cellulosic Sponges for Hepatotoxicity Testing.

    PubMed

    Tasnim, Farah; Toh, Yi-Chin; Qu, Yinghua; Li, Huan; Phan, Derek; Narmada, Balakrishnan C; Ananthanarayanan, Abhishek; Mittal, Nikhil; Meng, Ryan Q; Yu, Hanry

    2016-06-06

    Pluripotent stem cell derived hepatocyte-like cells (hPSC-HLCs) are an attractive alternative to primary human hepatocytes (PHHs) used in applications ranging from therapeutics to drug safety testing studies. It would be critical to improve and maintain mature hepatocyte functions of the hPSC-HLCs, especially for long-term studies. If 3D culture systems were to be used for such purposes, it would be important that the system can support formation and maintenance of optimal-sized spheroids for long periods of time, and can also be directly deployed in liver drug testing assays. We report the use of 3-dimensional (3D) cellulosic scaffold system for the culture of hPSC-HLCs. The scaffold has a macroporous network which helps to control the formation and maintenance of the spheroids for weeks. Our results show that culturing hPSC-HLCs in 3D cellulosic scaffolds increases functionality, as demonstrated by improved urea production and hepatic marker expression. In addition, hPSC-HLCs in the scaffolds exhibit a more mature phenotype, as shown by enhanced cytochrome P450 activity and induction. This enables the system to show a higher sensitivity to hepatotoxicants and a higher degree of similarity to PHHs when compared to conventional 2D systems. These results suggest that 3D cellulosic scaffolds are ideal for the long-term cultures needed to mature hPSC-HLCs. The mature hPSC-HLCs with improved cellular function can be continually maintained in the scaffolds and directly used for hepatotoxicity assays, making this system highly attractive for drug testing applications.

  20. Prediction of metabolism-induced hepatotoxicity on three-dimensional hepatic cell culture and enzyme microarrays.

    PubMed

    Yu, Kyeong-Nam; Nadanaciva, Sashi; Rana, Payal; Lee, Dong Woo; Ku, Bosung; Roth, Alexander D; Dordick, Jonathan S; Will, Yvonne; Lee, Moo-Yeal

    2018-03-01

    Human liver contains various oxidative and conjugative enzymes that can convert nontoxic parent compounds to toxic metabolites or, conversely, toxic parent compounds to nontoxic metabolites. Unlike primary hepatocytes, which contain myriad drug-metabolizing enzymes (DMEs), but are difficult to culture and maintain physiological levels of DMEs, immortalized hepatic cell lines used in predictive toxicity assays are easy to culture, but lack the ability to metabolize compounds. To address this limitation and predict metabolism-induced hepatotoxicity in high-throughput, we developed an advanced miniaturized three-dimensional (3D) cell culture array (DataChip 2.0) and an advanced metabolizing enzyme microarray (MetaChip 2.0). The DataChip is a functionalized micropillar chip that supports the Hep3B human hepatoma cell line in a 3D microarray format. The MetaChip is a microwell chip containing immobilized DMEs found in the human liver. As a proof of concept for generating compound metabolites in situ on the chip and rapidly assessing their toxicity, 22 model compounds were dispensed into the MetaChip and sandwiched with the DataChip. The IC 50 values obtained from the chip platform were correlated with rat LD 50 values, human C max values, and drug-induced liver injury categories to predict adverse drug reactions in vivo. As a result, the platform had 100% sensitivity, 86% specificity, and 93% overall predictivity at optimum cutoffs of IC 50 and C max values. Therefore, the DataChip/MetaChip platform could be used as a high-throughput, early stage, microscale alternative to conventional in vitro multi-well plate platforms and provide a rapid and inexpensive assessment of metabolism-induced toxicity at early phases of drug development.

  1. Oral metformin-ascorbic acid co-administration ameliorates alcohol-induced hepatotoxicity in rats.

    PubMed

    Adeneye, A A; Benebo, A S

    2007-01-01

    Alcoholic liver disease remains a major cause of liver failure worldwide with no available curative or prophylactic therapy as at present. High dose metformin is reported to ameliorate liver injuries in both human and animal models of acute and chronic alcoholic liver injuries. The aim of the present in vivo animal study was to determine whether metformin-ascorbic acid co-administration also prevents alcoholic hepatotoxicity in chronic alcohol exposure. In the present study, ameliorating effect of 200 mg/ kg/day of ascorbic acid (Asc), 500 mg/kg/day of metformin (Met) and their co-administration (Met-Asc) were investigated in 5 groups of 50% ethanol-treated male Wistar rats for 2 weeks of the experiment. The body weight of each rat was taken on days 1, 7, and 14 of the experiment, respectively. On day 15, fasted blood samples for plasma lipids and liver enzyme markers were collected via cardiac puncture from the rats under diethyl ether anaesthesia. Results showed that administration of graded oral doses of 50% ethanol for 14 days significantly (p<0.001) elevated the plasma liver enzymes--aspartate aminotransferase (AST), alanine aminotansferase (ALT) and alkaline phosphatase (ALP). Two weeks of ethanol treatment also induced alterations in the plasma triglycerides (PTG), total cholesterol (PTC), high density lipoprotein (HDL-c), and low density lipoprotein (LDL-c). However, these elevations were significantly (p<0.05) attenuated by Asc, Met, and Met-Asc after 14 days of oral treatment, with Met-Asc having higher significant (p<0.001) ameliorating effect than Asc alone but with comparative effect to that of Met alone. High dose metformin-ascorbic acid co-administration protected the liver against the deleterious effects of chronic high dose alcohol and the hepatoprotective effect of Met-Asc appeared to be due mainly to the metformin molecule of the drug combination. However, further studies would be required to evaluate the mechanisms underlying the observed

  2. Towards non-invasive 3D hepatotoxicity assays with optical coherence phase microscopy

    NASA Astrophysics Data System (ADS)

    Nelson, Leonard J.; Koulovasilopoulos, Andreas; Treskes, Philipp; Hayes, Peter C.; Plevris, John N.; Bagnaninchi, Pierre O.

    2015-03-01

    Three-dimensional tissue-engineered models are increasingly recognised as more physiologically-relevant than standard 2D cell culture for pre-clinical drug toxicity testing. However, many types of conventional toxicity assays are incompatible with dense 3D tissues. This study investigated the use of optical coherence phase microscopy (OCPM) as a novel approach to assess cell death in 3D tissue culture. For 3D micro-spheroid formation Human hepatic C3A cells were encapsulated in hyaluronic acid gels and cultured in 100μl MEME/10%FBS in 96-well plates. After spheroid formation the 3D liver constructs were exposed to acetaminophen on culture day 8. Acetaminophen hepatotoxicity in 3D cultures was evaluated using standard biochemical assays. An inverted OCPM in common path configuration was developed with a Callisto OCT engine (Thorlabs), centred at 930nm and a custom scanning head. Intensity data were used to perform in-depth microstructural imaging. In addition, phase fluctuations were measured by collecting several successive B scans at the same location, and statistics on the first time derivative of the phase, i.e. time fluctuations, were analysed over the acquisition time interval to retrieve overall cell viability. OCPM intensity (cell cluster size) and phase fluctuation statistics were directly compared with biochemical assays. In this study, we investigated optical coherence phase tomography to assess cell death in a 3d liver model after exposure to a prototypical hepatotoxin, acetaminophen. We showed that OCPM has the potential to assess noninvasively and label-free drug toxicity in 3D tissue models.

  3. Energy metabolism and biotransformation as endpoints to pre-screen hepatotoxicity using a liver spheroid model

    SciT

    Xu Jinsheng; Purcell, Wendy M.

    2006-10-15

    The current study investigated liver spheroid culture as an in vitro model to evaluate the endpoints relevant to the status of energy metabolism and biotransformation after exposure to test toxicants. Mature rat liver spheroids were exposed to diclofenac, galactosamine, isoniazid, paracetamol, m-dinitrobenzene (m-DNB) and 3-nitroaniline (3-NA) for 24 h. Pyruvate uptake, galactose biotransformation, lactate release and glucose secretion were evaluated after exposure. The results showed that pyruvate uptake and lactate release by mature liver spheroids in culture were maintained at a relatively stable level. These endpoints, together with glucose secretion and galactose biotransformation, were related to and could reflect themore » status of energy metabolism and biotransformation in hepatocytes. After exposure, all of the test agents significantly reduced glucose secretion, which was shown to be the most sensitive endpoint of those evaluated. Diclofenac, isoniazid, paracetamol and galactosamine reduced lactate release (P < 0.01), but m-DNB increased lactate release (P < 0.01). Diclofenac, isoniazid and paracetamol also reduced pyruvate uptake (P < 0.01), while galactosamine had little discernible effect. Diclofenac, galactosamine, paracetamol and m-DNB also reduced galactose biotransformation (P < 0.01), by contrast, isoniazid did not. The metabolite of m-DNB, 3-NA, which served as a negative control, did not cause significant changes in lactate release, pyruvate uptake or galactose biotransformation. It is concluded that pyruvate uptake, galactose biotransformation, lactate release and glucose secretion can be used as endpoints for evaluating the status of energy metabolism and biotransformation after exposure to test agents using the liver spheroid model to pre-screen hepatotoxicity.« less

  4. Overdose pattern and outcome in paracetamol-induced acute severe hepatotoxicity

    PubMed Central

    Craig, Darren G N; Bates, Caroline M; Davidson, Janice S; Martin, Kirsty G; Hayes, Peter C; Simpson, Kenneth J

    2011-01-01

    AIMS Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported. METHODS Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P < 0.001). The King's College poor prognostic criteria had reduced sensitivity in unintentional overdoses (77.8%, 95% confidence intervals (CI) 62.9, 88.8) compared with intentional overdoses (89.9%, 95% CI 83.4, 94.5). Unintentional overdose was independently predictive of death or liver transplantation on multivariate analysis (odds ratio 1.91 (95% CI 1.07, 3.43), P= 0.032). CONCLUSIONS Unintentional paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses. PMID:21219409

  5. Lycopene attenuates dichlorvos-induced oxidative damage and hepatotoxicity in rats.

    PubMed

    El-Saad, Am Abu; Ibrahim, M M; Hazani, A A; El-Gaaly, G A

    2016-06-01

    Because of the widespread use of dichlorvos (DDVP) for domestic applications, evaluation of their toxic effects is of major concern to public health. Lycopene may lower oxidative stress by a mechanism that is not fully elucidated. The present study was undertaken to evaluate the protective efficacy of lycopene in terms of normalization of altered biochemical parameters following DDVP treatment in rats. Animals were divided into four groups. The first group was used as control, while groups 2, 3, and 4 were orally treated with lycopene (10 mg kg(-1) body weight (b.w.)), DDVP (1.6 mg kg(-1) b.w.), and DDVP plus lycopene, respectively. Results showed that oral administration of DDVP for 30 days increased the levels of lipid peroxidation markers such as malondialdehyde, 4-hydroxynonanal, and protein carbonyl content in liver. Also, a decrease in levels of vitamin C, vitamin E, and reduced glutathione was detected due to DDVP administration. These were accompanied by a decrease in the activities of antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase, and glutathione-S-transferase in the liver tissue. Moreover, DDVP increased the activities of serum transaminases, alkaline phosphatase, lactate dehydrogenase, and lipoxygenase, and the levels of bilirubin, total cholesterol, low-density lipoprotein cholesterol, triglyceride and DNA-protein crosslinks, and 8-hydroxy-2-deoxyguanosine, while decreased the level of high-density lipoprotein cholesterol. Our results provide new insights into the biochemical studies of relation between DDVP hepatotoxicity and lycopene treatment. Administration of lycopene to DDVP-treated rats reverted the status of hepatic markers to near-normal levels. These data suggest that lycopene can protect against the liver damage induced by DDVP. © The Author(s) 2015.

  6. Synergistic activity of curcumin with methotrexate in ameliorating Freund's Complete Adjuvant induced arthritis with reduced hepatotoxicity in experimental animals.

    PubMed

    Banji, David; Pinnapureddy, Jyothi; Banji, Otilia J F; Saidulu, A; Hayath, Md Sikinder

    2011-10-01

    Methotrexate is employed in low doses for the treatment of rheumatoid arthritis. One of the major drawbacks with methotrexate is hepatotoxicity resulting in poor compliance of therapy. Curcumin is an extensively used spice possessing both anti-arthritic and hepatoprotective potential. The present study was aimed at investigating the effect of curcumin (30 and 100 mg/kg) in combination with subtherapeutic dose of methotrexate (1 mg/kg) is salvaging hepatotoxicity, oxidative stress and producing synergistic anti-arthritic action with methotrexate. Wistar albino rats were induced with arthritis by subplantar injection of Freund's Complete Adjuvant and pronounced arthritis was seen after 9 days of injection. Groups of animals were treated with subtherapeutic dose of methotrexate followed half an hour later with 30 and 100mg/kg of curcumin from day 9 up to days 45 by intraperitoneal route. Methotrexate treatment in Freund's Complete Adjuvant induced arthritic animals produced elevation in the levels of aminotransferases, alkaline phosphatase, total and direct bilirubin. Enhanced oxidative stress in terms of measured lipid peroxides was observed in the methotrexate treated group. Curcumin significantly circumvented hepatotoxicity induced by methotrexate as evidenced by a change in biochemical markers possibly due to its strong anti-oxidant action. Hepatoprotective potential of curcumin was also confirmed from histological evaluation. Sub-therapeutic dose of methotrexate elicited substantial anti-arthritic action when used in combination with curcumin implying that the latter potentiated its action. Concomitant administration of curcumin with methotrexate was also found to minimize liver damage. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Inhibition of Carbamyl Phosphate Synthetase-I and Glutamine Synthetase by Hepatotoxic Doses of Acetaminophen in Mice

    PubMed Central

    Gupta, Sanjiv; Rogers, Lynette K.; Taylor, Sarah K.; Smith, Charles V.

    2016-01-01

    The primary mechanisms proposed for acetaminophen-induced hepatic necrosis should deplete protein thiols, either by covalent binding and thioether formation or by oxidative reactions such as S-thiolations. However, in previous studies we did not detect significant losses of protein thiol contents in response to administration of hepatotoxic doses of acetaminophen in vivo. In the present study we employed derivatization with the thiol-specific agent monobromobimane and separation of proteins by SDS–PAGE to investigate the possible loss of specific protein thiols during the course of acetaminophen-induced hepatic necrosis. Fasted adult male mice were given acetaminophen, and protein thiol status was examined subsequently in subcellular fractions isolated by differential centrifugation. No decreases in protein thiol contents were indicated, with the exception of a marked decrease in the fluorescent intensity, but not of protein content, as indicated by staining with Coomassie blue, of a single band of approximately 130 kDa in the mitochondrial fractions of acetaminophen-treated mice. This protein was identified by isolation and N-terminal sequence analysis as carbamyl phosphate synthetase-I (CPS-I) (EC 6.3.4.16). Hepatic CPS-I activities were decreased in mice given hepatotoxic doses of acetaminophen. In addition, hepatic glutamine synthetase activities were lower, and plasma ammonia levels were elevated in mice given hepatotoxic doses of acetaminophen. The observed hyperammonemia may contribute to the adverse effects of toxic doses of acetaminophen, and elucidation of the specific mechanisms responsible for the hyperammonemia may prove to be useful clinically. However, the preferential depletion of protein thiol content of a mitochondrial protein by chemically reactive metabolites generated in the endoplasmic reticulum presents a challenging and potentially informative mechanistic question. PMID:9344900

  8. Hepatotoxicity associated with metformin therapy in treatment of type 2 diabetes mellitus with nonalcoholic fatty liver disease.

    PubMed

    Cone, Catherine J; Bachyrycz, Amy M; Murata, Glen H

    2010-10-01

    To report a case of idiosyncratic hepatotoxicity associated with metformin in the treatment of type 2 diabetes with nonalcoholic fatty liver disease (NAFLD). A 61-year-old obese man presented with jaundice, nausea, fatigue, and an unintentional weight loss 2 weeks following initiation of metformin. Laboratory findings revealed aminotransferase values 10-15 times the upper limit of normal. Potential causative agents, including metformin, simvastatin, and Niaspan (extended-release niacin), were discontinued. Two months later, the patient's signs and symptoms had resolved and aminotransferase values returned to normal. An objective causality assessment revealed that the adverse reaction was probably associated with metformin. Since numerous medications and disease states can cause abnormalities in liver enzymes, it is important for providers to be able to distinguish the cause(s) and take appropriate actions. This can take a great deal of time and effort in patients with multiple medications and comorbidities. In this patient's case, viral hepatitis, worsening NAFLD, and the concomitant drugs were highly suspected. As hydroxymethylglutaryl coenzyme A reductase inhibitors offer substantial cardiovascular benefits and as metformin is a first-line agent in helping to lower blood glucose concentrations and to normalize the metabolic profile in type 2 diabetes, reintroduction of metformin and simvastatin would likely be beneficial. This is a case report of metformin-induced hepatotoxicity. As the prevalence of type 2 diabetes and subsequent metabolic effects increases in the US, metformin use will likewise increase. As potential for increased idiosyncratic hepatotoxicity associated with metformin use is likely to occur, clinicians should be vigilant.

  9. The effect of natural antioxidants in cyclophosphamide-induced hepatotoxicity: Role of Nrf2/HO-1 pathway.

    PubMed

    Sherif, Iman O

    2018-05-22

    Hepatotoxicity induced by cyclophosphamide (Cyclo) is a major concern in clinical practice. This study was designed to investigate the possible cytoprotective effect of natural antioxidants as oleuropein and quercetin against Cyclo induced hepatotoxicity via the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Male Wistar rats were randomly divided into six groups and treated for 10 days as follow: Group I (Normal control) received saline, group II (Oleu control): received orally oleuropein 30 mg/kg/day, group III (Quer control): administered orally quercetin 50 mg/kg/day, group IV (Cyclo): received saline and injected with single intraperitoneal (i.p) dose of Cyclo 200 mg/kg at day 5, group V (Oleu ttt): treated with oleuropein plus Cyclo i.p. injection at day 5, and group VI (Quer ttt): treated with quercetin plus Cyclo i.p. injection at day 5. Injection of Cyclo showed marked increase in serum transaminases and alkaline phosphatase, hepatic malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-⍺) levels along with significant reduction in hepatic reduced glutathione (GSH), superoxide dismutase (SOD), and catalase levels in addition to downregulation of hepatic Nrf2 and HO-1 expressions and reduction in hepatic nuclear Nrf2 binding activity when compared with normal group. Histopathological examination of Cyclo treated rats revealed hepatic damage. Both oleuropein and quercetin exhibited an improvement in the biochemical and histopathological findings. In conclusion, the natural antioxidants oleuropein and quercetin counteract the Cyclo induced hepatotoxicity through activation of Nrf2/HO-1 signaling pathway with subsequent suppression of oxidative stress and inflammation. Copyright © 2018 Elsevier B.V. All rights reserved.

  10. Enniatin B and beauvericin are common in Danish cereals and show high hepatotoxicity on a high-content imaging platform.

    PubMed

    Svingen, Terje; Lund Hansen, Niels; Taxvig, Camilla; Vinggaard, Anne Marie; Jensen, Udo; Have Rasmussen, Peter

    2017-05-01

    Mycotoxins are fungi-born metabolites that can contaminate foods through mould-infected crops. They are a significant food/feed-safety issue across the globe and represent a substantial financial burden for the world economy. Moreover, with a changing climate and fungal biota, there is now much discussion about emerging mycotoxins that are measurable at significant levels in crops world-wide. Unfortunately, we still know very little about the bioavailability and toxic potentials of many of these less characterized mycotoxins, including the large family of enniatins. In this study, we present new occurrence data for enniatin A, A1, B, B1 and beauvericin in four Danish crops: oat, wheat, and barley from the 2010 harvest, and rye from 2011 harvest. The occurrence of the four enniatins were B > B1 > A1 > A. Enniatin B was detected in 100% of tested samples regardless of crop type. In addition to occurrence data, we report a proof-of-concept study using a human-relevant high-content hepatotoxicity, or "quadroprobe," assay to screen mycotoxins for their cytotoxic potential. The assay was sensitive for most cytotoxic compounds in the 0.009-100 µM range. Among eight tested mycotoxins (enniatin B, beauvericin, altenariol, deoxynivalenol, aflatoxin B1, andrastin A, citrinin, and penicillic acid), enniatin B and beauvericin showed significant cytotoxicity at a concentration lower than that for aflatoxin B1, which is the archetypal acute hepatotoxic and liver-carcinogenic mycotoxin. Hence, the quadroprobe hepatotoxicity assay may become a valuable assessment tool for toxicity assessment of mycotoxins in the future. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1658-1664, 2017. © 2016 Wiley Periodicals, Inc.

  11. A natural antioxidant, tannic acid mitigates iron-overload induced hepatotoxicity in Swiss albino mice through ROS regulation.

    PubMed

    Basu, Tapasree; Panja, Sourav; Shendge, Anil Khushalrao; Das, Abhishek; Mandal, Nripendranath

    2018-05-01

    Tannic acid (TA), a water soluble natural polyphenol with 8 gallic acids groups, is abundantly present in various medicinal plants. Previously TA has been investigated for its antimicrobial and antifungal properties. Being a large polyphenol, TA chelates more than 1 metal. Hence TA has been explored for potent antioxidant activities against reactive oxygen species (ROS), reactive nitrogen species (RNS) and as iron chelator in vitro thereby mitigating iron-overload induced hepatotoxicity in vivo. Iron dextran was injected intraperitoneally in Swiss albino mice to induce iron-overload triggered hepatotoxicity, followed by oral administration of TA for remediation. After treatment, liver, spleen, and blood samples were processed from sacrificed animals. The liver iron, serum ferritin, serum markers, ROS, liver antioxidant status, and liver damage parameters were assessed, followed by histopathology and protein expression studies. Our results show that TA is a prominent ROS and RNS scavenger as well as iron chelator in vitro. It also reversed the ROS levels in vivo and restricted the liver damage parameters as compared to the standard drug, desirox. Moreover, this natural polyphenol exclusively ameliorates the histopathological and fibrotic changes in liver sections reducing the iron-overload, along with chelation of liver iron and normalization of serum ferritin. The protective role of TA against iron-overload induced apoptosis in liver was further supported by changed levels of caspase 3, PARP as well as Bax/BCl-2 ratio. Thus, TA can be envisaged as a better orally administrable iron chelator to reduce iron-overload induced hepatotoxicity through ROS regulation. © 2018 Wiley Periodicals, Inc.

  12. Dynamic and accurate assessment of acetaminophen-induced hepatotoxicity by integrated photoacoustic imaging and mechanistic biomarkers in vivo.

    PubMed

    Brillant, Nathalie; Elmasry, Mohamed; Burton, Neal C; Rodriguez, Josep Monne; Sharkey, Jack W; Fenwick, Stephen; Poptani, Harish; Kitteringham, Neil R; Goldring, Christopher E; Kipar, Anja; Park, B Kevin; Antoine, Daniel J

    2017-10-01

    The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational non-invasive photoacoustic imaging of liver function with mechanistic circulating biomarkers of hepatotoxicity with histological assessment to facilitate the more accurate and precise characterization of APAP-ILI and the efficacy of therapeutic intervention. Perturbation of liver function and cellular viability was assessed in C57BL/6J male mice by Indocyanine green (ICG) clearance (Multispectral Optoacoustic Tomography (MSOT)) and by measurement of mechanistic (miR-122, HMGB1) and established (ALT, bilirubin) circulating biomarkers in response to the acetaminophen and its treatment with acetylcysteine (NAC) in vivo. We utilised a 60% partial hepatectomy model as a situation of defined hepatic functional mass loss to compared acetaminophen-induced changes to. Integration of these mechanistic markers correlated with histological features of APAP hepatotoxicity in a time-dependent manner. They accurately reflected the onset and recovery from hepatotoxicity compared to traditional biomarkers and also reported the efficacy of NAC with high sensitivity. ICG clearance kinetics correlated with histological scores for acute liver damage for APAP (i.e. 3h timepoint; r=0.90, P<0.0001) and elevations in both of the mechanistic biomarkers, miR-122 (e.g. 6h timepoint; r=0.70, P=0.005) and HMGB1 (e.g. 6h timepoint; r=0.56, P=0.04). For the first time we report the utility of this non-invasive longitudinal imaging approach to provide direct visualisation of the liver function coupled with mechanistic biomarkers, in the same animal, allowing the investigation of the toxicological and pharmacological aspects of APAP-ILI and hepatic regeneration. Copyright © 2017

  13. Analysis of changes in hepatic gene expression in a murine model of tolerance to acetaminophen hepatotoxicity (autoprotection)

    SciT

    O'Connor, Meeghan A., E-mail: meeghan.oconnor@boehringer-ingelheim.com; Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877-0368; Koza-Taylor, Petra, E-mail: petra.h.koza-taylor@pfizer.com

    Pretreatment of mice with a low hepatotoxic dose of acetaminophen (APAP) results in resistance to a subsequent, higher dose of APAP. This mouse model, termed APAP autoprotection was used here to identify differentially expressed genes and cellular pathways that could contribute to this development of resistance to hepatotoxicity. Male C57BL/6J mice were pretreated with APAP (400 mg/kg) and then challenged 48 h later with 600 mg APAP/kg. Livers were obtained 4 or 24 h later and total hepatic RNA was isolated and hybridized to Affymetrix Mouse Genome MU430{sub 2} GeneChip. Statistically significant genes were determined and gene expression changes weremore » also interrogated using the Causal Reasoning Engine (CRE). Extensive literature review narrowed our focus to methionine adenosyl transferase-1 alpha (MAT1A), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), flavin-containing monooxygenase 3 (Fmo3) and galectin-3 (Lgals3). Down-regulation of MAT1A could lead to decreases in S-adenosylmethionine (SAMe), which is known to protect against APAP toxicity. Nrf2 activation is expected to play a role in protective adaptation. Up-regulation of Lgals3, one of the genes supporting the Nrf2 hypothesis, can lead to suppression of apoptosis and reduced mitochondrial dysfunction. Fmo3 induction suggests the involvement of an enzyme not known to metabolize APAP in the development of tolerance to APAP toxicity. Subsequent quantitative RT-PCR and immunochemical analysis confirmed the differential expression of some of these genes in the APAP autoprotection model. In conclusion, our genomics strategy identified cellular pathways that might further explain the molecular basis for APAP autoprotection. - Highlights: • Differential expression of genes in mice resistant to acetaminophen hepatotoxicity. • Increased gene expression of Flavin-containing monooxygenase 3 and Galectin-3. • Decrease in MAT1A expression and compensatory hepatocellular regeneration. • Two distinct

  14. Risk assessment of hepatotoxicity among tuberculosis and human immunodeficiency virus/AIDS-coinfected patients under tuberculosis treatment.

    PubMed

    Ngouleun, Williams; Biapa Nya, Prosper Cabral; Pieme, Anatole Constant; Telefo, Phelix Bruno

    2016-12-01

    Tuberculosis (TB) is a worldwide public health problem. It is a contagious and grave disease caused by Mycobacterium tuberculosis. Current drugs such as isoniazid, pyrazinamide, and rifampicin used for the treatment of tuberculosis are potentially hepatotoxic and can lead to drug hepatitis. In order to improve the follow-up of TB patients in Cameroon, we carried out a study which aimed to evaluate the hepatotoxicity risk factors associated with anti-TB drugs. The studies were performed on 75 participants who had visited the Loum District Hospital located in the littoral region of Cameroon for their routine consultation. Participants have been selected based on pre-established criteria of inclusion and exclusion. Prior to the informed consent signature, patients were given compelling information about the objective and the result output of the study. They were questioned about antioxidant food and alcohol consumption as well as some clinical signs of hepatotoxicity such as fever, nausea, vomiting, and tiredness. The collected blood was tested for the determination of biochemical markers (transaminases and C-reactive protein) using standard spectrophotometric methods. Biochemical analysis of samples showed a significant increase (p<.05) of aspartate aminotransferase and alanine aminotransferase values in TB patients coinfected with human immunodeficiency virus/AIDS (33.28±16.58UI/L and 30.84±17.17UI/L, respectively) compared with the respective values of the controls (16.35±5.31UI/L and 16.45±4.83UI/L). Taking individually, the liver injury patient percentage of TB patients was significant compared to TBC when considering alanine aminotransferase and aspartate aminotransferase parameters. When considering risk factors, antioxidant food consumption significantly reduced the liver injury patient percentage for the above parameters, whereas an opposite situation was observed with alcohol consumption between TB-coinfection and TB patients. Regarding the C

  15. Fentanyl Enhances Hepatotoxicity of Paclitaxel via Inhibition of CYP3A4 and ABCB1 Transport Activity in Mice

    PubMed Central

    Pan, Jia-Hao; Bi, Bing-Tian; Feng, Kun-Yao; Huang, Wan; Zeng, Wei-An

    2015-01-01

    Fentanyl, a potent opioid analgesic that is used to treat cancer pain, is commonly administered with paclitaxel in advanced tumors. However, the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanism of action is not well studied. The purpose of this study was to investigate the effect of fentanyl on the hepatotoxicity of paclitaxel and its potential mechanisms of action. Pharmacokinetic parameters of paclitaxel were tested using reversed phase high-performance liquid chromatography (RP-HPLC). Aspartate transaminase (AST), alanine aminotransferase (ALT), and mouse liver histopathology were examined. Moreover, the cytotoxicity of anti-carcinogens was examined using 1-(4, 5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT), and the intracellular accumulation of doxorubicin and rhodamine 123 was detected by flow cytometry. Furthermore, the expression of ABCB1 and the activity of ABCB1 ATPase and CYP3A4 were also examined. In this study, the co-administration of fentanyl and paclitaxel prolonged the half-life (t1/2) of paclitaxel from 1.455 hours to 2.344 hours and decreased the clearance (CL) from 10.997 ml/h to 7.014 ml/h in mice. Fentanyl significantly increased the levels of ALT in mice to 88.2 U/L, which is more than 2-fold higher than the level detected in the control group, and it increased the histological damage in mouse livers. Furthermore, fentanyl enhanced the cytotoxicity of anti-carcinogens that are ABCB1 substrates and increased the accumulation of doxorubicin and rhodamine 123. Additionally, fentanyl stimulated ABCB1 ATPase activity and inhibited CYP3A4 activity in the liver microsomes of mice. Our study indicates that the obvious hepatotoxicity during this co-administration was due to the inhibition of CYP3A4 activity and ABCB1 transport activity. These findings suggested that the accumulation-induced hepatotoxicity of paclitaxel when it is combined with fentanyl should be avoided. PMID:26633878

  16. Acute Hepatotoxicity After Ingestion of Morinda citrifolia (Noni Berry) Juice in a 14-year-old Boy

    PubMed Central

    Yu, Elizabeth L.; Sivagnanam, Mamata; Ellis, Linda; Huang, Jeannie S.

    2017-01-01

    Morinda citrifolia, commonly known as the noni berry, is a tropical fruit that has been used for more than 2000 years as a Polynesian herbal remedy (1). Since 1996, it has been sold widely in the United States as a general remedy for a wide array of health problems including cancer, diabetes, HIV/AIDS, gastric ulcers, hypertension, infections, depression, and chronic fatigue (2,3). We report a case of acute hepatotoxicity after ingestion of an energy drink containing noni berries in a previously healthy 14-year-old boy. PMID:21119544

  17. Ribosomal Biosynthesis of the Cyclic Peptide Toxins of Amanita Mushrooms

    PubMed Central

    Walton, Jonathan D.; Hallen-Adams, Heather E.; Luo, Hong

    2014-01-01

    Some species of mushrooms in the genus Amanita are extremely poisonous and frequently fatal to mammals including humans and dogs. Their extreme toxicity is due to amatoxins such as α- and β-amanitin. Amanita mushrooms also biosynthesize a chemically related group of toxins, the phallotoxins, such as phalloidin. The amatoxins and phallotoxins (collectively known as the Amanita toxins) are bicyclic octa- and heptapeptides, respectively. Both contain an unusual Trp-Cys cross-bridge known as tryptathionine. We have shown that, in Amanita bisporigera, the amatoxins and phallotoxins are synthesized as proproteins on ribosomes and not by nonribosomal peptide synthetases. The proproteins are 34–35 amino acids in length and have no predicted signal peptides. The genes for α-amanitin (AMA1) and phallacidin (PHA1) are members of a large family of related genes, characterized by highly conserved amino acid sequences flanking a hypervariable “toxin” region. The toxin regions are flanked by invariant proline (Pro) residues. An enzyme that could cleave the proprotein of phalloidin was purified from the phalloidin-producing lawn mushroom Conocybe apala. The enzyme is a serine protease in the prolyl oligopeptidase (POP) subfamily. The same enzyme cuts at both Pro residues to release the linear hepta- or octapeptide. PMID:20564017

  18. The role of peel stresses in cyclic debonding

    NASA Technical Reports Server (NTRS)

    Everett, R. A., Jr.

    1982-01-01

    When an adhesively bonded joint is undergoing cyclic loading, one of the possible damage modes that occurs is called cyclic debonding - progressive separation of the adherends by failure of the adhesive bond under cyclic loading. In most practical structures, both peel and shear stresses exist in the adhesive bonding during cyclic loading. The results of an experimental and analytical study to determine the role of peel stresses on cyclic debonding in a mixed mode specimen are presented. Experimentally, this was done by controlling the forces that create the peel stresses by applying a clamping force to oppose the peel stresses. Cracked lap shear joints were chosen for this study. A finite element analysis was developed to assess the effect of the clamping force on the strain energy release rates due to shear and peel stresses. The results imply that the peel stress is the principal stress causing cyclic debonding.

  19. Corticosteroid receptors adopt distinct cyclical transcriptional signatures.

    PubMed

    Le Billan, Florian; Amazit, Larbi; Bleakley, Kevin; Xue, Qiong-Yao; Pussard, Eric; Lhadj, Christophe; Kolkhof, Peter; Viengchareun, Say; Fagart, Jérôme; Lombès, Marc

    2018-05-07

    Mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) are two closely related hormone-activated transcription factors that regulate major pathophysiologic functions. High homology between these receptors accounts for the crossbinding of their corresponding ligands, MR being activated by both aldosterone and cortisol and GR essentially activated by cortisol. Their coexpression and ability to bind similar DNA motifs highlight the need to investigate their respective contributions to overall corticosteroid signaling. Here, we decipher the transcriptional regulatory mechanisms that underlie selective effects of MRs and GRs on shared genomic targets in a human renal cellular model. Kinetic, serial, and sequential chromatin immunoprecipitation approaches were performed on the period circadian protein 1 ( PER1) target gene, providing evidence that both receptors dynamically and cyclically interact at the same target promoter in a specific and distinct transcriptional signature. During this process, both receptors regulate PER1 gene by binding as homo- or heterodimers to the same promoter region. Our results suggest a novel level of MR-GR target gene regulation, which should be considered for a better and integrated understanding of corticosteroid-related pathophysiology.-Le Billan, F., Amazit, L., Bleakley, K., Xue, Q.-Y., Pussard, E., Lhadj, C., Kolkhof, P., Viengchareun, S., Fagart, J., Lombès, M. Corticosteroid receptors adopt distinct cyclical transcriptional signatures.

  20. Effects of cyclic hydraulic pressure on osteocytes.

    PubMed

    Liu, Chao; Zhao, Yan; Cheung, Wing-Yee; Gandhi, Ronak; Wang, Liyun; You, Lidan

    2010-05-01

    Bone is able to adapt its composition and structure in order to suit its mechanical environment. Osteocytes, bone cells embedded in the calcified matrix, are believed to be the mechanosensors and responsible for orchestrating the bone remodeling process. Recent in vitro studies have shown that osteocytes are able to sense and respond to substrate strain and fluid shear. However the capacity of osteocytes to sense cyclic hydraulic pressure (CHP) associated with physiological mechanical loading is not well understood. In this study, we subjected osteocyte-like MLO-Y4 cells to controlled CHP of 68 kPa at 0.5 Hz, and investigated the effects of CHP on intracellular calcium concentration, cytoskeleton organization, mRNA expression of genes related to bone remodeling, and osteocyte apoptosis. We found that osteocytes were able to sense CHP and respond by increased intracellular calcium concentration, altered microtubule organization, a time-dependent increase in COX-2 mRNA level and RANKL/OPG mRNA ratio, and decreased apoptosis. These findings support the hypothesis that loading induced cyclic hydraulic pressure in bone serves as a mechanical stimulus to osteocytes and may play a role in regulating bone remodeling in vivo. Copyright (c) 2010 Elsevier Inc. All rights reserved.

  1. Theoretical Studies of Some HEDM Species: Cyclic O4, Cyclic O3 and Cubane

    NASA Technical Reports Server (NTRS)

    Walch, Stephen P.; Langhoff, Steve R. (Technical Monitor)

    1996-01-01

    Calculations have been carried out for the HEDM species (cyclic O4, cyclic O3, and cubane) using CASSCF/derivative and CASSCF/ICCI methods. Cyclic O4 is of interest both as a potential HEDM species and because of its possible role in the ozone deficit problem in atmospheric chemistry. We have studied the pathway for decomposition from the D(2d) minimum and also have found the approximate location of the singlet triplet crossing. The barrier to decomposition is found to be about 9 kcal/mol and is not limited by the singlet triplet crossing. For cyclic O3 we have focused on the crossings between the lowest five surfaces (X(1)A(1), s(1)A(1), (1)A(2), (1)B(1), and (1)B(2)) to provide some insight into ways to form cyclic O3 photochemically. The crossing region between the X(1)A(1) and 2(1)A(1) surfaces is in agreement with the work of Xantheas et al. The calculations show that vertical excitation from the ground state to the (1)A(2) state leads to a crossing with the (1)A(1) manifold near the crossing region of the X(1)A(1) and 2(1)A(1) surfaces. We have studied the decomposition pathways for cubane to benzene plus acetylene and to cyclooctatetraene. We have also studied the ground and excited states for the photochemical ring closure step. The state which closes to cubane can be described as a double triplet pi to pi* excitation with respect to the ground state. Thus, this state has only a small oscillator strength with respect to the ground state. However, there is a singlet pi to pi* state at nearly the same energy and excitation to this state followed by intersystem crossing could lead to the triplet pi to pi* state.

  2. Transplantation of allogenic bone marrow in canine cyclic neutropenia

    SciT

    Dale, D.C.; Graw, R.G. Jr.

    Transplantation of normal bone marrow cells to a gray collie dog with cyclic neutropenia resulted in normal granulocytopoiesis. The finding suggests that cyclic neutropenia occurs because the hematopoietic stem cells are defective. Because of the similarity of human and canine cyclic neutropenia, it also suggests that the human disease may be curable by marrow transplantation. One day before transplantation, the recipient received 1000 rads gamma irradiation from opposing /sup 60/Co sources at 9 rad/min. (CH)

  3. Electrochemistry of norcocaine nitroxide and related compounds: implications for cocaine hepatotoxicity.

    PubMed

    Charkoudian, J C; Shuster, L

    1985-08-15

    Norcocaine nitroxide, a free radical metabolite of cocaine, displays a reversible one-electron cyclic voltammogram which is abolished by the addition of reduced glutathione. The corresponding nitrosonium ion was synthesized. It showed the same electrochemical characteristics as the nitroxide. The spin label 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (TEMPOL) and its nitrosonium ion behaved like morcocaine nitroxide and its nitrosonium ion. The nitrosonium ion of TEMPOL caused hemolysis of red blood cells, but TEMPOL did not. These observations suggest that the highly reactive nitrosonium ion may be involved in the production of cocaine-induced hepatic necrosis in mice.

  4. Estrous Cyclicity of Mice During Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Moyer, Eric; Talyansky, Yuli; Scott, Ryan; Tash, Joseph; Christenson, Lane; Alwood, Joshua; Ronca, April

    2017-01-01

    Hindlimb unloading (HU) is a rodent model system used to simulate weightlessness experienced in space. However, some effects of this approach on rodent physiology are under-studied, specifically the effects on ovarian estrogen production which drives the estrous cycle. To resolve this deficiency, we conducted a ground-based validation study using the HU model, while monitoring estrous cycles in 16-weeks-old female C57BL6 mice. Animals were exposed to HU for 12 days following a 3 day HU cage acclimation period, and estrous cycling was analyzed in HU animals (n22), normally loaded HU Cage Pair-Fed controls (CPF; n22), and Vivarium controls fed ad libitum (VIV; n10). Pair feeding was used to control for potential nutritional deficits on ovarian function. Vaginal cells were sampled daily in all mice via saline lavage. Cells were dried and stained with crystal violet, and the smears evaluated using established vaginal cytology techniques by two individuals blinded to the animal treatment group. Estrous cyclicity was disrupted in nearly all HU and CPF mice, while those maintained in VIV had an average normal cycle length of 4.8 0.5 days, with all stages in the cycle visibly observed. CPF and HU animals arrested in the diestrous phase, which precedes the pre-ovulatory estrogen surge. Additionally, infection-like symptoms characterized by vaginal discharge and swelling arose in several HU animals, which we suspect was due to an inability of these mice to properly groom themselves, andor due to the change in the gravity vector relative to the vaginal opening, which prevented drainage of the lavage solution. Pair-feeding resulted in similar weight gains of HU and CPF (1.5 vs 3.0, respectively). The current results indicate that pair-feeding controlled weight gain and that the HU cage alone influenced estrous cyclicity. Thus, longer acclimation needs to be tested to determine if and when normal estrous cycling resumes in non-loaded mice in HU cages prior to HU testing. Future

  5. Estrous Cyclicity in Mice During Simulated Weightlessness

    NASA Technical Reports Server (NTRS)

    Moyer, E. L.; Talyansky, Y.; Scott, R. T.; Tash, J. S.; Christenson, L. K.; Alwood, J. S.; Ronca, A. E.

    2017-01-01

    Hindlimb unloading (HU) is a rodent model system used to simulate weightlessness experienced in space. However, some effects of this approach on rodent physiology are under-studied, specifically the effects on ovarian estrogen production which drives the estrous cycle. To resolve this deficiency, we conducted a ground-based validation study using the HU model, while monitoring estrous cycles in 16-weeks-old female C57BL6 mice. Animals were exposed to HU for 12 days following a 3 day HU cage acclimation period, and estrous cycling was analyzed in HU animals (n=22), normally loaded HU Cage Pair-Fed controls (CPF; n=22), and Vivarium controls fed ad libitum (VIV; n=10). Pair feeding was used to control for potential nutritional deficits on ovarian function. Vaginal cells were sampled daily in all mice via saline lavage. Cells were dried and stained with crystal violet, and the smears evaluated using established vaginal cytology techniques by two individuals blinded to the animal treatment group. Estrous cyclicity was disrupted in nearly all HU and CPF mice, while those maintained in VIV had an average normal cycle length of 4.8+/- 0.5 days, with all stages in the cycle visibly observed. CPF and HU animals arrested in the diestrous phase, which precedes the pre-ovulatory estrogen surge. Additionally, infection-like symptoms characterized by vaginal discharge and swelling arose in several HU animals, which we suspect was due to an inability of these mice to properly groom themselves, and/or due to the change in the gravity vector relative to the vaginal opening, which prevented drainage of the lavage solution. Pair-feeding resulted in similar weight gains of HU and CPF (1.5% vs 3.0%, respectively). The current results indicate that pair-feeding controlled weight gain and that the HU cage alone influenced estrous cyclicity. Thus, longer acclimation needs to be tested to determine if and when normal estrous cycling resumes in non-loaded mice in HU cages prior to HU

  6. Saikosaponin d protects against acetaminophen-induced hepatotoxicity by inhibiting NF-κB and STAT3 signaling.

    PubMed

    Liu, Aiming; Tanaka, Naoki; Sun, Lu; Guo, Bin; Kim, Jung-Hwan; Krausz, Kristopher W; Fang, Zhongze; Jiang, Changtao; Yang, Julin; Gonzalez, Frank J

    2014-11-05

    Overdose of acetaminophen (APAP) can cause acute liver injury that is sometimes fatal, requiring efficient pharmacological intervention. The traditional Chinese herb Bupleurum falcatum has been widely used for the treatment of several liver diseases in eastern Asian countries, and saikosaponin d (SSd) is one of its major pharmacologically-active components. However, the efficacy of Bupleurum falcatum or SSd on APAP toxicity remains unclear. C57/BL6 mice were administered SSd intraperitoneally once daily for 5days, followed by APAP challenge. Biochemical and pathological analysis revealed that mice treated with SSd were protected against APAP-induced hepatotoxicity. SSd markedly suppressed phosphorylation of nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) and reversed the APAP-induced increases in the target genes of NF-κB, such as pro-inflammatory cytokine Il6 and Ccl2, and those of STAT3, such as Socs3, Fga, Fgb and Fgg. SSd also enhanced the expression of the anti-inflammatory cytokine Il10 mRNA. Collectively, these results demonstrate that SSd protects mice from APAP-induced hepatotoxicity mainly through down-regulating NF-κB- and STAT3-mediated inflammatory signaling. This study unveils one of the possible mechanisms of hepatoprotection caused by Bupleurum falcatum and/or SSd. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. Protective and prophylactic effects of chlorogenic acid on aluminum-induced acute hepatotoxicity and hematotoxicity in mice.

    PubMed

    Cheng, Dai; Zhang, Xinyu; Xu, Lihan; Li, Xiang; Hou, Lihua; Wang, Chunling

    2017-08-01

    The possible health impact of the exposures to Al from environment would be inevitable for humans. Using chelating agents and natural antioxidants against Al-induced biotoxicity become a natural and modern way to prevent the adverse effects of Al in people. This study was undertaken to determine the effectiveness of chlorogenic acid (CGA, 5-O-caffeoylquinic acid) in preventing aluminum chloride (AlCl 3 ) induced hepatotoxicity and hematotoxicity in mice. Control, Al-treated (a single injection of 25 mg Al 3+ /kg, i.p.), Al + CGA (2 h after, a single dose of 100 mg/kg, i.p.), CGA + Al (administered to mice daily for 5 days at 30 mg/kg before Al-treatment) and group of CGA per se (administered to mice daily for 5 days at 30 mg/kg) were used. The levels of Al in liver and blood, the activities of transaminases in serum and osmotic fragility were increased by comparison with the control, while the activities of superoxide dismutase and catalase decreased significantly in the Al-treated group. However, treating mice with CGA at either dosing regimens, post- or pre- Al administration alleviate Al oxidative damaging effects, stabilize cell membrane, prevent hepatocyte apoptosis. CGA supplementation may be favorable to avoid Al-induced hematotoxicity and hepatotoxicity for humans. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Protective Effect of Boiled and Freeze-dried Mature Silkworm Larval Powder Against Diethylnitrosamine-induced Hepatotoxicity in Mice.

    PubMed

    Cho, Jae-Min; Kim, Kee-Young; Ji, Sang-Deok; Kim, Eun-Hee

    2016-09-01

    Hepatocellular carcinoma (HCC) is a representative inflammation-associated cancer and known to be the most frequent tumors. HCC may also induce important pro- and anti-tumor immune reactions. However, the underlying mechanisms are unsatisfactorily identified. We investigated the protective effect of boiled and freeze-dried mature silkworm larval powder (BMSP) on diethylnitrosamine (DEN)-induced hepatotoxicity in mice. Mice were fed with diet containing BMSP (0.1, 1, and 10 g/kg) for two weeks and DEN (100 mg/kg, intraperitoneally) was injected 18 hours before the end of this experiment. Liver toxicity was determined in serum and histopathological examination was assessed in the liver tissues. Infiltration of immune cells and expressions of inflammatory cytokines and chemokines were also examined. Pretreatment with BMSP reduced necrotic and histopathological changes induced by DEN in the liver. Measurement of serum biochemical indicators, the levels of alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase, showed that pretreatment with BMSP also decreased DEN-induced hepatotoxicity. In addition, BMSP inhibited the macrophage and CD31 infiltration in a dose-dependent manner. The expressions of interleukin-1β, IFN-γ and chemokines for T cell activation were decreased in BMSP pretreatment groups. BMSP may have a protective effect against acute liver injury by inhibiting necrosis and inflammatory response in DEN-treated mice.

  9. Repeated dose studies with pure Epigallocatechin-3-gallate demonstrated dose and route dependant hepatotoxicity with associated dyslipidemia.

    PubMed

    Ramachandran, Balaji; Jayavelu, Subramani; Murhekar, Kanchan; Rajkumar, Thangarajan

    2016-01-01

    EGCG (Epigallocatechin-3-gallate) is the major active principle catechin found in green tea. Skepticism regarding the safety of consuming EGCG is gaining attention, despite the fact that it is widely being touted for its potential health benefits, including anti-cancer properties. The lack of scientific data on safe dose levels of pure EGCG is of concern, while EGCG has been commonly studied as a component of GTE (Green tea extract) and not as a single active constituent. This study has been carried out to estimate the maximum tolerated non-toxic dose of pure EGCG and to identify the treatment related risk factors. In a fourteen day consecutive treatment, two different administration modalities were compared, offering an improved [i.p (intraperitoneal)] and limited [p.o (oral)] bioavailability. A trend of dose and route dependant hepatotoxicity was observed particularly with i.p treatment and EGCG increased serum lipid profile in parallel to hepatotoxicity. Fourteen day tolerable dose of EGCG was established as 21.1 mg/kg for i.p and 67.8 mg/kg for p.o. We also observed that, EGCG induced effects by both treatment routes are reversible, subsequent to an observation period for further fourteen days after cessation of treatment. It was demonstrated that the severity of EGCG induced toxicity appears to be a function of dose, route of administration and period of treatment.

  10. Combined effects of a high-fat diet and chronic valproic acid treatment on hepatic steatosis and hepatotoxicity in rats

    PubMed Central

    Zhang, Li-fang; Liu, Ling-sheng; Chu, Xiao-man; Xie, Hao; Cao, Li-juan; Guo, Cen; A, Ji-ye; Cao, Bei; Li, Meng-jie; Wang, Guang-ji; Hao, Hai-ping

    2014-01-01

    Aim: To investigate the potential interactive effects of a high-fat diet (HFD) and valproic acid (VPA) on hepatic steatosis and hepatotoxicity in rats. Methods: Male SD rats were orally administered VPA (100 or 500 mg·kg−1·d−1) combined with HFD or a standard diet for 8 weeks. Blood and liver samples were analyzed to determine lipid levels and hepatic function biomarkers using commercial kit assays. Low-molecular-weight compounds in serum, urine and bile samples were analyzed using a metabonomic approach based on GC/TOF-MS. Results: HFD alone induced extensive hepatocyte steatosis and edema in rats, while VPA alone did not cause significant liver lesions. VPA significantly aggravated HFD-induced accumulation of liver lipids, and caused additional spotty or piecemeal necrosis, accompanied by moderate infiltration of inflammatory cells in the liver. Metabonomic analysis of serum, urine and bile samples revealed that HFD significantly increased the levels of amino acids, free fatty acids (FFAs) and 3-hydroxy-butanoic acid, whereas VPA markedly decreased the levels of amino acids, FFAs and the intermediate products of the tricarboxylic acid cycle (TCA) compared with the control group. HFD aggravated VPA-induced inhibition on lipid and amino acid metabolism. Conclusion: HFD magnifies VPA-induced impairment of mitochondrial β-oxidation of FFAs and TCA, thereby increases hepatic steatosis and hepatotoxicity. The results suggest the patients receiving VPA treatment should be advised to avoid eating HFD. PMID:24442146

  11. Morphological, biochemical, histological, and ultrastructural protective effects of misoprostol on cisplatin induced-hepatotoxicity in adult male rats.

    PubMed

    Nasr, Ashraf Y

    2013-12-01

    To investigate the possible protective effect of misoprostol on cisplatin-induced hepatotoxicity. Four-equal sized groups (control, cisplatin-treated, misoprostol-treated, combined misoprostol, and cisplatin-treated) adult male Wistar rats (6 each) were used in this study. Body weight, liver weight, and liver weight/body weight ratio was calculated. Blood samples were obtained from the hearts of rats to determine the levels of total serum bilirubin (TSB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and albumin. Liver specimens were prepared for both light and electron microscopes. The study was carried out between June 2012 and April 2013 at the Anatomy Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt, and the Department of Anatomy, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia. A single cisplatin dose (7.5 mg/kg intraperitoneally) resulted in significant elevation of AST, ALT, and TSB serum levels, and a significant reduction of serum albumin level, body weight, liver weight, and liver weight/body weight ratio. A combination of misoprostol (200 ug/kg/day) with cisplatin improved most of the previous parameters. Examination of specimens by both light and electron microscopes revealed pericentral hepatic necrosis, periportal fibrosis, dilatation, and congestion of central vein and blood sinusoids, diminished glycogen content, degenerated mitochondria, vesicular dilated rough endoplasmic reticulum, and nuclear changes in cisplatin-treated rats. Oral intake of misoprostol with cisplatin improved many of these changes. The results indicate that misoprostol may have a protective effect on cisplatin-induced hepatotoxicity.

  12. The protective effect of Capparis ovata on 6-mercaptopurine-induced hepatotoxicity and oxidative stress in rats.

    PubMed

    Tülümen, Tuğçe; Ayata, Ali; Özen, Metehan; Sütçü, Recep; Canatan, Duran

    2015-05-01

    Capparis ovata is a member of Capparidacaeae family has been used in phytomedicine with a lot of positive effects such as an antioxidative, antihyperlipidemic, anti-inflammatory, and antihepatotoxic agent. The aim of this study was to research the protective effect of C. ovata on 6-mercaptopurine (6-MP) induced to hepatotoxicity and oxidative stress in rats. The rats were divided into 4 groups: control, 6-MP, C. ovataovate, and 6-MP + C. ovata. A complete blood count was performed, liver function test and antioxidant enzymes levels such as superoxide dismutase, glutathione peroxidase, catalase, and malondialdehyde were measured in blood before and after a 14-day test period. White blood cell and platelet counts were lower in the 6-MP group than other 3 groups (P < 0.005). Hepatic transaminase levels were higher in 6-MP group than the 3 groups (P < 0.05). Superoxide dismutase, glutathione peroxidase, and CAT levels were lower and malondialdehyde was higher in blood samples in 6-MP group than other 3 groups (P < 0.005). In conclusion, our tests were showed that C. ovata may be useful in patients receiving 6-MP therapy to prevent hepatotoxicity and in order to maintain uninterrupted therapy possibly reducing the risk of relapse. Although additional studies ensure that Capparis does not affect 6-MP antileukemic activity. We believe these results are important contribution to the literature.

  13. Modulatory effects of some natural products on hepatotoxicity induced by combination of sodium valproate and paracetamol in rats.

    PubMed

    Zaky, Hanan S; Gad, Amany M; Nemr, Ekram; Hassan, Wedad; Abd El-Raouf, Ola M; Ali, Aza A

    2018-05-25

    Possible hepatoprotective effect of Curcuma longa and/or Nigella sativa against hepatotoxicity induced by coadministration of sodium valproate (SV) and paracetamol was studied. Rats were divided into 10 groups, control groups 1, 2, 3, and 4 received vehicles, C. longa (200 mg/kg, p.o.), N. sativa (250 mg/kg, p.o.), or both herbs for 21 days, respectively. Toxicity groups 5, 6, and 7 received SV (300 mg/kg, i.p.), paracetamol (1000 mg/kg, p.o.) for the last 4 days or both for 21 days, respectively. Protection groups 8, 9, and 10 received C. longa, N. sativa, or both, respectively, 1 h before the administration of both the drugs for 21 days. SV and/or paracetamol significantly increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, relative liver/body weight ratio, malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), and caspase-3 (Casp-3) while significantly decreased albumin, total protein, glutathione (GSH) reduced, GSH peroxidase, and superoxide dismutase (SOD). Preadministration of C. longa and/or N. sativa caused protective effect against the hepatotoxicity induced by both drugs. © 2018 Wiley Periodicals, Inc.

  14. Amelioration of Paracetamol-Induced Hepatotoxicity in Rat by the Administration of Methanol Extract of Muntingia calabura L. Leaves

    PubMed Central

    Mahmood, N. D.; Mamat, S. S.; Kamisan, F. H.; Yahya, F.; Kamarolzaman, M. F. F.; Nasir, N.; Mohtarrudin, N.; Tohid, S. F. Md.; Zakaria, Z. A.

    2014-01-01

    Muntingia calabura L. is a tropical plant species that belongs to the Elaeocarpaceae family. The present study is aimed at determining the hepatoprotective activity of methanol extract of M. calabura leaves (MEMC) using two models of liver injury in rats. Rats were divided into five groups (n = 6) and received 10% DMSO (negative control), 50 mg/kg N-acetylcysteine (NAC; positive control), or MEMC (50, 250, and 500 mg/kg) orally once daily for 7 days and on the 8th day were subjected to the hepatotoxic induction using paracetamol (PCM). The blood and liver tissues were collected and subjected to biochemical and microscopical analysis. The extract was also subjected to antioxidant study using the 2,2-diphenyl-1-picrylhydrazyl-(DPPH) and superoxide anion-radical scavenging assays. At the same time, oxygen radical antioxidant capacity (ORAC) and total phenolic content were also determined. From the histological observation, lymphocyte infiltration and marked necrosis were observed in PCM-treated groups (negative control), whereas maintenance of hepatic structure was observed in group pretreated with N-acetylcysteine and MEMC. Hepatotoxic rats pretreated with NAC or MEMC exhibited significant decrease (P < 0.05) in ALT and AST enzymes level. Moreover, the extract also exhibited good antioxidant activity. In conclusion, MEMC exerts potential hepatoprotective activity that could be partly attributed to its antioxidant activity and, thus warrants further investigations. PMID:24868543

  15. Decreased hepatotoxic bile acid composition and altered synthesis in progressive human nonalcoholic fatty liver disease

    SciT

    Lake, April D.; Novak, Petr; Shipkova, Petia

    2013-04-15

    Bile acids (BAs) have many physiological roles and exhibit both toxic and protective influences within the liver. Alterations in the BA profile may be the result of disease induced liver injury. Nonalcoholic fatty liver disease (NAFLD) is a prevalent form of chronic liver disease characterized by the pathophysiological progression from simple steatosis to nonalcoholic steatohepatitis (NASH). The hypothesis of this study is that the ‘classical’ (neutral) and ‘alternative’ (acidic) BA synthesis pathways are altered together with hepatic BA composition during progression of human NAFLD. This study employed the use of transcriptomic and metabolomic assays to study the hepatic toxicologic BAmore » profile in progressive human NAFLD. Individual human liver samples diagnosed as normal, steatosis, and NASH were utilized in the assays. The transcriptomic analysis of 70 BA genes revealed an enrichment of downregulated BA metabolism and transcription factor/receptor genes in livers diagnosed as NASH. Increased mRNA expression of BAAT and CYP7B1 was observed in contrast to decreased CYP8B1 expression in NASH samples. The BA metabolomic profile of NASH livers exhibited an increase in taurine together with elevated levels of conjugated BA species, taurocholic acid (TCA) and taurodeoxycholic acid (TDCA). Conversely, cholic acid (CA) and glycodeoxycholic acid (GDCA) were decreased in NASH liver. These findings reveal a potential shift toward the alternative pathway of BA synthesis during NASH, mediated by increased mRNA and protein expression of CYP7B1. Overall, the transcriptomic changes of BA synthesis pathway enzymes together with altered hepatic BA composition signify an attempt by the liver to reduce hepatotoxicity during disease progression to NASH. - Highlights: ► Altered hepatic bile acid composition is observed in progressive NAFLD. ► Bile acid synthesis enzymes are transcriptionally altered in NASH livers. ► Increased levels of taurine and conjugated bile

  16. Mechanism-based biomarker gene sets for glutathione depletion-related hepatotoxicity in rats

    SciT

    Gao Weihua; Mizukawa, Yumiko; Nakatsu, Noriyuki

    scoring systems, could be promising biomarkers for preclinical examination of hepatotoxicity.« less

  17. Taurine zinc solid dispersions attenuate doxorubicin-induced hepatotoxicity and cardiotoxicity in rats

    SciT

    Wang, Yu; Mei, Xueting; Yuan, Jingquan

    2015-11-15

    . - Highlights: • Dissolution of taurine zinc complex can be increased by solid dispersions (SDs). • Taurine zinc SDs blocked doxorubicin-induced hepatotoxicity and cardiotoxicity. • Taurine zinc SDs can alleviate oxidative stress and dampen JNK phosphorylation. • Taurine zinc SDs increased the expression of UGT, HO-1 at mRNA and protein level. • Taurine zinc SDs revealed greater hepatoprotective effects than silymarin.« less

  18. Formononetin protects against acetaminophen-induced hepatotoxicity through enhanced NRF2 activity.

    PubMed

    Jin, Fen; Wan, Chunpeng; Li, Weifang; Yao, Liangliang; Zhao, Hongqian; Zou, Yuan; Peng, Dewei; Huang, Weifeng

    2017-01-01

    To examine the effects of formononetin (FMN) on Acetaminophen (APAP)-induced liver injury in vitro and in vivo. Human non-tumor hepatic cells LO2 were pretreated with either vehicle or FMN (20, 40 μM), for 6 h, followed by incubation with or without APAP (10 mM) for 24 h. In an in vivo assay, male BALB/c mice were randomly divided into four groups: (1) control group; (2) APAP group; (3) APAP + FMN (50 mg/Kg); (4) APAP + FMN (100 mg/Kg). The mice in the control and APAP groups were pre-treated with vehicle; the other two groups were pretreated daily with FMN (50, 100 mg/Kg) orally for 7 consecutive days. After the final treatment, acute liver injury was induced in all groups, except the control group, by intraperitoneal (i.p.) injection of 300 mg/Kg APAP. In LO2 cells, APAP exposure decreased the cell viability and glutathione (GSH) content, which were both greatly restored by FMN pretreatment. Overdose of APAP increased hepatic malondialdehyde (MDA) content, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity in experimental mice. Supplementation with 100 mg/Kg FMN significantly reduced APAP-induced elevated levels of MDA (1.97 ± 0.27 vs 0.55 ± 0.14 nmol/mg protein, p < 0.001), ALT (955.80 ± 209.40 vs 46.90 ± 20.40 IU/L, p < 0.001) and AST (1533.80 ± 244.80 vs 56.70 ± 28.80 IU/L, p < 0.001), and hepatic GSH level (5.54 ± 0.93 vs 8.91 ± 1.11 μmol/mg protein, p < 0.001) was significantly increased. These results were further validated by histopathology and TdT-mediated biotin-dUTP nick-endlabeling (TUNEL) staining, pretreatment with 100 mg/Kg FMN significant decreased APAP-induced hepatocellular damage and cell apoptosis (36.55 ± 3.82 vs 2.58 ± 1.80%, p < 0.001). Concomitantly, FMN stimulated the expression of Nrf2 and antioxidant gene expression in the presence of APAP. These data provide an experimental basis for the use of FMN in the treatment of patients with APAP-induced hepatotoxicity.

  19. Formononetin protects against acetaminophen-induced hepatotoxicity through enhanced NRF2 activity

    PubMed Central

    Li, Weifang; Yao, Liangliang; Zhao, Hongqian; Zou, Yuan; Peng, Dewei; Huang, Weifeng

    2017-01-01

    To examine the effects of formononetin (FMN) on Acetaminophen (APAP)-induced liver injury in vitro and in vivo. Human non-tumor hepatic cells LO2 were pretreated with either vehicle or FMN (20, 40 μM), for 6 h, followed by incubation with or without APAP (10 mM) for 24 h. In an in vivo assay, male BALB/c mice were randomly divided into four groups: (1) control group; (2) APAP group; (3) APAP + FMN (50 mg/Kg); (4) APAP + FMN (100 mg/Kg). The mice in the control and APAP groups were pre-treated with vehicle; the other two groups were pretreated daily with FMN (50, 100 mg/Kg) orally for 7 consecutive days. After the final treatment, acute liver injury was induced in all groups, except the control group, by intraperitoneal (i.p.) injection of 300 mg/Kg APAP. In LO2 cells, APAP exposure decreased the cell viability and glutathione (GSH) content, which were both greatly restored by FMN pretreatment. Overdose of APAP increased hepatic malondialdehyde (MDA) content, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity in experimental mice. Supplementation with 100 mg/Kg FMN significantly reduced APAP-induced elevated levels of MDA (1.97 ± 0.27 vs 0.55 ± 0.14 nmol/mg protein, p < 0.001), ALT (955.80 ± 209.40 vs 46.90 ± 20.40 IU/L, p < 0.001) and AST (1533.80 ± 244.80 vs 56.70 ± 28.80 IU/L, p < 0.001), and hepatic GSH level (5.54 ± 0.93 vs 8.91 ± 1.11 μmol/mg protein, p < 0.001) was significantly increased. These results were further validated by histopathology and TdT-mediated biotin-dUTP nick-endlabeling (TUNEL) staining, pretreatment with 100 mg/Kg FMN significant decreased APAP-induced hepatocellular damage and cell apoptosis (36.55 ± 3.82 vs 2.58 ± 1.80%, p < 0.001). Concomitantly, FMN stimulated the expression of Nrf2 and antioxidant gene expression in the presence of APAP. These data provide an experimental basis for the use of FMN in the treatment of patients with APAP-induced hepatotoxicity. PMID:28234915

  20. Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats

    PubMed Central

    Akbulut, Sami; Elbe, Hulya; Eris, Cengiz; Dogan, Zumrut; Toprak, Gulten; Otan, Emrah; Erdemli, Erman; Turkoz, Yusuf

    2014-01-01

    AIM: To investigate the potential role of oxidative stress and the possible therapeutic effects of N-acetyl cysteine (NAC), amifostine (AMF) and ascorbic acid (ASC) in methotrexate (MTX)-induced hepatotoxicity. METHODS: An MTX-induced hepatotoxicity model was established in 44 male Sprague Dawley rats by administration of a single intraperitoneal injection of 20 mg/kg MTX. Eleven of the rats were left untreated (Model group; n = 11), and the remaining rats were treated with a 7-d course of 50 mg/kg per day NAC (MTX + NAC group; n = 11), 50 mg/kg per single dose AMF (MTX + AMF group; n = 11), or 10 mg/kg per day ASC (MTX + ASC group; n = 11). Eleven rats that received no MTX and no treatments served as the negative control group. Structural and functional changes related to MTX- and the various treatments were assessed by histopathological analysis of liver tissues and biochemical assays of malondialdehyde (MDA), superoxide dismutase (SOD), catalase, glutathione (GSH) and xanthine oxidase activities and of serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and total bilirubin. RESULTS: Exposure to MTX caused structural and functional hepatotoxicity, as evidenced by significantly worse histopathological scores [median (range) injury score: control group: 1 (0-3) vs 7 (6-9), P = 0.001] and significantly higher MDA activity [409 (352-466) nmol/g vs 455.5 (419-516) nmol/g, P < 0.05]. The extent of MTX-induced perturbation of both parameters was reduced by all three cytoprotective agents, but only the reduction in hepatotoxicity scores reached statistical significance [4 (3-6) for NAC, 4.5 (3-5) for AMF and 6 (5-6) for ASC; P = 0.001, P = 0.001 and P < 0.005 vs model group respectively]. Exposure to MTX also caused a significant reduction in the activities of GSH and SOD antioxidants in liver tissues [control group: 3.02 (2.85-3.43) μmol/g and 71.78 (61.88-97.81) U/g vs model group: 2.52 (2.07-3.34) μmol/g and 61.46 (58

  1. COSP - A computer model of cyclic oxidation

    NASA Technical Reports Server (NTRS)

    Lowell, Carl E.; Barrett, Charles A.; Palmer, Raymond W.; Auping, Judith V.; Probst, Hubert B.

    1991-01-01

    A computer model useful in predicting the cyclic oxidation behavior of alloys is presented. The model considers the oxygen uptake due to scale formation during the heating cycle and the loss of oxide due to spalling during the cooling cycle. The balance between scale formation and scale loss is modeled and used to predict weight change and metal loss kinetics. A simple uniform spalling model is compared to a more complex random spall site model. In nearly all cases, the simpler uniform spall model gave predictions as accurate as the more complex model. The model has been applied to several nickel-base alloys which, depending upon composition, form Al2O3 or Cr2O3 during oxidation. The model has been validated by several experimental approaches. Versions of the model that run on a personal computer are available.

  2. A cyclic universe approach to fine tuning

    DOE PAGES

    Alexander, Stephon; Cormack, Sam; Gleiser, Marcelo

    2016-04-05

    We present a closed bouncing universe model where the value of coupling constants is set by the dynamics of a ghost-like dilatonic scalar field. We show that adding a periodic potential for the scalar field leads to a cyclic Friedmann universe where the values of the couplings vary randomly from one cycle to the next. While the shuffling of values for the couplings happens during the bounce, within each cycle their time-dependence remains safely within present observational bounds for physically-motivated values of the model parameters. Our model presents an alternative to solutions of the fine tuning problem based on stringmore » landscape scenarios. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Funded by SCOAP(3).« less

  3. A cyclic universe approach to fine tuning

    SciT

    Alexander, Stephon; Cormack, Sam; Gleiser, Marcelo

    We present a closed bouncing universe model where the value of coupling constants is set by the dynamics of a ghost-like dilatonic scalar field. We show that adding a periodic potential for the scalar field leads to a cyclic Friedmann universe where the values of the couplings vary randomly from one cycle to the next. While the shuffling of values for the couplings happens during the bounce, within each cycle their time-dependence remains safely within present observational bounds for physically-motivated values of the model parameters. Our model presents an alternative to solutions of the fine tuning problem based on stringmore » landscape scenarios. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Funded by SCOAP(3).« less

  4. Statistical cyclicity of the supercontinent cycle

    NASA Astrophysics Data System (ADS)

    Rolf, T.; Coltice, N.; Tackley, P. J.

    2014-04-01

    Supercontinents like Pangea impose a first-order control on Earth's evolution as they modulate global heat loss, sea level, climate, and biodiversity. In a traditional view, supercontinents form and break up in a regular, perhaps periodic, manner in a cycle lasting several 100 Myr as reflected in the assembly times of Earth's major continental aggregations: Columbia, Rodinia, and Pangea. However, modern views of the supercontinent cycle propose a more irregular evolution on the basis of an improved understanding of the Precambrian geologic record. Here we use fully dynamic spherical mantle convection models featuring plate-like behavior and continental drift to investigate supercontinent formation and breakup. We further dismiss the concept of regularity but suggest a statistical cyclicity in which the supercontinent cycle may have a characteristic period imposed by mantle and lithosphere properties, but this is hidden in immense fluctuations between different cycles that arise from the chaotic nature of mantle flow.

  5. OBSERVATIONS ON A CASE OF CYCLIC ALBUMINURIA.

    PubMed

    Mendel, L B; Hooker, D B

    1901-10-01

    The preceding observations record a new instance of the occurrence of cyclic albuminuria in an otherwise apparently healthy young man. The typical course of the proteid excretion from hour to hour under various conditions has been reviewed and its independence of the changes in diet or muscular work pointed out. No relationship between the volume of urine eliminated and the quantity of proteid excreted has been ascertained. The specific effect of the horizontal posture in dispelling the albuminuria is the most interesting feature observed. The attempt to refer this to attendant circulatory changes in the kidneys is, for the present, no more than an interesting speculation. See PDF for Structure See PDF for Structure.

  6. A Practical Beginner's Guide to Cyclic Voltammetry

    ERIC Educational Resources Information Center

    Elgrishi, Noémie; Rountree, Kelley J.; McCarthy, Brian D.; Rountree, Eric S.; Eisenhart, Thomas T.; Dempsey, Jillian L.

    2018-01-01

    Despite the growing popularity of cyclic voltammetry, many students do not receive formalized training in this technique as part of their coursework. Confronted with self-instruction, students can be left wondering where to start. Here, a short introduction to cyclic voltammetry is provided to help the reader with data acquisition and…

  7. High-Temperature Cyclic Oxidation Data, Volume 1

    NASA Technical Reports Server (NTRS)

    Barrett, C. A.; Garlick, R. G.; Lowell, C. E.

    1984-01-01

    This first in a series of cyclic oxidation handbooks contains specific-weight-change-versus-time data and X-ray diffraction results derived from high-temperature cyclic tests on high-temperature, high-strength nickel-base gamma/gamma' and cobalt-base turbine alloys. Each page of data summarizes a complete test on a given alloy sample.

  8. Flexural creep of structural flakeboards under cyclic humidity

    M.C. Yeh; R.C. Tang; Chung-Yun Hse

    1990-01-01

    Flexural creep behavior of randomly oriented structural flakeboards under cyclic humidity is presented. Specimens fabricated with 5 and 7 percent phenol-formaldehyde resin were subjected to constant concentrated load in bending under slow and fast cyclic relative humidity (RH) between 65 and 95 percent for 100 days. The temperature was set at a constant 75°F through...

  9. MICROWAVE-ASSISTED PREPARATION OF CYCLIC UREAS FROM DIAMINES

    EPA Science Inventory

    Rajender S. Varma* and Yong-Jin Kim
    Cyclic ureas are useful intermediates for a variety of pharmaceuticals and pesticides. One of the attractive approaches for the synthesis of cyclic ureas uses condensation of diamines with urea as a carbonyl source under dynamic evacuation. ...

  10. Evaluating cyclic fatigue of sealants during outdoor testing

    R. Sam Williams; Steven Lacher; Corey Halpin; Christopher White

    2009-01-01

    A computer-controlled test apparatus (CCTA) and other instrumentation for subjecting sealant specimens to cyclic fatigue during outdoor exposure was developed. The CCTA enables us to use weather-induced conditions to cyclic fatigue specimens and to conduct controlled tests in-situ during the outdoor exposure. Thermally induced dimensional changes of an aluminum bar...

  11. Phenomenon of low-alloy steel parametrization transformation at cyclic loading in low-cyclic area

    NASA Astrophysics Data System (ADS)

    Shipachev, A. M.; Nazarova, M. N.

    2017-10-01

    Following the results of measurements of hardness, magnetizing force and the rate of ultrasonic longitudinal waves of 09G2S steel samples at various cyclic operating time values, there is a phenomenon of transformation from the normal law of speed distribution of these parameters in power-mode distribution. It shows the submission of the behavior of metal as a complex system to the theory of the self-organized criticality.

  12. Tolerance to Acetaminophen Hepatotoxicity in the Mouse Model of Autoprotection is Associated with Induction of Flavin-containing Monooxygenase-3 (FMO3) in Hepatocytes

    EPA Science Inventory

    Acetaminophen (APAP) pretreatment with a low hepatotoxic dose in mice results in resistance to a second, higher dose of APAP (APAP autoprotection). Recent microarray work by our group showed a drastic induction of liver flavin containing monooxygenase-3 (Fmo3) mRNA expression in...

  13. Expression and polymorphism (rs4880) of mitochondrial superoxide dismutase (SOD2) and asparaginase induced hepatotoxicity in adult patients with acute lymphoblastic leukemia

    PubMed Central

    Alachkar, Houda; Fulton, Noreen; Sanford, Ben; Malnassy, Greg; Mutonga, Martin; Larson, Richard A.; Bloomfield, Clara D.; Marcucci, Guido; Nakamura, Yusuke; Stock, Wendy

    2016-01-01

    Asparaginase, which depletes asparagine and glutamine, activates amino acid stress response. Oxidative stress mediated by excessive reactive oxygen species (ROS) causes enhanced mitochondrial permeabilization and subsequent cell apoptosis and is considered a plausible mechanism for drug-induced hepatotoxicity, a common toxicity of asparaginase in adults with acute lymphoblastic leukemia (ALL). Studies investigating the pharmacogenetics of asparaginase in ALL are limited and focused on asparaginase-induced allergic reaction common in pediatric patients. Here, we sought to determine a potential association between the variant rs4880 in SOD2 gene, a key mitochondrial enzyme that protects cells against ROS, and hepatotoxicity during asparaginase-based therapy in 224 patients enrolled on CALGB-10102, a treatment trial for adults with ALL. We report that the CC genotype of rs4880 is associated with increased hepatotoxicity following asparaginase-based treatment. Thus, rs4880 likely contributes to asparaginase-induced hepatotoxicity, and functional studies investigating this SNP are needed to develop therapeutic approaches that mitigate this toxicity. PMID:27019981

  14. The involvement of Nrf2 in the protective effects of (-)-Epigallocatechin-3-gallate (EGCG) on NaAsO2-induced hepatotoxicity.

    PubMed

    Han, Xiao-Dong; Zhang, Yan-Yan; Wang, Ke-Lei; Huang, Yong-Pan; Yang, Zhong-Bao; Liu, Zhi

    2017-09-12

    Arsenic exposure produces hepatotoxicity. The common mechanism determining its toxicity is the generation of oxidative stress. Oxidative stress induced by arsenic leads to the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. (-)-Epigallocatechin-3-gallate (EGCG) possesses a potent antioxidant capacity and exhibits extensive pharmacological activities. This study aims to evaluate effects of EGCG on arsenic-induced hepatotoxicity and activation of Nrf2 pathway. Plasma activities of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase were measured; Histological analyses were conducted to observe morphological changes; Biochemical indexes such as oxidative stress (Catalase (CAT), malonyldialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH), reactive oxygen species (ROS)), Nrf2 signaling related genes ( Nrf2, Nqo1, and Ho-1 ) were assessed. The results showed that EGCG inhibited arsenic-induced hepatic pathological damage, liver ROS level and MDA level. Arsenic decreases the antioxidant enzymes SOD, GPX, and CAT activity and the decrease was inhibited by treatment of EGCG. Furthermore, EGCG attenuated the retention of arsenic in liver tissues and improved the expressions of Nrf2 signaling related genes ( Nrf2, Nqo1, and Ho-1 ). These findings provide evidences that EGCG may be useful for reducing hepatotoxicity associated with oxidative stress by the activation of Nrf2 signaling pathway. Our findings suggest a possible mechanism of antioxidant EGCG in preventing hepatotoxicity, which implicate that EGCG may be a potential treatment for arsenicosis therapy.

  15. History-independent cyclic response of nanotwinned metals

    NASA Astrophysics Data System (ADS)

    Pan, Qingsong; Zhou, Haofei; Lu, Qiuhong; Gao, Huajian; Lu, Lei

    2017-11-01

    Nearly 90 per cent of service failures of metallic components and structures are caused by fatigue at cyclic stress amplitudes much lower than the tensile strength of the materials involved. Metals typically suffer from large amounts of cumulative, irreversible damage to microstructure during cyclic deformation, leading to cyclic responses that are unstable (hardening or softening) and history-dependent. Existing rules for fatigue life prediction, such as the linear cumulative damage rule, cannot account for the effect of loading history, and engineering components are often loaded by complex cyclic stresses with variable amplitudes, mean values and frequencies, such as aircraft wings in turbulent air. It is therefore usually extremely challenging to predict cyclic behaviour and fatigue life under a realistic load spectrum. Here, through both atomistic simulations and variable-strain-amplitude cyclic loading experiments at stress amplitudes lower than the tensile strength of the metal, we report a history-independent and stable cyclic response in bulk copper samples that contain highly oriented nanoscale twins. We demonstrate that this unusual cyclic behaviour is governed by a type of correlated ‘necklace’ dislocation consisting of multiple short component dislocations in adjacent twins, connected like the links of a necklace. Such dislocations are formed in the highly oriented nanotwinned structure under cyclic loading and help to maintain the stability of twin boundaries and the reversible damage, provided that the nanotwins are tilted within about 15 degrees of the loading axis. This cyclic deformation mechanism is distinct from the conventional strain localizing mechanisms associated with irreversible microstructural damage in single-crystal, coarse-grained, ultrafine-grained and nanograined metals.

  16. The enhanced atorvastatin hepatotoxicity in diabetic rats was partly attributed to the upregulated hepatic Cyp3a and SLCO1B1

    PubMed Central

    Shu, Nan; Hu, Mengyue; Ling, Zhaoli; Liu, Peihua; Wang, Fan; Xu, Ping; Zhong, Zeyu; Sun, Binbin; Zhang, Mian; Li, Feng; Xie, Qiushi; Liu, Xiaodong; Liu, Li

    2016-01-01

    Liver injury is a common adverse effect of atorvastatin. This study aimed to investigate atorvastatin-induced hepatotoxicity in diabetic rats induced by high-fat diet combined with streptozotocin. The results showed that 40 mg/kg atorvastatin was lethal to diabetic rats, whose mean survival time was 6.2 days. Severe liver injury also occurred in diabetic rats treated with 10 mg/kg and 20 mg/kg atorvastatin. The in vitro results indicated that atorvastatin cytotoxicity in hepatocytes of diabetic rats was more severe than normal and high-fat diet feeding rats. Expressions and activities of hepatic Cyp3a and SLCO1B1 were increased in diabetic rats, which were highly correlated with hepatotoxicity. Antioxidants (glutathione and N-Acetylcysteine), Cyp3a inhibitor ketoconazole and SLCO1B1 inhibitor gemfibrozil suppressed cytotoxicity and ROS formation in primary hepatocytes of diabetic rats. In HepG2 cells, up-regulations of CYP3A4 and SLCO1B1 potentiated hepatotoxicity and ROS generation, whereas knockdowns of CYP3A4 and SLCO1B1 as well as CYP3A4/SLCO1B1 inhibitions showed the opposite effects. Phenobarbital pretreatment was used to induce hepatic Cyp3a and SLCO1B1 in rats. Phenobarbital aggravated atorvastatin-induced hepatotoxicity, while decreased plasma exposure of atorvastatin. All these findings demonstrated that the upregulations of hepatic Cyp3a and SLCO1B1 in diabetic rats potentiated atorvastatin-induced hepatotoxicity via increasing ROS formation. PMID:27624558

  17. Predictivity of dog co-culture model, primary human hepatocytes and HepG2 cells for the detection of hepatotoxic drugs in humans

    SciT

    Atienzar, Franck A., E-mail: franck.atienzar@ucb.com; Novik, Eric I.; Gerets, Helga H.

    Drug Induced Liver Injury (DILI) is a major cause of attrition during early and late stage drug development. Consequently, there is a need to develop better in vitro primary hepatocyte models from different species for predicting hepatotoxicity in both animals and humans early in drug development. Dog is often chosen as the non-rodent species for toxicology studies. Unfortunately, dog in vitro models allowing long term cultures are not available. The objective of the present manuscript is to describe the development of a co-culture dog model for predicting hepatotoxic drugs in humans and to compare the predictivity of the canine modelmore » along with primary human hepatocytes and HepG2 cells. After rigorous optimization, the dog co-culture model displayed metabolic capacities that were maintained up to 2 weeks which indicates that such model could be also used for long term metabolism studies. Most of the human hepatotoxic drugs were detected with a sensitivity of approximately 80% (n = 40) for the three cellular models. Nevertheless, the specificity was low approximately 40% for the HepG2 cells and hepatocytes compared to 72.7% for the canine model (n = 11). Furthermore, the dog co-culture model showed a higher superiority for the classification of 5 pairs of close structural analogs with different DILI concerns in comparison to both human cellular models. Finally, the reproducibility of the canine system was also satisfactory with a coefficient of correlation of 75.2% (n = 14). Overall, the present manuscript indicates that the dog co-culture model may represent a relevant tool to perform chronic hepatotoxicity and metabolism studies. - Highlights: • Importance of species differences in drug development. • Relevance of dog co-culture model for metabolism and toxicology studies. • Hepatotoxicity: higher predictivity of dog co-culture vs HepG2 and human hepatocytes.« less

  18. Interuniversal entanglement in a cyclic multiverse

    NASA Astrophysics Data System (ADS)

    Robles-Pérez, Salvador; Balcerzak, Adam; Dąbrowski, Mariusz P.; Krämer, Manuel

    2017-04-01

    We study scenarios of parallel cyclic multiverses which allow for a different evolution of the physical constants, while having the same geometry. These universes are classically disconnected, but quantum-mechanically entangled. Applying the thermodynamics of entanglement, we calculate the temperature and the entropy of entanglement. It emerges that the entropy of entanglement is large at big bang and big crunch singularities of the parallel universes as well as at the maxima of the expansion of these universes. The latter seems to confirm earlier studies that quantum effects are strong at turning points of the evolution of the universe performed in the context of the timeless nature of the Wheeler-DeWitt equation and decoherence. On the other hand, the entropy of entanglement at big rip singularities is going to zero despite its presumably quantum nature. This may be an effect of total dissociation of the universe structures into infinitely separated patches violating the null energy condition. However, the temperature of entanglement is large/infinite at every classically singular point and at maximum expansion and seems to be a better measure of quantumness.

  19. Beyond Inflation:. A Cyclic Universe Scenario

    NASA Astrophysics Data System (ADS)

    Turok, Neil; Steinhardt, Paul J.

    2005-08-01

    Inflation has been the leading early universe scenario for two decades, and has become an accepted element of the successful 'cosmic concordance' model. However, there are many puzzling features of the resulting theory. It requires both high energy and low energy inflation, with energy densities differing by a hundred orders of magnitude. The questions of why the universe started out undergoing high energy inflation, and why it will end up in low energy inflation, are unanswered. Rather than resort to anthropic arguments, we have developed an alternative cosmology, the cyclic universe [1], in which the universe exists in a very long-lived attractor state determined by the laws of physics. The model shares inflation's phenomenological successes without requiring an epoch of high energy inflation. Instead, the universe is made homogeneous and flat, and scale-invariant adiabatic perturbations are generated during an epoch of low energy acceleration like that seen today, but preceding the last big bang. Unlike inflation, the model requires low energy acceleration in order for a periodic attractor state to exist. The key challenge facing the scenario is that of passing through the cosmic singularity at t = 0. Substantial progress has been made at the level of linearised gravity, which is reviewed here. The challenge of extending this to nonlinear gravity and string theory remains.

  20. Beyond Inflation: A Cyclic Universe Scenario

    NASA Astrophysics Data System (ADS)

    Turok, Neil; Steinhardt, Paul J.

    2005-01-01

    Inflation has been the leading early universe scenario for two decades, and has become an accepted element of the successful `cosmic concordance' model. However, there are many puzzling features of the resulting theory. It requires both high energy and low energy inflation, with energy densities differing by a hundred orders of magnitude. The questions of why the universe started out undergoing high energy inflation, and why it will end up in low energy inflation, are unanswered. Rather than resort to anthropic arguments, we have developed an alternative cosmology, the cyclic universe, in which the universe exists in a very long-lived attractor state determined by the laws of physics. The model shares inflation's phenomenological successes without requiring an epoch of high energy inflation. Instead, the universe is made homogeneous and flat, and scale-invariant adiabatic perturbations are generated during an epoch of low energy acceleration like that seen today, but preceding the last big bang. Unlike inflation, the model requires low energy acceleration in order for a periodic attractor state to exist. The key challenge facing the scenario is that of passing through the cosmic singularity at t = 0. Substantial progress has been made at the level of linearised gravity, which is reviewed here. The challenge of extending this to nonlinear gravity and string theory remains.

  1. The cyclic fatigue behavior of adhesive joints

    NASA Astrophysics Data System (ADS)

    Kinloch, A. J.; Toh, T.

    1995-06-01

    In the last six months we have: (1) Concentrated our efforts on the fatigue failure of carbon-fiber PEEK/AFl63 lap joints, and in particular we have started to predict the life time of single-lap joints under cyclic fatigue loading. The analysis is based on data obtained from double cantilever beam (DCB) fracture mechanics tests; (2) Further, we have been successful in measuring the rate of crack growth in lap joints during fatigue fracture using ultrasonic scanning; (3) Preliminary test data on the static fracture of glass-fiber reinforced poly(phenylene sulphide) (PPS)/AF163 joints have also been studied; and (4) A comparison has been made in computing the critical strain energy release rate G(sub c) for the glass-fiber PPS/AF163 joints based on the compliance method, beam theory and corrected beam theory. The last method accounts for large non-linear deflections and the associated crack root rotations along with the necessary corrections for the increase in stiffness introduced by the presence of end blocks.

  2. Copper Regulates Cyclic AMP-Dependent Lipolysis

    PubMed Central

    Krishnamoorthy, Lakshmi; Cotruvo, Joseph A.; Chan, Jefferson; Kaluarachchi, Harini; Muchenditsi, Abigael; Pendyala, Venkata S.; Jia, Shang; Aron, Allegra T.; Ackerman, Cheri M.; Vander Wal, Mark N.; Guan, Timothy; Smaga, Lukas P.; Farhi, Samouil L.; New, Elizabeth J.; Lutsenko, Svetlana; Chang, Christopher J.

    2016-01-01

    Cell signaling relies extensively on dynamic pools of redox-inactive metal ions such as sodium, potassium, calcium, and zinc, but their redox-active transition metal counterparts such as copper and iron have been studied primarily as static enzyme cofactors. Here we report that copper is an endogenous regulator of lipolysis, the breakdown of fat, which is an essential process in maintaining the body's weight and energy stores. Utilizing a murine model of genetic copper misregulation, in combination with pharmacological alterations in copper status and imaging studies in a 3T3-L1 white adipocyte model, we demonstrate that copper regulates lipolysis at the level of the second messenger, cyclic AMP (cAMP), by altering the activity of the cAMP-degrading phosphodiesterase PDE3B. Biochemical studies of the copper-PDE3B interaction establish copper-dependent inhibition of enzyme activity and identify a key conserved cysteine residue within a PDE3-specific loop that is essential for the observed copper-dependent lipolytic phenotype. PMID:27272565

  3. Cyclic flow underground coal gasification process

    DOEpatents

    Bissett, Larry A.

    1978-01-01

    The present invention is directed to a method of in situ coal gasification for providing the product gas with an enriched concentration of carbon monoxide. The method is practiced by establishing a pair of combustion zones in spaced-apart boreholes within a subterranean coal bed and then cyclically terminating the combustion in the first of the two zones to establish a forward burn in the coal bed so that while an exothermic reaction is occurring in the second combustion zone to provide CO.sub.2 -laden product gas, an endothermic CO-forming reaction is occurring in the first combustion zone between the CO.sub.2 -laden gas percolating thereinto and the hot carbon in the wall defining the first combustion zone to increase the concentration of CO in the product gas. When the endothermic reaction slows to a selected activity the roles of the combustion zones are reversed by re-establishing an exothermic combustion reaction in the first zone and terminating the combustion in the second zone.

  4. Cyclic Game Dynamics Driven by Iterated Reasoning

    PubMed Central

    Frey, Seth; Goldstone, Robert L.

    2013-01-01

    Recent theories from complexity science argue that complex dynamics are ubiquitous in social and economic systems. These claims emerge from the analysis of individually simple agents whose collective behavior is surprisingly complicated. However, economists have argued that iterated reasoning–what you think I think you think–will suppress complex dynamics by stabilizing or accelerating convergence to Nash equilibrium. We report stable and efficient periodic behavior in human groups playing the Mod Game, a multi-player game similar to Rock-Paper-Scissors. The game rewards subjects for thinking exactly one step ahead of others in their group. Groups that play this game exhibit cycles that are inconsistent with any fixed-point solution concept. These cycles are driven by a “hopping” behavior that is consistent with other accounts of iterated reasoning: agents are constrained to about two steps of iterated reasoning and learn an additional one-half step with each session. If higher-order reasoning can be complicit in complex emergent dynamics, then cyclic and chaotic patterns may be endogenous features of real-world social and economic systems. PMID:23441191

  5. Cyclic voltammetry of fast conducting electrocatalytic films.

    PubMed

    Costentin, Cyrille; Savéant, Jean-Michel

    2015-07-15

    In the framework of contemporary energy challenges, cyclic voltammetry is a particularly useful tool for deciphering the kinetics of catalytic films. The case of fast conducting films is analyzed, whether conduction is of the ohmic type or proceeds through rapid electron hopping. The rate-limiting factors are then the diffusion of the substrate in solution and through the film as well as the catalytic reaction itself. The dimensionless combination of the characteristics of these factors allows reducing the number of actual parameters to a maximum of two. The kinetics of the system may then be fully analyzed with the help of a kinetic zone diagram. Observing the variations of the current-potential responses with operational parameters such as film thickness, the potential scan rate and substrate concentration allows a precise assessment of the interplay between these factors and of the values of the rate controlling factors. A series of thought experiments is described in order to render the kinetic analysis more palpable.

  6. Switching Cyclic Nucleotide-Selective Activation of Cyclic Adenosine Monophosphate-Dependent Protein Kinase Holoenzyme Reveals Distinct Roles of Tandem Cyclic Nucleotide-Binding Domains.

    PubMed

    He, Daniel; Lorenz, Robin; Kim, Choel; Herberg, Friedrich W; Lim, Chinten James

    2017-12-15

    The cyclic adenosine monophosphate (cAMP)- and cyclic guanosine monophosphate (cGMP)-dependent protein kinases (PKA and PKG) are key effectors of cyclic nucleotide signaling. Both share structural features that include tandem cyclic nucleotide-binding (CNB) domains, CNB-A and CNB-B, yet their functions are separated through preferential activation by either cAMP or cGMP. Based on structural studies and modeling, key CNB contact residues have been identified for both kinases. In this study, we explored the requirements for conversion of PKA activation from cAMP-dependent to cGMP-dependent. The consequences of the residue substitutions T192R/A212T within CNB-A or G316R/A336T within CNB-B of PKA-RIα on cyclic nucleotide binding and holoenzyme activation were assessed in vitro using purified recombinant proteins, and ex vivo using RIα-deficient mouse embryonic fibroblasts genetically reconstituted with wild-type or mutant PKA-RIα. In vitro, a loss of binding and activation selectivity was observed when residues in either one of the CNB domains were mutated, while mutations in both CNB domains resulted in a complete switch of selectivity from cAMP to cGMP. The switch in selectivity was also recapitulated ex vivo, confirming their functional roles in cells. Our results highlight the importance of key cyclic nucleotide contacts within each CNB domain and suggest that these domains may have evolved from an ancestral gene product to yield two distinct cyclic nucleotide-dependent protein kinases.

  7. [Assessment of sulfasalazine and hydroxichloroqine hepatotoxicity in patients with rheumatic arthritis and isolated HBS-antigen positivity].

    PubMed

    Petrov, A V

    2004-01-01

    Findings were based on long-period survey (12-16 month) of 39 patients with rheumatoid arthritis (RA) and isolated persistent HBS-antigen. The patients were prescribed Hydroxichloroqine (H) and Sulfasolin (SF). Clinical data, laboratory tests, ultrasonic diagnostics to evaluate liver condition have been analyzed. HBs, Hbe-antigenes, DNA-virus B hepatitis blood test, nucleus dimensions, proliferative FGA response test and immune CD 8+, CD 14+ and CD 16+ cells to Fas-induced apoptosis were taken. SF therapy was found to be more hepatotoxic and likely to activate a latent virus B hepatitis as compared with Hydroxichloroqine and combine H and SF therapies. Triggering replication of virus B hepatitis occurs against a background of decreasing in functional activity of CD 14+ and CD 16+ cells. The immune critical level needed to activate VHB was determined.

  8. Balancing Low-density Lipoprotein Cholesterol Reduction and Hepatotoxicity With Lomitapide Mesylate and Mipomersen in Patients With Homozygous Familial Hypercholesterolemia.

    PubMed

    Won, Jane I; Zhang, Jun; Tecson, Kristen M; McCullough, Peter A

    2017-01-01

    Homozygous familial hypercholesterolemia (HoFH) is an autosomal codominant disorder manifested by high concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol, and premature cardiovascular disease. Despite conventional lipid-lowering therapy, LDL cholesterol levels remain elevated in patients with HoFH; these patients are considered to be at high risk for cardiovascular events. In 2012-2013, two drugs with novel mechanisms of action were approved by the US Food and Drug Administration for the treatment of HoFH: lomitapide mesylate and mipomersen. Both of these treatments reduce total cholesterol, LDL cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein a, and triglyceride levels. This review describes the clinical tradeoffs in efficacy and hepatotoxicity of these drugs in two cases of HoFH.

  9. The mycotoxin definition reconsidered towards fungal cyclic depsipeptides.

    PubMed

    Taevernier, Lien; Wynendaele, Evelien; De Vreese, Leen; Burvenich, Christian; De Spiegeleer, Bart

    2016-04-02

    Currently, next to the major classes, cyclic depsipeptides beauvericin and enniatins are also positioned as mycotoxins. However, as there are hundreds more fungal cyclic depsipeptides already identified, should these not be considered as mycotoxins as well? The current status of the mycotoxin definition revealed a lack of consistency, leading to confusion about what compounds should be called mycotoxins. Because this is of pivotal importance in risk assessment prioritization, a clear and quantitatively expressed mycotoxin definition is proposed, based on data of widely accepted mycotoxins. Finally, this definition is applied to a set of fungal cyclic depsipeptides, revealing that some of these should indeed be considered as mycotoxins.

  10. Cyclic plasticity models and application in fatigue analysis

    NASA Technical Reports Server (NTRS)

    Kalev, I.

    1981-01-01

    An analytical procedure for prediction of the cyclic plasticity effects on both the structural fatigue life to crack initiation and the rate of crack growth is presented. The crack initiation criterion is based on the Coffin-Manson formulae extended for multiaxial stress state and for inclusion of the mean stress effect. This criterion is also applied for the accumulated damage ahead of the existing crack tip which is assumed to be related to the crack growth rate. Three cyclic plasticity models, based on the concept of combination of several yield surfaces, are employed for computing the crack growth rate of a crack plane stress panel under several cyclic loading conditions.

  11. Cyclic behavior at quasi-parallel collisionless shocks

    NASA Technical Reports Server (NTRS)

    Burgess, D.

    1989-01-01

    Large scale one-dimensional hybrid simulations with resistive electrons have been carried out of a quasi-parallel high-Mach-number collisionless shock. The shock initially appears stable, but then exhibits cyclic behavior. For the magnetic field, the cycle consists of a period when the transition from upstream to downstream is steep and well defined, followed by a period when the shock transition is extended and perturbed. This cyclic shock solution results from upstream perturbations caused by backstreaming gyrating ions convecting into the shock. The cyclic reformation of a sharp shock transition can allow ions, at one time upstream because of reflection or leakage, to contribute to the shock thermalization.

  12. Influence of cyclic torsional preloading on cyclic fatigue resistance of nickel - titanium instruments.

    PubMed

    Pedullà, E; Lo Savio, F; Boninelli, S; Plotino, G; Grande, N M; Rapisarda, E; La Rosa, G

    2015-11-01

    To evaluate the effect of different torsional preloads on cyclic fatigue resistance of endodontic rotary instruments constructed from conventional nickel-titanium (NiTi), M-Wire or CM-Wire. Eighty new size 25, 0.06 taper Mtwo instruments (Sweden & Martina), size 25, 0.06 taper HyFlex CM (Coltene/Whaledent, Inc) and X2 ProTaper Next (Dentsply Maillefer) were used. The Torque and distortion angles at failure of new instruments (n = 10) were measured, and 0% (n = 10), 25%, 50% and 75% (n = 20) of the mean ultimate torsional strength as preloading condition were applied according to ISO 3630-1 for each brand. The twenty files tested for every extent of preload were subjected to 20 or 40 torsional cycles (n = 10). After torsional preloading, the number of cycles to failure was evaluated in a simulated canal with 60° angle of curvature and 5 mm of radius of curvature. Data were analysed using two-way analysis of variance. The fracture surface of each fragment was examined with a scanning electron microscope (SEM). Data were analysed by two-way analyses of variance. Preload repetitions did not influence the cyclic fatigue of the three brands; however, the 25%, 50% and 75% torsional preloading significantly reduced the fatigue resistance of all instruments tested (P < 0.01, P < 0.001 and P < 0.0001, respectively) except for the HyFlex CM preloaded with 25% of the maximum torsional strength (P > 0.05). Torsional preloads reduced the cyclic fatigue resistance of conventional and treated (M-wire and CM-wire) NiTi rotary instruments except for size 25, 0.06 taper HyFlex CM instruments with a 25% of torsional preloading. © 2014 International Endodontic Journal. Published by John Wiley & Sons Ltd.

  13. Acetaminophen-Induced Hepatotoxicity in Mice Occurs with Inhibition of Activity and Nitration of Mitochondrial Manganese Superoxide Dismutase

    PubMed Central

    Agarwal, Rakhee; MacMillan-Crow, Lee Ann; Rafferty, Tonya M.; Saba, Hamida; Roberts, Dean W.; Fifer, E. Kim; James, Laura P.

    2011-01-01

    In overdose the analgesic/antipyretic acetaminophen (APAP) is hepatotoxic. Toxicity is mediated by initial hepatic metabolism to N-acetyl-p-benzoquinone imine (NAPQI). After low doses NAPQI is efficiently detoxified by GSH. However, in overdose GSH is depleted, NAPQI covalently binds to proteins as APAP adducts, and oxygen/nitrogen stress occurs. Toxicity is believed to occur by mitochondrial dysfunction. Manganese superoxide dismutase (MnSOD) inactivation by protein nitration has been reported to occur during other oxidant stress-mediated diseases. MnSOD is a critical mitochondrial antioxidant enzyme that prevents peroxynitrite formation within the mitochondria. To examine the role of MnSOD in APAP toxicity, mice were treated with 300 mg/kg APAP. GSH was significantly reduced by 65% at 0.5 h and remained reduced from 1 to 4 h. Serum alanine aminotransferase did not significantly increase until 4 h and was 2290 IU/liter at 6 h. MnSOD activity was significantly reduced by 50% at 1 and 2 h. At 1 h, GSH was significantly depleted by 62 and 80% at nontoxic doses of 50 and 100 mg/kg, respectively. No further GSH depletion occurred with hepatotoxic doses of 200 and 300 mg/kg APAP. A dose response decrease in MnSOD activity was observed for APAP at 100, 200, and 300 mg/kg. Immunoprecipitation of MnSOD from livers of APAP-treated mice followed by Western blot analysis revealed nitrated MnSOD. APAP-MnSOD adducts were not detected. Treatment of recombinant MnSOD with NAPQI did not produce APAP protein adducts. The data indicate that MnSOD inactivation by nitration is an early event in APAP-induced hepatic toxicity. PMID:21205919

  14. Alleviative effects of s-allyl cysteine and s-ethyl cysteine on MCD diet-induced hepatotoxicity in mice.

    PubMed

    Lin, Chun-che; Yin, Mei-chin; Liu, Wen-hu

    2008-11-01

    Alleviative effects of s-allyl cysteine (SAC) and s-ethyl cysteine (SEC) upon methionine and choline deficient (MCD) diet-induced hepatotoxicity in mice were examined. SAC or SEC at 1g/L was added into drinking water for 7 weeks with MCD diet. MCD feeding significantly increased hepatic triglyceride and cholesterol levels, and elevated the activity of glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme, fatty acid synthase (FAS) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (P < 0.05). However, the intake of SAC or SEC significantly decreased hepatic triglyceride accumulation, and reduced G6PDH and FAS activities (P < 0.05). MCD feeding significantly lowered serum and hepatic glutathione (GSH) levels, increased malondialdehyde (MDA) and oxidized glutathione (GSSG) formation, and suppressed the activity and mRNA expression of glutathione peroxidase (GPX), superoxide dismutase (SOD) and catalase (P < 0.05). The intake of SAC or SEC significantly increased serum and hepatic GSH levels, decreased MDA and GSSG formation, restored the activity and mRNA expression of GPX, SOD and catalase (P < 0.05). MCD feeding significantly enhanced the mRNA expression of interleukin (IL)-1beta, IL-6, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, matrix metalloproteinases-9 (MMP-9) and collagen-alpha1 (P < 0.05). The intake of SAC and SEC significantly blunted the mRNA expression of IL-1beta, IL-6, TNF-alpha, TGF-beta1 and collagen-alpha1 (P < 0.05). SEC was greater than SAC in suppressing IL-6 and TNF-alpha expression (P < 0.05), but SAC was greater than SEC in suppressing collagen-alpha1 and TGF-beta1 expression (P < 0.05). These data suggest that SAC and SEC are potent agents against MCD-induced hepatotoxicity.

  15. Virgin coconut oil supplementation attenuates acute chemotherapy hepatotoxicity induced by anticancer drug methotrexate via inhibition of oxidative stress in rats.

    PubMed

    Famurewa, Ademola C; Ufebe, Odomero G; Egedigwe, Chima A; Nwankwo, Onyebuchi E; Obaje, Godwin S

    2017-03-01

    The emerging health benefit of virgin coconut oil (VCO) has been associated with its potent natural antioxidants; however, the antioxidant and hepatoprotective effect of VCO against methotrexate-induced liver damage and oxidative stress remains unexplored. The study explored the antioxidant and hepatoprotective effects of VCO against oxidative stress and liver damage induced by anticancer drug methotrexate (MTX) in rats. Liver damage was induced in Wistar rats pretreated with dietary supplementation of VCO (5% and 15%) by intraperitoneal administration of MTX (20mg/kg bw) on day 10 only. After 12days of treatment, assays for serum liver biomarkers (aminotransferases), alkaline phosphatase, albumin and total protein as well as hepatic content of malondialdehyde, reduced glutathione and antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) were carried out. Liver was used to examine histopathological changes. MTX administration induced significant increase in serum liver enzymes along with marked decrease in albumin and total protein compared to control group. Hepatic activities of antioxidant enzymes were significantly decreased, while malondialdehyde increased significantly. Treatment with VCO supplemented diet prior to MTX administration attenuated MTX-induced liver injury and oxidative stress evidenced by significant improvements in serum liver markers, hepatic antioxidant enzymes and malondialdehyde comparable to control group. Histopathological alterations were prevented and correlated well with the biochemical indices. The study suggests antioxidant and hepatoprotective effects of VCO supplementation against hepatotoxicity and oxidative damage via improving antioxidant defense system in rats. Our findings may have beneficial application in the management of hepatotoxicity associated with MTX cancer chemotherapy. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  16. EFFICIENCY OF BORAGE SEEDS OIL AGAINST GAMMA IRRADIATION-INDUCED HEPATOTOXICITY IN MALE RATS: POSSIBLE ANTIOXIDANT ACTIVITY.

    PubMed

    Khattab, Hala A H; Abdallah, Inas Z A; Yousef, Fatimah M; Huwait, Etimad A

    2017-01-01

    Borage ( Borago officinal L.) is an annual herbaceous plant of great interest because its oil contains a high percentage of γ-linolenic acid (GLA). The present work was carried out to detect fatty acids composition of the oil extracted from borage seeds (BO) and its potential effectiveness against γ-irradiation- induced hepatotoxicity in male rats. GC-MS analysis of fatty acids methyl esters of BO was performed to identify fatty acids composition. Sixty rats were divided into five groups (12 rats each): Control, irradiated; rats were exposed to (6.5 Gy) of whole body γ-radiation, BO (50 mg/kg b.wt), irradiated BO post-treated and irradiated BO prepost-treated. Six rats from each group were sacrificed at two time intervals 7 and 15 days post-irradiation. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyl transferase (GGT) levels, lipids profile, as well as serum and hepatic reduced glutathione (GSH) and lipid peroxide (malondialdehyde) (MDA) levels were assessed. Histopathological examination of liver sections were also carried out. The results showed that the high contents of BO extracted by cold pressing, were linoleic acid (34.23%) and GLA (24.79%). Also, oral administration of BO significantly improved serum levels of liver enzymes, lipids profile, as well as serum and hepatic GSH and MDA levels (p<0.001) as compared with irradiated rats after 15 days post irradiation. Moreover, it exerted marked amelioration against irradiation-induced histopathological changes in liver tissues. The improvement was more pronounced in irradiated BO prepost-treated group than irradiated BO post-treated. BO has a beneficial role in reducing hepatotoxicity and oxidative stress induced by radiation exposure. Therefore, BO may be used as a beneficial supplement for patients during radiotherapy treatment.

  17. Evaluation of miR-122 as a Serum Biomarker for Hepatotoxicity in Investigative Rat Toxicology Studies.

    PubMed

    Sharapova, T; Devanarayan, V; LeRoy, B; Liguori, M J; Blomme, E; Buck, W; Maher, J

    2016-01-01

    MicroRNAs are short noncoding RNAs involved in regulation of gene expression. Certain microRNAs, including miR-122, seem to have ideal properties as biomarkers due to good stability, high tissue specificity, and ease of detection across multiple species. Recent reports have indicated that miR-122 is a highly liver-specific marker detectable in serum after liver injury. The purpose of the current study was to assess the performance of miR-122 as a serum biomarker for hepatotoxicity in short-term (5-28 days) repeat-dose rat toxicology studies when benchmarked against routine clinical chemistry and histopathology. A total of 23 studies with multiple dose levels of experimental compounds were examined, and they included animals with or without liver injury and with various hepatic histopathologic changes. Serum miR-122 levels were quantified by reverse transcription quantitative polymerase chain reaction. Increases in circulating miR-122 levels highly correlated with serum elevations of liver enzymes, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH). Statistical analysis showed that miR-122 outperformed ALT as a biomarker for histopathologically confirmed liver toxicity and was equivalent in performance to AST and GLDH. Additionally, an increase of 4% in predictive accuracy was obtained using a multiparameter approach incorporating miR-122 with ALT, AST, and GLDH. In conclusion, serum miR-122 levels can be utilized as a biomarker of hepatotoxicity in acute and subacute rat toxicology studies, and its performance can rival or exceed those of standard enzyme biomarkers such as the liver transaminases. © The Author(s) 2015.

  18. The hepatoprotective activity of olive oil and Nigella sativa oil against CCl4 induced hepatotoxicity in male rats.

    PubMed

    Al-Seeni, Madeha N; El Rabey, Haddad A; Zamzami, Mazin A; Alnefayee, Abeer M

    2016-11-04

    Liver disease is the major cause of serious health problem leading to morbidity and mortality worldwide and the problem has increased in search for hepatotherapeutic agents from plants. The present study was designed to compare the probable hepatoprotective activity of olive oil and N. sativa oil on CCl 4 induced liver damage in male rats. Forty males of a new model of albino rats (Wistar strain) (175-205 g) were divided into four groups. The 1st Group (G1) was the negative control group, the remaining rats were injected with CCl 4 (1 ml/kg body weight) with equal amount of olive oil on the 1st and 4th day of every week for 4 weeks. The 2nd group (G2) was the positive control, the 3rd group (G3) and the fourth group (G4) were treated orally with N. sativa oil and olive oils using stomach tube. The positive control group showed an increase in hepatic enzymes, total bilirubin, creatinine, uric acid, lipid peroxide total cholesterol, triglyceride, low density lipoprotein, very low density lipoproteins, interleukin-6, and a decrease in antioxidant enzymes, high density lipoprotein cholesterol, a decrease in total protein and albumin an when compared with negative control group. Histology of the CCl 4 treated group revealed inflammation and damage of liver cells. Treating the hepatotoxic rats with olive oil and N. sativa oil showed a significant improvement in all biochemical tests compared with the positive CCl 4 control group. In addition, the liver tissues of olive oil treated group showed mild improvement in inflammatory infiltration and in N. sativa oil treated group showed normal hepatocytes with no evidence of inflammation. This study revealed that olive oil and N. sativa oil have a protective effect against CCl 4 -induced hepatotoxicity in male rats. Nigella sativa oil was more effective than olive oil.

  19. Anti-hepatotoxic activities of Hibiscus sabdariffa L. in animal model of streptozotocin diabetes-induced liver damage.

    PubMed

    Adeyemi, David O; Ukwenya, Victor O; Obuotor, Efere M; Adewole, Stephen O

    2014-07-30

    Flavonoid-rich aqueous fraction of methanolic extract of Hibiscus sabdariffa calyx was evaluated for its anti-hepatotoxic activities in streptozotocin-induced diabetic Wistar rats. Diabetes Mellitus was induced in Wistar rats by a single i.p injection of 80 mg/kg b.w. streptozotocin (STZ) dissolved in 0.1 M citrate buffer (pH 6.3). The ameliorative effects of the extract on STZ-diabetes induced liver damage was evident from the histopathological analysis and the biochemical parameters evaluated in the serum and liver homogenates. Reduced levels of glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) (3.76 ± 0.38 μM, 0.42 ± 0.04 U/L, 41.08 ± 3.04 U/ml, 0.82 ± 0.04 U/L respectively) in the liver of diabetic rats were restored to a near normal level in the Hibiscus sabdariffa-treated rats (6.87 ± 0.51 μM, 0.72 ± 0.06 U/L, 87.92 ± 5.26 U/ml, 1.37 ± 0.06 U/L respectively). Elevated levels of aspartate amino transferase (AST), alanine amino transferase (ALT) and alkaline phosphatase (ALP) in the serum of diabetic rats were also restored in Hibiscus sabdariffa -treated rats. Examination of stained liver sections revealed hepatic fibrosis and excessive glycogen deposition in the diabetic rats. These pathological changes were ameliorated in the extract-treated rats. The anti-hepatotoxic activity of Hibiscus sabdariffa extract in STZ diabetic rats could be partly related to its antioxidant activity and the presence of flavonnoids.

  20. Modeling Individual Cyclic Variation in Human Behavior

    PubMed Central

    Pierson, Emma; Althoff, Tim; Leskovec, Jure

    2018-01-01

    Cycles are fundamental to human health and behavior. Examples include mood cycles, circadian rhythms, and the menstrual cycle. However, modeling cycles in time series data is challenging because in most cases the cycles are not labeled or directly observed and need to be inferred from multidimensional measurements taken over time. Here, we present Cyclic Hidden Markov Models (CyH-MMs) for detecting and modeling cycles in a collection of multidimensional heterogeneous time series data. In contrast to previous cycle modeling methods, CyHMMs deal with a number of challenges encountered in modeling real-world cycles: they can model multivariate data with both discrete and continuous dimensions; they explicitly model and are robust to missing data; and they can share information across individuals to accommodate variation both within and between individual time series. Experiments on synthetic and real-world health-tracking data demonstrate that CyHMMs infer cycle lengths more accurately than existing methods, with 58% lower error on simulated data and 63% lower error on real-world data compared to the best-performing baseline. CyHMMs can also perform functions which baselines cannot: they can model the progression of individual features/symptoms over the course of the cycle, identify the most variable features, and cluster individual time series into groups with distinct characteristics. Applying CyHMMs to two real-world health-tracking datasets—of human menstrual cycle symptoms and physical activity tracking data—yields important insights including which symptoms to expect at each point during the cycle. We also find that people fall into several groups with distinct cycle patterns, and that these groups differ along dimensions not provided to the model. For example, by modeling missing data in the menstrual cycles dataset, we are able to discover a medically relevant group of birth control users even though information on birth control is not given to the model

  1. Highly Efficient Protein Misfolding Cyclic Amplification

    PubMed Central

    Ostapchenko, Valeriy G.; Savtchenk, Regina; Alexeeva, Irina; Rohwer, Robert G.; Baskakov, Ilia V.

    2011-01-01

    Protein misfolding cyclic amplification (PMCA) provides faithful replication of mammalian prions in vitro and has numerous applications in prion research. However, the low efficiency of conversion of PrPC into PrPSc in PMCA limits the applicability of PMCA for many uses including structural studies of infectious prions. It also implies that only a small sub-fraction of PrPC may be available for conversion. Here we show that the yield, rate, and robustness of prion conversion and the sensitivity of prion detection are significantly improved by a simple modification of the PMCA format. Conducting PMCA reactions in the presence of Teflon beads (PMCAb) increased the conversion of PrPC into PrPSc from ∼10% to up to 100%. In PMCAb, a single 24-hour round consistently amplified PrPSc by 600-700-fold. Furthermore, the sensitivity of prion detection in one round (24 hours) increased by 2-3 orders of magnitude. Using serial PMCAb, a 1012-fold dilution of scrapie brain material could be amplified to the level detectible by Western blotting in 3 rounds (72 hours). The improvements in amplification efficiency were observed for the commonly used hamster 263K strain and for the synthetic strain SSLOW that otherwise amplifies poorly in PMCA. The increase in the amplification efficiency did not come at the expense of prion replication specificity. The current study demonstrates that poor conversion efficiencies observed previously have not been due to the scarcity of a sub-fraction of PrPC susceptible to conversion nor due to limited concentrations of essential cellular cofactors required for conversion. The new PMCAb format offers immediate practical benefits and opens new avenues for developing fast ultrasensitive assays and for producing abundant quantities of PrPSc in vitro. PMID:21347353

  2. Modeling Individual Cyclic Variation in Human Behavior.

    PubMed

    Pierson, Emma; Althoff, Tim; Leskovec, Jure

    2018-04-01

    Cycles are fundamental to human health and behavior. Examples include mood cycles, circadian rhythms, and the menstrual cycle. However, modeling cycles in time series data is challenging because in most cases the cycles are not labeled or directly observed and need to be inferred from multidimensional measurements taken over time. Here, we present Cyclic Hidden Markov Models (CyH-MMs) for detecting and modeling cycles in a collection of multidimensional heterogeneous time series data. In contrast to previous cycle modeling methods, CyHMMs deal with a number of challenges encountered in modeling real-world cycles: they can model multivariate data with both discrete and continuous dimensions; they explicitly model and are robust to missing data; and they can share information across individuals to accommodate variation both within and between individual time series. Experiments on synthetic and real-world health-tracking data demonstrate that CyHMMs infer cycle lengths more accurately than existing methods, with 58% lower error on simulated data and 63% lower error on real-world data compared to the best-performing baseline. CyHMMs can also perform functions which baselines cannot: they can model the progression of individual features/symptoms over the course of the cycle, identify the most variable features, and cluster individual time series into groups with distinct characteristics. Applying CyHMMs to two real-world health-tracking datasets-of human menstrual cycle symptoms and physical activity tracking data-yields important insights including which symptoms to expect at each point during the cycle. We also find that people fall into several groups with distinct cycle patterns, and that these groups differ along dimensions not provided to the model. For example, by modeling missing data in the menstrual cycles dataset, we are able to discover a medically relevant group of birth control users even though information on birth control is not given to the model.

  3. Coping with cyclic oxygen availability: evolutionary aspects.

    PubMed

    Flück, Martin; Webster, Keith A; Graham, Jeffrey; Giomi, Folco; Gerlach, Frank; Schmitz, Anke

    2007-10-01

    Both the gradual rise in atmospheric oxygen over the Proterozoic Eon as well as episodic fluctuations in oxygen over several million-year time spans during the Phanerozoic Era, have arguably exerted strong selective forces on cellular and organismic respiratory specialization and evolution. The rise in atmospheric oxygen, some 2 billion years after the origin of life, dramatically altered cell biology and set the stage for the appearance of multicelluar life forms in the Vendian (Ediacaran) Period of the Neoproterozoic Era. Over much of the Paleozoic, the level of oxygen in the atmosphere was near the present atmospheric level (21%). In the Late Paleozoic, however, there were extended times during which the level of atmospheric oxygen was either markedly lower or markedly higher than 21%. That these Paleozoic shifts in atmospheric oxygen affected the biota is suggested by the correlations between: (1) Reduced oxygen and the occurrences of extinctions, a lowered biodiversity and shifts in phyletic succession, and (2) During hyperoxia, the corresponding occurrence of phenomena such as arthropod gigantism, the origin of insect flight, and the evolution of vertebrate terrestriality. Basic similarities in features of adaptation to hyopoxia, manifest in living organisms at levels ranging from genetic and cellular to physiological and behavioral, suggest the common and early origin of a suite of adaptive mechanisms responsive to fluctuations in ambient oxygen. Comparative integrative approaches addressing the molecular bases of phenotypic adjustments to cyclic oxygen fluctuation provide broad insight into the incremental steps leading to the early evolution of homeostatic respiratory mechanisms and to the specialization of organismic respiratory function.

  4. In vivo assessment of the hepatotoxicity of a new Nostoc isolate from the Nile River: Nostoc sp. strain NRI.

    PubMed

    Abu-Serie, Marwa M; Nasser, Nermine; Abd El-Wahab, Abeer; Shehawy, Rehab; Pienaar, Harrison; Baddour, Nahed; Amer, Ranya

    2018-03-01

    Nostoc sp. is one of the most widely distributed cyanobacterial genera that produce potentially protein phosphatase (PP) inhibitor; microcystins (MCs). MCs have posed a worldwide concern due to predominant hepatotoxicity to human health. We have previously isolated a Nostoc strain (NR1) from the Nile River (the main water supply in Egypt) and this strain exerted production of rare and highly toxic MC; demethylated microcystin-LR. There is no data concerning risk factors of liver diseases for human and animal exposure to NR1-contaminated drinking water yet. It is thus important to evaluate acute (LD 50 dose), subacute (0.01% and 10% of LD 50 dose) and subchronic (0.01% and 10% of LD 50 dose) hepatotoxicity's NR1 extract using experimental mice. Mice groups, who orally received 0.01% LD 50 , represented a permissible concentration of the World Health Organization (WHO) for MC in drinking water. Several parameters were detected, including hepatotoxicity (i.e. PP activity, liver function, oxidative stress markers and DNA fragmentation), pro-inflammatory cytokine (TNF-α) and liver histopathology. Our results demonstrated LD 50 of NR1 extract was at 15,350 mg/kg body weight and caused hepatotoxicity that attributed to PP inhibition and a significant increase of hepatic damage biomarkers with lipid accumulation. Moreover, NR1 extract induced hepatic oxidative damage that may have led to DNA fragmentation and production of TNF-α. As demonstrated from the histopathological study, NR1 extract caused a severe collapse of cytoskeleton with subsequent focal degeneration of hepatocytes, necroinflammation and steatosis. The grade of hepatotoxicity in subacute (10% of LD 50 ) group was higher than that in the subchronic (10% of LD 50 and 0.01% of LD 50 , WHOch, respectively) groups. No significant hepatotoxicity was detectable for subacute (0.01% of LD 50 , WHOac) group. NR1 is therefore considered as one of the harmful and life-threatening cyanobacteria for Egyptian people

  5. Safety Discrete Event Models for Holonic Cyclic Manufacturing Systems

    NASA Astrophysics Data System (ADS)

    Ciufudean, Calin; Filote, Constantin

    In this paper the expression “holonic cyclic manufacturing systems” refers to complex assembly/disassembly systems or fork/join systems, kanban systems, and in general, to any discrete event system that transforms raw material and/or components into products. Such a system is said to be cyclic if it provides the same sequence of products indefinitely. This paper considers the scheduling of holonic cyclic manufacturing systems and describes a new approach using Petri nets formalism. We propose an approach to frame the optimum schedule of holonic cyclic manufacturing systems in order to maximize the throughput while minimize the work in process. We also propose an algorithm to verify the optimum schedule.

  6. Liquid crystal organization of self-assembling cyclic peptides.

    PubMed

    Amorín, Manuel; Pérez, Ana; Barberá, Joaquín; Ozores, Haxel Lionel; Serrano, José Luis; Granja, Juan R; Sierra, Teresa

    2014-01-21

    Self-assembling cyclic peptides decorated with mesogens form porous columnar mesophases in which, depending on the number of hydrocarbon chains, double or single channels are formed along each column.

  7. 21 CFR 862.1230 - Cyclic AMP test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems § 862... measure the level of adenosine 3′, 5′-monophosphate (cyclic AMP) in plasma, urine, and other body fluids...

  8. The Cyclical Relationship Approach in Teaching Basic Accounting Principles.

    ERIC Educational Resources Information Center

    Golen, Steven

    1981-01-01

    Shows how teachers can provide a more meaningful presentation of various accounting principles by illustrating them through a cyclical relationship approach. Thus, the students see the entire accounting relationship as a result of doing business. (CT)

  9. Cyclical Behavior of Productivity in the Machine Tool Industry.

    ERIC Educational Resources Information Center

    Duke, John; Brand, Horst

    1981-01-01

    Productivity growth was slow during 1958-80, partly because of the industry's tendency to retain skilled workers during cyclical downturns; computers and other electronic equipment aided production, but diffusion of such innovations has been slow. (Author)

  10. Gonadotropin level abnormalities in women with cyclic mastalgia.

    PubMed

    Ecochard, R; Marret, H; Rabilloud, M; Boehringer, H; Mathieu, C; Guerin, J F

    2001-01-01

    Women with cyclic mastalgia seem to be at risk of fibrocystic breast disease and/or breast cancer. We studied the relationships between mastalgia and hormone levels throughout the menstrual cycle. Ostensibly healthy women were monitored during a sum of 326 cycles. A case-control study compared personal and hormonal variables of 30 women experiencing cyclic mastalgia with those of 77 women without this symptom. Except sleeping times, no significant differences were found in personal variables. Cyclic mastalgia and symptoms of fluid retention were slightly associated. Menses and the luteal phase were significantly longer in cases than in controls. Gonadotropin but not ovarian hormone levels were also significantly higher in cases throughout the cycle. Cyclic mastalgia is less related to symptoms of fluid retention or to ovarian hormone levels than to regularly high gonadotropin levels, specific inhibitors might thus be used to alleviate the symptom.

  11. Exposure of mallards (Anas platyrhynchos) to the hepatotoxic cyanobacterium Nodularia spumigena

    Sipia, V.O.; Franson, J. Christian; Sjovall, O.; Pflugmacher, S.; Shearn-Bochsler, Valerie I.; Rocke, Tonie E.; Meriluoto, J.A.O.

    2008-01-01

    Nodularin (NODLN) is a cyclic pentapeptide hepatotoxin produced by the cyanobacterium Nodularia spumigena, which forms extensive blooms during the summer in the Baltic Sea. Nodularin was detected in liver, muscle and/or feather samples of several common eiders (Somateria mollissima) from the Gulf of Finland (northern Baltic Sea) in 2002-2005. Published information on the adverse effects of NODLN in marine birds is scarce. The aim of this study was to evaluate the toxicity of NODLN, and determine the concentrations of NODLN in liver and muscle tissue in mallards (Anas platyrhynchos) exposed to N. spumigena. Mallards received a single or multiple exposure via oral gavage with an aqueous slurry containing toxic N. spumigena. Dosages ranged from 200 to 600 ??g NODLN per kg body weight (bw). There were minimal histopathological changes in liver tissue, and brain cholinesterase activity did not differ among treatment groups. Concentrations of NODLN measured by LC-MS in liver varied between approximately 3-120 ??g kg-1 dry weight (dw) and ducks receiving multiple exposures had significantly greater liver toxin levels than ducks receiving the two lowest single exposures. In muscle, NODLN concentrations were approximately 2-6 ??g kg-1 dw, but did not differ significantly among exposure groups. This is the first in vivo lab study examining the effects and bioaccumulation of NODLN from N. spumigena in birds. The mallards in this study were resistant to adverse effects and did not bioaccumulate substantial levels of NODLN at the doses given. ?? 2008 Taylor & Francis.

  12. Microgravity changes in heart structure and cyclic-AMP metabolism

    NASA Technical Reports Server (NTRS)

    Philpott, D. E.; Fine, A.; Kato, K.; Egnor, R.; Cheng, L.

    1985-01-01

    The effects of microgravity on cardiac ultrastructure and cyclic AMP metabolism in tissues of rats flown on Spacelab 3 are reported. Light and electron microscope studies of cell structure, measurements of low and high Km phosphodiesterase activity, cyclic AMP-dependent protein kinase activity, and regulatory subunit compartmentation show significant deviations in flight animals when compared to ground controls. The results indicate that some changes have occurred in cellular responses associated with catecholamine receptor interactions and intracellular signal processing.

  13. More Cyclic-Oxidation Data For Turbine Alloys

    NASA Technical Reports Server (NTRS)

    Barrett, Charles A.; Garlick, Ralph G.

    1993-01-01

    Document presents data on cyclic oxidation of high-temperature, high-strength, nickel-base and cobalt-base alloys for turbines. Completes presentation of data begun in NASA Technical Memorandum 83665 (Revised 1989), "High-Temperature Cyclic Oxidation Data, Turbine Alloys, Part 1." Data consist of plots and tabulations of changes in specific weight as function of time, and lists of surface and spalled material phases identified by x-ray diffraction measurements.

  14. A computer program for cyclic plasticity and structural fatigue analysis

    NASA Technical Reports Server (NTRS)

    Kalev, I.

    1980-01-01

    A computerized tool for the analysis of time independent cyclic plasticity structural response, life to crack initiation prediction, and crack growth rate prediction for metallic materials is described. Three analytical items are combined: the finite element method with its associated numerical techniques for idealization of the structural component, cyclic plasticity models for idealization of the material behavior, and damage accumulation criteria for the fatigue failure.

  15. Levocarnitine and vitamin B complex for the treatment of pegaspargase-induced hepatotoxicity: A case report and review of the literature.

    PubMed

    Blackman, Alison; Boutin, Alyssa; Shimanovsky, Alexei; Baker, William J; Forcello, Nicholas

    2018-07-01

    Asparaginase is a chemotherapeutic agent that is commonly used in combination with other medications for the treatment of acute lymphoblastic leukemia. An adverse effect of asparaginase includes hepatotoxicity, which can lead to severe liver failure and death. Several reports have documented successful treatment of asparaginase-induced hepatotoxicity using levocarnitine (l-carnitine) and vitamin B complex. Herein, we report a patient with acute lymphoblastic leukemia that experienced acute liver injury following pegaspargase administration. Our patient was successfully treated with l-carnitine and vitamin B complex for 8 days and achieved recovery of hepatic function. Furthermore, we review the current literature and provide a recommendation on a regimen that can be used as an option for the treatment of asparaginase-induced hepatic injury.

  16. Protective effect of ganodermanondiol isolated from the Lingzhi mushroom against tert-butyl hydroperoxide-induced hepatotoxicity through Nrf2-mediated antioxidant enzymes.

    PubMed

    Li, Bin; Lee, Dong-Sung; Kang, Yue; Yao, Nai-Qi; An, Ren-Bo; Kim, Youn-Chul

    2013-03-01

    Ganodermanondiol, a biologically active compound, was isolated from the Lingzhi mushroom (Ganoderma lucidum). The present study examined the protective effects of ganodermanondiol against tert-butyl hydroperoxide (t-BHP)-induced hepatotoxicity. Ganodermanondiol protected human liver-derived HepG2 cells through nuclear factor-E2-related factor 2 (Nrf2) pathway-dependent heme oxygenase-1 expressions. Moreover, ganodermanondiol increased cellular glutathione levels and the expression of the glutamine-cysteine ligase gene in a dose-dependent manner. Furthermore, ganodermanondiol exposure enhanced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its upstream kinase activators, LKB1 and Ca(2+)/calmodulin-dependent protein kinase-II (CaMKII). This study indicates that ganodermanondiol exhibits potent cytoprotective effects on t-BHP-induced hepatotoxicity in human liver-derived HepG2 cells, presumably through Nrf2-mediated antioxidant enzymes and AMPK. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. Protective effects of an ethanol extract of Angelica keiskei against acetaminophen-induced hepatotoxicity in HepG2 and HepaRG cells

    PubMed Central

    Choi, Yoon-Hee; Lee, Hyun Sook; Chung, Cha-Kwon

    2017-01-01

    BACKGROUND/OBJECTIVE Although Angelica keiskei (AK) has widely been utilized for the purpose of general health improvement among Asian, its functionality and mechanism of action. The aim of this study was to determine the protective effect of ethanol extract of AK (AK-Ex) on acute hepatotoxicity induced by acetaminophen (AAP) in HepG2 human hepatocellular liver carcinoma cells and HepaRG human hepatic progenitor cells. MATERIALS/METHODS AK-Ex was prepared HepG2 and HepaRG cells were cultured with various concentrations and 30 mM AAP. The protective effects of AK-Ex against AAP-induced hepatotoxicity in HepG2 and HepaRG cells were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide, lactate dehydrogenase (LDH) assay, flow cytometry, and Western blotting. RESULTS AK-Ex, when administered prior to AAP, increased cell growth and decreased leakage of LDH in a dose-dependent manner in HepG2 and HepaRG cells against AAP-induced hepatotoxicity. AK-Ex increased the level of Bcl-2 and decreased the levels of Bax, Bok and Bik decreased the permeability of the mitochondrial membrane in HepG2 cells intoxicated with AAP. AK-Ex decreased the cleavage of poly (ADP-ribose) polymerase (PARP) and the activation of caspase-9, -7, and -3. CONCLUSIONS These results demonstrate that AK-Ex downregulates apoptosis via intrinsic and extrinsic pathways against AAP-induced hepatotoxicity. We suggest that AK could be a useful preventive agent against AAP-induced apoptosis in hepatocytes. PMID:28386382

  18. Alcohol-induced S-adenosylhomocysteine accumulation in the liver sensitizes to TNF hepatotoxicity: possible involvement of mitochondrial S-adenosylmethionine transport.

    PubMed

    Song, Zhenyuan; Zhou, Zhanxiang; Song, Ming; Uriarte, Silvia; Chen, Theresa; Deaciuc, Ion; McClain, Craig J

    2007-08-01

    Hepatocytes are resistant to tumor necrosis factor-alpha- (TNF) induced killing/apoptosis under normal circumstances, but primary hepatocytes from rats chronically fed alcohol have increased TNF cytotoxicity. Therefore, there must be mechanism(s) by which alcohol exposure "sensitizes" to TNF hepatotoxicity. Abnormal metabolism of methionine and S-adenosylmethionine (SAM) are well-documented acquired metabolic abnormalities in ALD. S-adenosylhomocysteine (SAH) is the product of SAM in hepatic transmethylation reactions, and SAH hydrolase (SAHH) is the only enzyme to metabolize SAH to homocysteine and adenosine. Our previous studies demonstrated that chronic intracellular accumulation of SAH sensitized hepatocytes to TNF cytotoxicity in vitro. In the current study, we extended our previous observations by further characterizing the effects of chronic alcohol intake on mitochondrial SAM levels in liver and examining its possible involvement in SAH sensitization to TNF hepatotoxicity. Chronic alcohol consumption in mice not only increased cytosolic SAH levels, but also decreased mitochondrial SAM concentration, leading to decreased mitochondrial SAM to SAH ratio. Moreover, accumulation of hepatic SAH induced by administration of 3-deaza-adenosine (DZA-a potent inhibitor of SAHH) enhanced lipopolysaccharide (LPS)/TNF hepatotoxicity in mice in vivo. Inhibition of SAHH by DZA resulted not only in accumulation of cytoplasmic SAH, but also in depletion of the mitochondrial SAM pool. Further studies using mitochondrial SAM transporter inhibitors showed that inhibition of SAM transport into mitochondria sensitized HepG2 cells to TNF cytotoxicity. In conclusion, our results demonstrate that depletion of the mitochondrial SAM pool by SAH, which is elevated during chronic alcohol consumption, plays a critical role in SAH induced sensitization to TNF hepatotoxicity.

  19. [3D evaluation model for drug hepatotoxicity testing on HepG2 cells and its application in drug safety evaluation].

    PubMed

    Li, Dan-Dan; Tang, Xiang-Lin; Tan, Hong-Ling; Liang, Qian-de; Wang, Yu-Guang; Ma, Zeng-Chun; Xiao, Cheng-Rong; Gao, Yue

    2016-04-01

    3D in vitro toxicity testing model was developed by magnetic levitation method for culture of the human hepatoma cell line HepG2 and applied to evaluate the drug hepatotoxicity. After formation of stable 3D structure for HepG2 cells, their glycogen storage capacity under 2D and 3D culture conditions were detected by immunohistochemistry technology, and the mRNA expression levels of phase Ⅰ and Ⅱ drug metabolism enzymes, drug transporters, nuclear receptors and liver-specific marker albumin(ALB) were compared between 2D and 3D culture conditions by using RT-PCR method. Immunohistochemistry results showed that HepG2 cells had abundant glycogen storage capacity under 3D culture conditions, which was similar to human liver tissues. The mRNA expression levels of major drug metabolism enzymes, drug transporters, nuclear receptors and ALB in HepG2 cells under 3D culture conditions were up-regulated as compared with 2D culture conditions. For drug hepatotoxicity evaluation, the typical hepatotoxic drug acetaminophen(APAP), and most reported drugs Polygonum multiflorum Thunb.(Chinese name He-shou-wu) and Psoraleae corylifolia L.(Chinese name Bu-gu-zhi) were selected for single dose and repeated dose(7 d) exposure. In the repeated dose exposure test, 3D HepG2 cells showed higher sensitivity. This established 3D HepG2 cells model with magnetic levitation 3D culture techniques was more close to the human liver tissues both in morphology and functions, so it was a better 3D hepatotoxicity evaluation model. Copyright© by the Chinese Pharmaceutical Association.

  20. Acetaminophen-induced hepatotoxicity is associated with early changes in NF-kB and NF-IL6 DNA binding activity.

    PubMed

    Blazka, M E; Germolec, D R; Simeonova, P; Bruccoleri, A; Pennypacker, K R; Luster, M I

    Nuclear transcription factors, such as NF-kB and NF-IL6, are believed to play an important role in regulating the expression of genes that encode for products involved in tissue damage and inflammation and, thus, may represent early biomarkers for chemical toxicities. In the present study changes in DNA binding activity of these factors were examined in livers of mice administered hepatotoxic doses of acetaminophen (APAP). NF-kB and NF-IL6 DNA binding occurred constitutively in control mouse liver. However, within 4 hr following administration of hepatotoxic doses of APAP, their binding activities were transiently lost and is in contrast to AP-1 transcription factor where activation occurs under similar conditions. These changes corresponded with increased release of inflammatory mediators (IL-6, serum amyloid A) and increased levels of enzymatic markers of hepatocyte damage. Similarly, treatment of mice with gadolinium chloride, an inhibitor of Kupffer cell activation and known to protect against APAP-induced hepatotoxicity, reduced the observed pathophysiological response in the liver while altering the APAP-associated changes in NF-kB DNA binding activity. NF-kB was found predominantly in parenchymal and endothelial cells and was composed primarily of relatively inactive p50 homodimer subunits in control liver. Taken together, these studies suggest that hepatotoxicity is associated with early and complex changes in DNA binding activities of specific transcription factors. In particular, NF-kB and NF-IL6 may serve as negative regulators of hepatocyte-derived inflammatory mediators and is analogous to that previously observed in certain other cell systems such as B lymphocytes.

  1. Sources of Water to Wells for Transient Cyclic Systems

    Reilly, T.E.; Pollock, D.W.

    1996-01-01

    Many state agencies are currently (1995) developing wellhead protection programs. The thrust of some of these programs is to protect water supplies by determining the areas contributing recharge to water-supply wells and by specifying regulations to minimize the opportunity for contamination of the recharge water by activities at the land surface. The area contributing recharge to a discharging well is the surface area at the water table through which the water flowing to the well entered the ground-water system. In the analyses of ground-water flow systems, steady-state average conditions are commonly used to simplify the problem and make a solution tractable. However, recharge is usually cyclic in nature, with seasonal cycles and longer term climatic cycles. The effect of these cyclic stresses on the area contributing recharge to wells is quantitatively analyzed for a hypothetical alluvial valley aquifer system that is representative of a large class of ground-water systems that are extensively developed for water supply. The analysis shows that, in many cases, these cyclic changes in the recharge rates do not significantly affect the location and size of the areas contributing recharge to wells. The ratio of the mean travel time to the length of the cyclic stress period appears to be an indicator of whether the transient effects of the cyclic stress must be explicitly represented in the analysis of contributing areas to wells. For the cases examined, if the ratio of the mean travel time to the period of the cyclic stress was much greater than one, then the transient area contributing recharge to wells was similar to the area calculated using an average steady-state condition. However, cyclic stresses on systems with ratios less than one do have an effect on the location and size of the areas contributing recharge to wells.

  2. A Material Model for the Cyclic Behavior of Nitinol

    NASA Astrophysics Data System (ADS)

    Rebelo, Nuno; Zipse, Achim; Schlun, Martin; Dreher, Gael

    2011-07-01

    The uniaxial behavior of Nitinol in different forms and at different temperatures has been well documented in the literature. Mathematical models for the three-dimensional behavior of this class of materials, covering superelasticity, plasticity, and shape memory effects have been previously developed. Phenomenological models embedded in FEA analysis are part of common practice today in the development of devices made out of Nitinol. In vivo loading of medical devices has cyclic characteristics. There have been some indications in the literature that cyclic loading of Nitinol modifies substantially its behavior. A consortium of several stent manufacturers, Safe Technology and Dassault Systèmes Simulia Corp., dedicated to the development of fatigue laws suitable for life prediction of Nitinol devices, has conducted an extensive experimental study of the modifications in uniaxial behavior of both Nitinol wire and tubing due to cyclic loading. The Abaqus Nitinol material model has been extended to capture some of the phenomena observed and is described in this article. Namely, a preload beyond 6% strain alters the transformation plateaus; if the cyclic load amplitude is large enough, permanent deformations (residual martensite) are observed; the lower plateau increases; and the upper plateau changes. The modifications to the upper plateau are very interesting in the sense that it appears broken: its start stress gets lowered creating a new plateau up to the highest level of cyclic strain, followed by resuming the original plateau until full transformation. Since quite often the geometry of a device at the point at which it is subjected to cyclic loading is very much dependent on the manufacturing, deployment, and preloading sequence, it is important that analyses be conducted with the original material behavior up to that point, and then with the cyclic behavior thereafter.

  3. BENZYL ALCOHOL PROTECTS AGAINST ACETAMINOPHEN HEPATOTOXICITY BY INHIBITING CYTOCHROME P450 ENZYMES BUT CAUSES MITOCHONDRIAL DYSFUNCTION AND CELL DEATH AT HIGHER DOSES

    PubMed Central

    Du, Kuo; McGill, Mitchell R.; Xie, Yuchao; Jaeschke, Hartmut

    2015-01-01

    Acetaminophen (APAP) hepatotoxicity is a serious public health problem in western countries. Current treatment options for APAP poisoning are limited and novel therapeutic intervention strategies are needed. A recent publication suggested that benzyl alcohol (BA) protects against APAP hepatotoxicity and could serve as a promising antidote for APAP poisoning. To assess the protective mechanisms of BA, C56Bl/6J mice were treated with 400mg/kg APAP and/or 270mg/kg BA. APAP alone caused extensive liver injury at 6h and 24h post-APAP. This injury was attenuated by BA co-treatment. Assessment of protein adduct formation demonstrated that BA inhibits APAP metabolic activation. In support of this, in vitro experiments also showed that BA dose-dependently inhibits cytochrome P450 activities. Correlating with the hepatoprotection of BA, APAP-induced oxidant stress and mitochondrial dysfunction were reduced. Similar results were obtained in primary mouse hepatocytes. Interestingly, BA alone caused mitochondrial membrane potential loss and cell toxicity at high doses, and its protective effect could not be reproduced in primary human hepatocytes (PHH). We conclude that BA protects against APAP hepatotoxicity mainly by inhibiting cytochrome P450 enzymes in mice. Considering its toxic effect and the loss of protection in PHH, BA is not a clinically useful treatment option for APAP overdose patient. PMID:26522885

  4. Camellia sinensis L. Extract and Its Potential Beneficial Effects in Antioxidant, Anti-Inflammatory, Anti-Hepatotoxic, and Anti-Tyrosinase Activities.

    PubMed

    Thitimuta, Surached; Pithayanukul, Pimolpan; Nithitanakool, Saruth; Bavovada, Rapepol; Leanpolchareanchai, Jiraporn; Saparpakorn, Patchreenart

    2017-03-04

    The aims of this study were to investigate the potential benefits of antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase activities of a methanolic extract of fresh tea leaves (FTE) ( Camellia sinensis L.). The antioxidant capacity was investigated using three different methods at different temperatures. The anti-inflammatory activity was studied in vitro by the inhibition of 5-lipoxygenase assay. The anti-hepatotoxic effect was investigated in CCl₄-induced liver injury in rats. The anti-tyrosinase activities of the FTE and its principal phenolic compounds were investigated in l-3,4-dihydroxyphenylalanine (l-DOPA) oxidation by a mushroom tyrosinase. A molecular docking study was conducted to determine how the FTE's principal catechins interact with the tyrosinase. The FTE exhibited the best shelf life at low temperatures and demonstrated concentration-dependent antioxidant, anti-inflammatory, anti-hepatotoxic, and anti-tyrosinase effects compared to positive references. Treatment of rats with the FTE at 2000 mg/kg/day for 28 consecutive days reversed CCl₄-induced oxidative damage in hepatic tissues by lowering the levels of alanine aminotransferase by 69% and malondialdehyde by 90%. Our findings suggest that the FTE has the capacity to scavenge free radicals and can protect against oxidative stress induced by CCl₄ intoxication. The docking results were consistent with our in vitro data, indicating the anti-tyrosinase potency of the principal catechins.

  5. Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans.

    PubMed

    Yu, Dianke; Wu, Leihong; Gill, Pritmohinder; Tolleson, William H; Chen, Si; Sun, Jinchun; Knox, Bridgett; Jin, Yaqiong; Xiao, Wenming; Hong, Huixiao; Wang, Yong; Ren, Zhen; Guo, Lei; Mei, Nan; Guo, Yongli; Yang, Xi; Shi, Leming; Chen, Yinting; Zeng, Linjuan; Dreval, Kostiantyn; Tryndyak, Volodymyr; Pogribny, Igor; Fang, Hong; Shi, Tieliu; McCullough, Sandra; Bhattacharyya, Sudeepa; Schnackenberg, Laura; Mattes, William; Beger, Richard D; James, Laura; Tong, Weida; Ning, Baitang

    2018-02-01

    Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine. In the current study, the mRNA and microRNA (miRNA) expression profiles derived from next generation sequencing data for APAP-treated (5 and 10 mM) HepaRG cells and controls were analyzed systematically. Putative miRNAs targeting key dysregulated genes involved in APAP hepatotoxicity were selected using in silico prediction algorithms, un-biased gene ontology, and network analyses. Luciferase reporter assays, RNA electrophoresis mobility shift assays, and miRNA pull-down assays were performed to investigate the role of miRNAs affecting the expression of dysregulated genes. Levels of selected miRNAs were measured in serum samples obtained from children with APAP overdose (58.6-559.4 mg/kg) and from healthy controls. As results, 2758 differentially expressed genes and 47 miRNAs were identified. Four of these miRNAs (hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p) suppressed drug metabolizing enzyme (DME) levels involved in APAP-induced liver injury by downregulating HNF1A, HNF4A and NR1I2 expression. Exogenous transfection of these miRNAs into HepaRG cells effectively rescued them from APAP toxicity, as indicated by decreased alanine aminotransferase levels. Importantly, hsa-miR-320a and hsa-miR-877-5p levels were significantly elevated in serum samples obtained from children with APAP overdose compared to health controls. Collectively, these data indicate that hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p suppress DME expression involved in APAP-induced hepatotoxicity and they contribute to an adaptive response in hepatocytes.

  6. Modulatory potentials of the aqueous stem bark extract of Mangifera indica on carbon tetrachloride-induced hepatotoxicity in rats

    PubMed Central

    Adeneye, Adejuwon Adewale; Awodele, Olufunsho; Aiyeola, Sheriff Aboyade; Benebo, Adokiye Senibo

    2015-01-01

    group, with more protection offered in the curative than the chemopreventive models of CCl4 hepatotoxicity. Thus, these results indicate that MIASE has a profound protective effect against acute CCl4-induced hepatotoxicity in rats, which may be due to its free radicals scavenging effect, inhibition of lipid peroxidation, and its ability to increase antioxidant activity. PMID:26151020

  7. Topological chaos, braiding and bifurcation of almost-cyclic sets.

    PubMed

    Grover, Piyush; Ross, Shane D; Stremler, Mark A; Kumar, Pankaj

    2012-12-01

    In certain two-dimensional time-dependent flows, the braiding of periodic orbits provides a way to analyze chaos in the system through application of the Thurston-Nielsen classification theorem (TNCT). We expand upon earlier work that introduced the application of the TNCT to braiding of almost-cyclic sets, which are individual components of almost-invariant sets [Stremler et al., "Topological chaos and periodic braiding of almost-cyclic sets," Phys. Rev. Lett. 106, 114101 (2011)]. In this context, almost-cyclic sets are periodic regions in the flow with high local residence time that act as stirrers or "ghost rods" around which the surrounding fluid appears to be stretched and folded. In the present work, we discuss the bifurcation of the almost-cyclic sets as a system parameter is varied, which results in a sequence of topologically distinct braids. We show that, for Stokes' flow in a lid-driven cavity, these various braids give good lower bounds on the topological entropy over the respective parameter regimes in which they exist. We make the case that a topological analysis based on spatiotemporal braiding of almost-cyclic sets can be used for analyzing chaos in fluid flows. Hence, we further develop a connection between set-oriented statistical methods and topological methods, which promises to be an important analysis tool in the study of complex systems.

  8. Mechanical annealing under low-amplitude cyclic loading in micropillars

    NASA Astrophysics Data System (ADS)

    Cui, Yi-nan; Liu, Zhan-li; Wang, Zhang-jie; Zhuang, Zhuo

    2016-04-01

    Mechanical annealing has been demonstrated to be an effective method for decreasing the overall dislocation density in submicron single crystal. However, simultaneously significant shape change always unexpectedly happens under extremely high monotonic loading to drive the pre-existing dislocations out of the free surfaces. In the present work, through in situ TEM experiments it is found that cyclic loading with low stress amplitude can drive most dislocations out of the submicron sample with virtually little change of the shape. The underlying dislocation mechanism is revealed by carrying out discrete dislocation dynamic (DDD) simulations. The simulation results indicate that the dislocation density decreases within cycles, while the accumulated plastic strain is small. By comparing the evolution of dislocation junction under monotonic, cyclic and relaxation deformation, the cumulative irreversible slip is found to be the key factor of promoting junction destruction and dislocation annihilation at free surface under low-amplitude cyclic loading condition. By introducing this mechanics into dislocation density evolution equations, the critical conditions for mechanical annealing under cyclic and monotonic loadings are discussed. Low-amplitude cyclic loading which strengthens the single crystal without seriously disturbing the structure has the potential applications in the manufacture of defect-free nano-devices.

  9. Micromechanics of soil responses in cyclic simple shear tests

    NASA Astrophysics Data System (ADS)

    Cui, Liang; Bhattacharya, Subhamoy; Nikitas, George

    2017-06-01

    Offshore wind turbine (OWT) foundations are subjected to a combination of cyclic and dynamic loading arising from wind, wave, rotor and blade shadowing. Under cyclic loading, most soils change their characteristics including stiffness, which may cause the system natural frequency to approach the loading frequency and lead to unplanned resonance and system damage or even collapse. To investigate such changes and the underlying micromechanics, a series of cyclic simple shear tests were performed on the RedHill 110 sand with different shear strain amplitudes, vertical stresses and initial relative densities of soil. The test results showed that: (a) Vertical accumulated strain is proportional to the shear strain amplitude but inversely proportional to relative density of soil; (b) Shear modulus increases rapidly in the initial loading cycles and then the rate of increase diminishes and the shear modulus remains below an asymptote; (c) Shear modulus increases with increasing vertical stress and relative density, but decreasing with increasing strain amplitude. Coupled DEM simulations were performed using PFC2D to analyse the micromechanics underlying the cyclic behaviour of soils. Micromechanical parameters (e.g. fabric tensor, coordination number) were examined to explore the reasons for the various cyclic responses to different shear strain amplitudes or vertical stresses. Both coordination number and magnitude of fabric anisotropy contribute to the increasing shear modulus.

  10. Degradation forecast for PEMFC cathode-catalysts under cyclic loads

    NASA Astrophysics Data System (ADS)

    Moein-Jahromi, M.; Kermani, M. J.; Movahed, S.

    2017-08-01

    Degradation of Fuel Cell (FC) components under cyclic loads is one of the biggest bottlenecks in FC commercialization. In this paper, a novel experimental based algorithm is presented to predict the Catalyst Layer (CL) performance loss during cyclic load. The algorithm consists of two models namely Models 1 and 2. The Model 1 calculates the Electro-Chemical Surface Area (ECSA) and agglomerate size (e.g.