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Nicholls-Grzemski, Felicity April. "The effect of short-term pretreatment with peroxisome proliferators on the acute toxicity of various toxicants, including paracetamol /." Title page, table of contents and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phn6158.pdf.
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Weng, Yu-I. "Acute and chronic ethanol effects on liver p42/44 mitogen activated protein kinase." free to MU campus, to others for purchase, 2001. http://wwwlib.umi.com/cr/mo/fullcit?p3036867.
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Gronert, Álvarez Anna Christina [Verfasser], and Hans-Heinrich [Akademischer Betreuer] Wedemeyer. "Regulatory T cells in liver transplantation : phenotypical characterisation and effects of immunosuppressive drugs / Anna Christina Gronert Álvarez. Klinik für Gastroenterologie, Hepatologie und Endokrinologie der Medizinischen Hochschule Hannover. Betreuer: Hans-Heinrich Wedemeyer." Hannover : Bibliothek der Medizinischen Hochschule Hannover, 2014. http://d-nb.info/1050008200/34.
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Eng, Heather Sui-Fong. "Evaluating the use of cryopreserved hepatocytes for the prediction of in vivo hepatic clearance /." See Full Text at OhioLINK ETD Center (Requires Adobe Acrobat Reader for viewing), 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=toledo1091638312.
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Thesis (M.S.P.)--University of Toledo, 2004.Typescript. "A thesis [submitted] as partial fulfillment of the requirements of the Master of Science degree in Pharmaceutical Sciences." Bibliography: leaves 64-68.
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Silberstein, D. J. "The effect of renal failure on the elimination of drugs by the liver." Thesis, University of Leeds, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.379649.
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Ngamratanapaiboon, Surachai. "Metabolomics investigations of the effect of drugs on mammalian cells." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/41178/.
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Cell-based metabolomics using LC-MS systemizes the study of the uniqueness of small-molecule metabolite (metabolomes) profiles in cellular processes. Cell-based metabolomics can potentially be used in many applications for the study of biological perturbation from stimulants in cellular pathways. The advantages of cell-based metabolomics include ease of control and interpretation when compared to the study of human subjects and animal models. Furthermore, this method can decrease some highly challenging problems that occur in genomics, transcriptomics and proteomics. Nowadays, cell culture in metabolomics studies has been used in many applications. These include cell culture and bioreactor optimisation, phenotype classification, stimulant testing effect, target and toxicity analysis, metabolic networks determination and modelling, and biomarker and drug target discovery. In this study, the reverse phase-liquid chromatography-mass spectrometry and hydrophilic interaction chromatography-mass spectrometry for comprehensive metabolic profiling well suited to the untargeted analysis of non-polar and polar metabolites in mammalian cells were developed, optimized and validated. These methods can separate and detect most of hydrophobic and polar metabolites that are normally found in mammalian cell lines. After that the LC-MS methods were applied to assess the effects of drugs with known and unknown cellular metabolic effects on three mammalian cell lines, namely HMVECs for antipsychotics experiment, MCF-7 cells for cordycepin experiment and MIN6 cells for fluoxetine experiment by using untargeted metabolic profiling. The global effects of antipsychotics at high therapeutic dosage in HMVECs were investigated. The results support for the toxicity hypothesis with measurements that confirm previous findings and reveal the exact biological pathways of antipsychotic-altered BBB functions. It was found that antipsychotics may affect the bioenergetics pathway due to mitochondrial dysfunction resulted in ketoacidosis and inducing oxide stress by reactive oxygen species generation. In the MCF- cell experiment, the results of the untargeted metabolite profiling demonstrated the clear anti-breast cancer effects of cordycepin and pentostatin. By investigating the metabolite profiles, clear synergistic effects of cordycepin and pentostatin combined in comparison to cordycepin activity alone in MCF-7 cells was observed. Furthermore, the pathway analysis indicated that anti-breast cancer activity was mainly responsible for alterations in purine and pyrimidine metabolism and bioenergetics. Additionally, cordycepin may be involved in the inhibition of cell proliferation and differentiation, and the activation of cell apoptosis. The last experiment on MIN6 cells, the developed and optimized HILIC-MS approach in order to determine the biological pathways which are impaired by fluoxetine on glucose-stimulated insulin secretion on MIN6 cell lines was performed. It is found that fluoxetine may impair glycolysis, TCA and fatty acid metabolism on MIN6 cell lines. Moreover, it is also reveal that the alteration of biological pathways on MIN6 cells by known ETC inhibitors (rotenone (Complex I inhibitor) antimycin (Complex III inhibitor)) and azide (a complex IV inhibitor). From comparison with these ETC inhibitors, it is found that fluoxetine may have the same effect pattern with azide.
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Abumansour, Hamza M. A. "Quantitative pharmacoproteomics investigation of anti-cancer drugs in mouse : development and optimisation of proteomics workflows for evaluating the effect of anti-cancer drugs on mouse liver." Thesis, University of Bradford, 2016. http://hdl.handle.net/10454/15724.
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Minimizing anti-cancer drug toxicity is a major challenge for the pharmaceutical industry. Toxicity is most frequently due to either the direct interaction of the drug on previously unidentified targets or its conversion to metabolites by drug metabolizing enzymes (e.g. CYP450 enzymes) that cause cellular, tissue or organ damage. Pharmacoproteomics is beginning to take a central role in studying changes in protein expression corresponding to drug administration, the results of which, inform about the mode of action, toxicity, and resistance in pre-clinical and clinical stages of drug development. The main aim of this research is to apply comparative proteomics studies on livers from male and female mice xenograft models treated with major anti-cancer drugs (5-flourouracil, paclitaxel, cisplatin, and doxorubicin) and CYP inducer, TCPOBOP, to investigate their effect on protein expression profiles (proteome). Within this thesis, an attention is paid to optimise a highly validated proteomics workflow for biomarker identification. Proteins were extracted from liver microsomes of mice treated in two separate sets; Set A – male (5-fluoruracil, doxorubicin, cisplatin and untreated) or Set B – female (5-fluoruracil, paclitaxel, TCPOBOP and untreated) using cryo-pulverization and sonication method. The extracts were digested with trypsin ii and the resulting peptides labelled with 4-plex iTRAQ reagents. The labelled peptides were subjected for separation in two-dimensions by iso-electric focusing (IEF) and RP-HPLC techniques before analysis by mass spectrometry and database searching for protein identification. Set A and Set B resulted in identification and quantification of 1146 and 1743 proteins, respectively. Moreover, Set A and Set B recovered 26 and 34 cytochrome P450 isoforms, respectively. The microsomal changes after drug treatments were quite similar. However, more changes were observed in the male set. Up-regulation of MUPs showed the greatest distinction in the protein expression patterns in the treated samples comparing to the untreated controls. In Set A, 5-fluoruracil and cisplatin increased the expression of three isoforms (MUP1, 2, and 6), whereas doxorubicin has increased the expression of four isoforms (MUP1, 2, 3, and 6). On the other side, only TCPOBOP in Set B has increased the expression of two isoforms (MUP1 and 6). Our findings showed that the expression of MUP, normally involved in binding and excretion of pheromones, have drug- and sex-specific differences. The mechanism and significance of MUP up-regulation are ambiguous. Therefore, the impact of each therapeutic agent on MUP and xenobiotic enzymes will be discussed.
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Teng, Shuzhi, and 滕曙智. "Hepatocellular injury induced by endotoxin and galactosamine." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31241037.
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Kassahun, Kelem. "Mechanistic studies of valproic acid hepatotoxicity : identification and characterization of thiol conjugates." Thesis, University of British Columbia, 1991. http://hdl.handle.net/2429/30831.
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The severe hepatotoxicity of the antiepileptic drug valproic acid (VPA) is believed to be mediated through chemically reactive metabolites. The monounsaturated metabolite 4-ene VPA is steatogenic in the rat, and in a similar fashion to the hepatotoxin 4-pentenoic acid, is thought to be oxidized by mitochondria to a highly reactive α,β-unsaturated ketone, 3-keto-4-ene VPA. The tripeptide thiol, glutathione (GSH), is known to react with a variety of electrophilic compounds that have the potential to interact with cellular macromolecules. The identification and structural characterization of GSH conjugates provides a means of identifying short-lived unstable electrophiles and thus an insight into the mechanisms of toxicity. This thesis describes the synthesis and characterization of thiol conjugates of reactive metabolites derived from the in vivo metabolism of VPA, 4-ene VPA, (E)-2,4-diene VPA, and 4-pentenoic acid.
A negative ion chemical ionization gas chromatographic/mass spectrometric (NICI/GC/MS) method for the determination of VPA and 14 of its metabolites in a single chromatographic run was developed. A combination of pentafluorobenzyl and trimethylsilyl derivatization resulted in the [M-181]̄̄̄ ̄anion as the base peak for all the metabolites measured. When these ions were monitored sensitivities in the low picogram range were achieved. The VPA metabolite profile was determined in pediatric patients on VPA monotherapy and on combined therapy with either carbamazepine or clobazam. 4-Ene- and (E)-2,4-diene-VPA were found to be minor metabolites with serum levels below 1% that of VPA. In patients on combined therapy with carbamazepine, the ω and ω-l pathways of VPA metabolism were induced, while products of β-oxidation were significantly decreased. Polytherapy had no significant effect on the serum levels of 4-ene- or (E)-2,4-diene-VPA.
Rats were dosed intraperitoneally with 100 mg/kg of the sodium salts of VPA, 4-ene-, (E)-2,4-diene-VPA, 4-pentenoic or (E)-2,4-pentadienoic acids. Methylated bile extracts were analyzed by high pressure liquid chromatography and liquid chromatography/tandem mass spectrometry (LC/MS/MS) for GSH conjugates while urine samples were analyzed by GC/MS and LC/MS for N-acetylcysteine (NAC) conjugates and other metabolites. The GSH conjugate of (E)-2,4-diene VPA was detected in the bile of rats treated with 4-ene- and (E)-2,4-diene-VPA. The NAC conjugate was a major urinary metabolite of rats given (E)-2,4-diene VPA and was a prominent urinary metabolite of those animals given 4-ene VPA. The structures of these metabolites were confirmed by comparing GC/MS or LC/MS properties of the isolated metabolites to those of synthetic standards.
The GSH and NAC conjugates of (E)-2,4-diene VPA were chemically synthesized and their structures established to be (E)-5-(glutathion-S-yl)-3-ene VPA and (E)-5-(N-acetylcystein-S-yl)-3-ene VPA by nuclear magnetic resonance spectroscopy and mass spectrometry. In contrast to the very slow reaction of the free acid of (E)-2,4-diene VPA with GSH, the methyl ester reacted rapidly with GSH to yield the adduct. In vivo it appears the diene forms an intermediate with enhanced electrophilic reactivity to GSH as indicated by the facile reaction of the diene with GSH in vivo (about 40% of the (E)-2,4-diene VPA administered to rats was excreted as the NAC conjugate in 24 hr). In rats treated with 4-pentenoic and/or (E)-2,4-pentadienoic acids the following conjugates were identified and characterized by synthesis: GSH and cysteine conjugates of 3-oxo-4-pentenoic acid, GSH and NAC conjugates of (E)-2,4-pentadienoic acid, and the NAC conjugate of acrylic acid. The results thus provided the first direct biochemical evidence for the in vivo formation of the metabolite of 4-pentenoic acid considered responsible for the irreversible inhibition of fatty acid metabolism. The results also revealed basic differences between the mitochondrial metabolism of 4-ene VPA and 4-pentenoic acid.
The 3-keto-4-ene VPA and its GSH and NAC conjugates were synthesized in order to facilitate the in vivo identification of these compounds following the administration of VPA, 4-ene-, or (E)-2,4-diene-VPA to rats. However, neither the 3-keto-4-ene VPA nor its thiol derivatives were evident in any of the treatments.
The NAC conjugate of (E)-2,4-diene VPA was also found to be a metabolite of VPA in patients. The level of the conjugate appeared to be higher in two patients who recovered from VPA-induced liver toxicity. The characterization of GSH and NAC (in humans and rats) conjugates of (E)-2,4-diene VPA suggests that VPA is metabolized to a chemically reactive intermediate that may contribute to the hepatotoxicity of the drug.Pharmaceutical Sciences, Faculty of
Graduate
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Jansen, Robert Walter. "Modified human serum albumins as carriers for the specific delivery of antiviral drugs to liver- and blood cells." [S.l. : [Groningen : s.n.] ; University of Groningen] [Host], 2008. http://irs.ub.rug.nl/ppn/.
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Abdelhadi, Mohamed Mohamed. "Posttransplantation bone disease : the effect of immunosuppressive drugs on bone: clinical and experimental studies /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-384-8/.
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Kita, Sadahiko. "The protective effect of transplanted liver cells into the mesentery on the rescue of acute liver failure after massive hepatectomy." Kyoto University, 2016. http://hdl.handle.net/2433/216179.
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出版日2016/2/15を明示する必要あり。発行号・ページ数が決まっていればそれらも明示する必要あり。 Final publication is available at http://dx.doi.org/10.3727/096368916X690999Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第19925号
医博第4145号
新制||医||1017(附属図書館)
33011
京都大学大学院医学研究科医学専攻
(主査)教授 長船 健二, 教授 伊達 洋至, 教授 坂井 義治
学位規則第4条第1項該当
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Smith, Darron Louis. "The effect and mechanism of action of volatile fatty acids on the catabolism of progesterone." Morgantown, W. Va. : [West Virginia University Libraries], 2005. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=4243.
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Thesis (Ph. D.)--West Virginia University, 2005.Title from document title page. Document formatted into pages; contains x, 88 p. : ill. Vita. Includes abstract. Includes bibliographical references.
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Bunaciu, Rodica Petruta. "THE EFFECT OF POLYCHLORINATED BIPHENYLS ON LIVER TUMOR PROMOTION: A ROLE FOR KUPFFER CELLS?" Lexington, Ky. : [University of Kentucky Libraries], 2005. http://lib.uky.edu/ETD/ukynusi2005d00298/etd.pdf.
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Thesis (Ph. D.)--University of Kentucky, 2005.Title from document title page (viewed on November 4, 2005). Document formatted into pages; contains viii, 188 p. : ill. Includes abstract and vita. Includes bibliographical references (p. 165-184).
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Stevens, Jeffrey Charles 1963. "Selective inactivation of four rat liver microsomal androstenedione hydroxylases by chloramphenicol analogs." Thesis, The University of Arizona, 1988. http://hdl.handle.net/10150/276700.
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The steroid androstenedione has been shown to be a valuable tool for the study of selective inactivation of rat liver cytochrome P-450 isozymes. The validity of this method was investigated using microsomes, purified cytochromes P-450, cytochrome P-450 antibodies, and the mechanism-based inactivator chloramphenicol. Enzyme inactivation and antibody inhibition studies show that microsomes from phenobarbital- and non-phenobarbital-treated rats are needed to accurately monitor the inactivation of the major phenobarbital-inducible P-450 isozyme (PB-B) and of the major constitutive androstenedione 16-alpha hydroxylase (UT-A). Enzyme inactivation studies showed that the antibiotic chloramphenicol caused different rates of NADPH-dependent enzyme inactivation among four androstenedione hydroxylases (16-beta > 6-beta > 16-alpha > 7-alpha). The results with twelve chloramphenicol analogs show that their selectivity as cytochrome P-450 inactivators is dependent upon at least three structural features: (1) the number of halogen atoms, (2) the presence of a para-nitro group on the phenyl ring, and (3) substitutions on the ethyl side chain.
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Vaino, Andrew Rein. "Synthesis of agents for the targeting of drugs to the human liver and elucidation of the reverse anomeric effect." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ31959.pdf.
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Müller, Daniel [Verfasser], and Elmar [Akademischer Betreuer] Heinzle. "Organotypic functional cultures of human liver cells for long-term maintenance and assessment of drug-induced metabolome effects / Daniel Müller. Betreuer: Elmar Heinzle." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2012. http://d-nb.info/1052338445/34.
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Charanek, Ahmad. "The Bile Canaliculus Revisited : Morphological And Functional Alterations Induced By Cholestatic Drugs In HepaRG Cells." Thesis, Rennes 1, 2015. http://www.theses.fr/2015REN1B011/document.
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La cholestase est l'une des manifestations les plus courantes des lésions induitespar des médicaments. Dans 40% des cas elle n’est pas prévisible; une meilleure prédictibilité représente donc un défi majeur. Tout d'abord, nous avons démontré que les cellules hépatiques humaines HepaRG différenciées sont un modèle approprié pour étudier la cholestase induite par les médicaments en comparant la localisation et l’activité des transporteurs d'influx et d'efflux avec les hépatocytes humains primaires. Tous les transporteurs d'efflux et d’influx testés ont été correctement localisés au niveau des membranes canaliculaire (BSEP, MRP2, MDR1 et MDR3) et basolatéral (NTCP, MRP3) et sont fonctionnels. En outre, ces cellules expriment également les enzymes qui métabolisent les acides biliaires (ABs) et ont la capacité de les synthétiser et de les conjuguer avec la taurine, la glycine et le sulfate, à un taux similaire à celui des hépatocytes primaires. Des changements ont été observés sur la répartition des ABs totaux après traitements de cellules HepaRG par un médicament cholestatique, la cyclosporine A (CsA), de manière concentration- dépendante. L'inhibition de l'efflux et de l'influx de taurocholate a été observée après 15 min et 1 h respectivement. Ces premiers effets ont été associés à la dérégulation de la voie des cPKC et l'induction d’un stress du réticulum endoplasmique puis d’un stress oxydant. Nous avons également montré pour la première fois une accumulation intracellulaire d’ABs endogènes avec un médicament cholestatique in vitro. En outre, notre travail apporte des preuves que la motilité des canalicules biliaires (BC) est indispensable à la clairance des ABs. La voie ROCK et le complexe actomyosine sont fortement impliqués. Nous avons fourni la première démonstration que la voie ROCK et les dynamiques des BC sont des cibles majeures des composés cholestatiques. Nos données devraient contribuer à l'élaboration de méthodes de screening pour la prédiction précoce des effets secondaires induits par les médicaments cholestatiquesCholestasis is one of the most common manifestations of drug-induced liver injury (DILI). Since up to now it is unpredictable in 40% of all cases its accurate prediction represents a major challenge. First, we validated that differentiated HepaRG human liver cells are a suitable in vitro model to study drug-induced cholestasis, by comparing localization of influx and efflux transporters and their functional activity in these cells and primary human hepatocytes. All tested influx and efflux transporters were correctly localized to canalicular (BSEP, MRP2, MDR1, and MDR3) or basolateral (NTCP, MRP3) membrane domains and were functional. In addition, the HepaRG cell line also exhibits bile acids (BAs) metabolizing enzymes and has the capacity to synthesize BAs and to further amidate these BAs with taurine and glycine as well as sulfate, at a rate similar to that of primary hepatocytes. Concentration- dependent changes were observed in total BAs disposition after treatment of HepaRG cells by the cholestatic drug cyclosporine A (CsA). Inhibition of efflux and uptake of taurocholate was evidenced as early as 15 min and 1 h respectively. These early effects were associated with deregulation of cPKC pathway and induction of endoplasmic reticulum stress that preceded generation of oxidative stress. We also showed for the first time intracellular accumulation of endogenous BAs by a cholestatic drug in vitro. In addition, our work brings evidences that motility of bile canaliculi (BC) is essential for BAs clearance where ROCK pathway and actomyosin complex are highly implicated. We provided the first demonstration that ROCK pathway and BC dynamics are major targets of cholestatic compounds. Our data should help in the development of screening methods for early prediction of drug-induced cholestatic side effects
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Davies, Richard. "Effect of selective COX-2 inhibitors on hepatic progenitor cells and the pathologies of experimental hepatocarcinogenesis." University of Western Australia. School of Medicine and Pharmacology, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0190.
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[Truncated abstract] Hepatocellular carcinoma (HCC) is the major malignancy complicating chronic liver disease. New therapies for the prevention of HCC are required due to the limited success and high tumour recurrence rates of existing treatments. Emerging evidence suggests that HCC arise from the transformation of adult liver progenitor cells (LPCs), which have the capacity to differentiate into hepatocytes and biliary cells during liver regeneration. LPC activation precedes neoplasia in experimental hepatocarcinogenesis. LPCs share antigenic epitopes with HCCs, including α-fetoprotein (AFP) and M2- pyruvate kinase (M2PK). In animal models of hepatocarcinogenesis, attenuation of the LPC response reduces the incidence of HCC following prolonged liver injury via a tumour necrosis factor (TNF) dependent mechanism. As TNF is a pro-inflammatory cytokine, these data suggest that anti-inflammatory agents may be effective in inhibiting LPC activation and hepatocarcinogenesis. Cyclo-oxygenase-2 (COX-2) is an inducible enzyme that mediates the production of many prostaglandins during inflammation and carcinogenesis. Recent investigations show that the administration of selective COX-2 inhibitors (SC2Is) may reduce the incidence of a variety of tumours including breast, colon and skin. The broad aim of this thesis was to conduct a series of detailed studies on the effects of a SC2I on LPC activation and the hepatic pathologies associated with hepatocarcinogenesis in order to test the hypothesis that S2CIs may be a beneficial therapy that can reduce liver injury and pre-neoplastic changes in the choline-deficient, ethionine supplemented (CDE) murine model of hepatocarcinogenesis. Administration of a SC2I (SC-236) significantly inhibited a variety of hepatic cell populations that expand during the first month of the CDE mouse model of hepatocarcinogenesis (a choline deficient, ethionine supplemented diet). Numbers of M2PK-positive LPCs (which are more hepatocytic in morphology and are also COX-2 positive) and inflammatory cells were all significantly reduced by SC-236. In contrast, numbers of A6-positive LPCs (which are more biliary cell-like in morphology and do not express COX-2) were unchanged. ... In summary, these data suggest that COX-2 inhibitors such as SC-236 inhibit LPC activation and a variety of pre-neoplastic liver pathologies as a result of COX-2 dependent and independent mechanisms that may be mediated through inhibition of Akt phosphorylation and induction of apoptosis. Moreover, SC2Is may be useful as preventative treatment strategies for HCC in patients with chronic liver disease.
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廖寶韶 and Po-shiu Jackie Liu. "Effects of flavonoids on proliferation of breast cancer cells and vascular smooth muscle cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011394.
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Almaawi, Abdulaziz. "Effect of acetaminophen and nonsteroidal anti-inflammatory drugs on gene expression of human mesenchymal stem cells." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114405.
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A major drawback of cartilage tissue engineering is that human mesenchymalStem cells (MSCs) from patients with osteoarthritis (OA) express high levels of type X collagen. Type X collagen is a marker of late stage chondrocyte hypertrophy, linked with endochondral ossification. Also, MSCs from OA patients express osteogenic marker genes such as alkaline phosphatase (ALK), bone sialoprotein (BSP), and osteocalcin (OC) as well as aggrecan (ACAN), a marker of chondrogenesis, but not type II collagen. OA patients, in an attempt to relieve pain and other symptoms, often take NSAIDs and pain relievers like acetaminophen. The aim of this present study was to determine how these drugs influence human MSC gene expression of different chondrogenic and osteogenic markers. MSCs isolated from the bone marrow of osteoarthritic patients or from normal donors were cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) without or with Acetaminophen (Acet) or non-steroidal anti-inflammatory drugs (NSAIDs), Ibuprofen (Ibu), Diclofenac (Dic), Naproxen (Npx) and Celecoxib (Cele). After 3 days of culture, the cells were collected and gene expression was measured using quantitative PCR for type X collagen (COL10A1), aggrecan (ACAN) and type 1 collagen，as well as osteogenic marker genes such as alkaline phosphatase (ALP), bone sialoprotein (BSP), osteocalcin (OC) and Runt-related transcription factor 2 (RUNX2). Acet and Npx supplementation led to a significant increase in COL10A1 & RUNX2 expression when compared to control. Furthermore, with Ibu, Acet and Npx supplementation, aggrecan message levels were decreased. In contrast, addition of Cele significantly increased aggrecan gene expression. Finally, Ibu, Acet and Npx decreased type I collagen expression while Cele had a tendency to increase type I collagen expression. The present study showed that NSAIDs and Acet could affect Osteogenic and chondrogenic differentiation of human MSCs. These are features that could interfere with intervertebral disc (IVD) or cartilage repair. Thus, caution must be exercised when using MSCs from OA patients in biological repair of articular cartilage or disc.Un des principaux problèmes de l'ingénierie tissulaire du cartilage réside dans le fait que les cellules souches mésenchymateuses humaines (hCSMs) de patients osteoarthritiques (OA) expriment fortement le collagène de type X (Col X) qui est un marqueur de l'hypertrophie des chondrocvytes, hypertrophie qui est associée à l'ossification. Les hCSMs de patients OA expriment également des marqueurs de l'ostéogénèse tels que la phosphatase alcaline (ALK), une sialoprotéine de l'os (BSP) et l'ostéocalcine (OC), ainsi que l'aggrécane (AGG), un marqueur de la chondrogenèse. Dans le but de diminuer la douleur et autres symptômes reliés à leur maladie, les patients OA consomment des drogues anti-inflammatoires non-stéroïdiennes (NSAIDs). Le but de la présente étude était de déterminer si ces drogues pouvaient influencer l'expression de gènes associés à la chondrogenèse ou à l'ostéogénèse dans les hCSMs. Les CSMs isolées de la moelle osseuse de patients OA ou de donneurs normaux ont été cultivées dans du milieu Eagle modifié selon Dulbecco (DMEM) supplémenté avec 10% de sérum de veau fétal (SVF), sans ou avec Acétominophène (Acét), Ibuprofène (Ibu), Dichlorofenac (Dic), Naproxen (Npx) et Célécoxib (célé). L'expression des marqueurs ostéogéniques et du Col X a été mesurée par PCR quantitatif après 3 jours en culture. Les résultats montrent que l'Acét et le Npx induisaient significativement l'expression du Col X et diminuaient, tout comme l'Ibu, l'expression de l'AGG et du Col de type I (Col I). Cependant, Célé stimulait de façon significative l'expression de l'AGG et inhibait, mais de façon non significative, l'expression du Col I. En résumé, la présente étude montre que les NSAIDs peuvent moduler l'expression de gènes associés à l'ostéogénèse et à la chondrogenèse dans les hCSMs, indiquant qu'ils pourraient interférer dans la réparation du cartilage. L'utilisation de hCSMs de patients OA devrait donc être faite avec prudence pour la réparation biologique du cartilage articulaire et même du disque intervertébral.
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Al-Mayyahi, Rawaa Salim. "An investigation of the mechanisms underpinning the effect of anti-inflammatory drugs on neural stem cells." Thesis, Keele University, 2017. http://eprints.keele.ac.uk/4257/.
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Anti-inflammatory drugs such as corticosteroids (CSs) and minocycline (MINO) are widely used in the treatment of a range of clinical conditions and to suppress graft rejection in stem cell transplantation therapy. However, such treatment is associated with adverse effects on brain development. The effects of anti-inflammatory drug on neural stem cells (NSCs) are largely unknown and the molecular mechanisms underlying these effects are poorly documented. The focus of this project is to systematically investigate the effects of different anti-inflammatory drug at different concentrations on the fate of NSCs using two different in vitro models. In this thesis, it is shown that all three types of CSs (dexamethasone, prednisone and methylprednisolone) affect NSCs propagated in monolayers and neurospheres. Comparison of the monolayer and neurosphere growth formats for NSCs following CS treatment revealed that CS decreased NSCs proliferation and neuronal differentiation while accelerated the maturation of oligodendrocytes without concomitant effects on cell viability and apoptosis. The findings suggest that the difference in the physical format of NSCs does not impact on CS influences on these cells with similar results obtained for both culture systems. Further, label-free quantitative proteomics was used to study methylprednisolone effects on NSCs at the cellular and molecular levels in monolayer cultures. Proteomics and bioinformatics analyses revealed that methylprednisolone induced downregulation of growth associated protein 43 and matrix metallopeptidase 16 with upregulation of the cytochrome P450 family 51 subfamily A member 1. These findings support the hypothesis that neurological deficits associated with CS treatment mediated via effects on NSCs, and highlight putative target mechanisms underpinning such effects. Finally, the organotypic spinal cord slice model was used to investigate the efficacy of MINO as a combinatorial therapy with transplanted NSCs. The data from neurosphere culture showed that MINO had no direct effect on key regenerative properties of NSCs such as proliferation and differentiation. While, the findings from organotypic spinal cord slice culture showed the astrogliosis and activated microglia were reduced and the outgrowth of the nerve fibres was increased following a combinatorial therapy. This study demonstrates the utility of the organotypic spinal cord slice model to test the efficacy of MINO as a combinatorial therapy with transplanted NSCs.
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Alaedin, MohamadTaher [Verfasser]. "Effect of an inflammatory stimulus on mitochondrial functionality in liver cells of dairy cows / MohamadTaher Alaedin." Bonn : Universitäts- und Landesbibliothek Bonn, 2021. http://d-nb.info/1238687458/34.
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周淑雅 and S. N. Chow. "Investigation of radio- and chemosensitivity mechanisms in Nasopharyngeal Carcinoma cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31224283.
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Martinez, Francisca. "The effect of selected drugs on pokeweed mitogen-stimulated IgG synthesis by human peripheral blood mononuclear cells." Thesis, University of Liverpool, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.279718.
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Ellis, Lucy C. J. "Human and rat multidrug resistance-associated proteins (MRP/Mrp)." Thesis, University of Aberdeen, 2010. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=128325.
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The multidrug resistance associated proteins (MRP(human)Mrp (rat) are ATP-dependent transporters responsible for the efflux of a wide range of substrates, including endogenous compounds e.g. bilirubin, drug metabolites e.g. paracetamol glucuronide and fluorescent dyes e.g. 5 (and 6)-carboxy-2’,7’-dichlorofluorescein (CDF). Mrp1-6 (abccl-6) are expressed in rat liver, with Mrp2 being expressed at the highest level. Isolation of hepatocytes by in situ collagenase perfusion causes bile canalicular disruption and internalisation of Mrp2. Cells cultured in a sandwich configuration of Matrigel or collagen (Type 1) showed bile canalicular reformation at different days in cell culture, depending on the extracellular matrix and time of overlay. We have developed a method for quantifying Mrp-mediated efflux in hepatocytes cultured in a sandwich configuration of collagen (Type 1). This method is unique in its ability to distinguish between sinusoidal efflux, canalicular efflux and diffusion in intact hepatocytes. Alternative in vitro models of Mrp2-mediated efflux include the vesicular (direct and indirect methods) and the ATPase assays. We have used these assays to identify atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin as substrates of human and rat MRP2/Mrp2. A close correlation was seen between the kinetic parameters of transport of the Mrp2 substrate; CDF determined in sandwich cultured rat hepatocytes using the method above (Km = 3.5 – 9.9 μM), vesicle preparations (Km = 37.9 μM) and membrane preparations (Km = 18.7 μM). We also present data to implicate the nuclear receptors, PXR, CAR and FXR in the regulation of abcc2 and abcc3 and PXR and CAR in abcc1 gene regulation. Abcc2 and abcc5 are also up-regulated in response to a toxic insult to the cell, probably via Nrf2 activation, suggesting a role in cell defence.
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Cleveland, Beth Marie. "The effect of [alpha]-aminoadipate [delta]-semialdehyde synthase knockdown on the lysine requirement and urate oxidase knockdown on oxidate stress in a murine hepatic cell line." Morgantown, W. Va. : [West Virginia University Libraries], 2007. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=5272.
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Thesis (Ph. D.)--West Virginia University, 2007.Title from document title page. Document formatted into pages; contains vii, 112 p. : ill. (some col.). Includes abstract. Includes bibliographical references.
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Segolela, Jane Choene. "Potential effect of senna italica on glucose transport receptors - translocation go GLUT4 in NIH-3T3-L1 preadipocytes and C2C12 muscle cells." Thesis, University of Limpopo, 2015. http://hdl.handle.net/10386/1558.
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Thesis (M. Sc. (Biochemistry)) -- University of Limpopo, 2015Diabetes mellitus is one of the major diseases worldwide that is life threatening and is reaching an epidemic proportion. The most important approach in reducing the burden of the disease worldwide is to search for effective, low cost hypoglycaemic drugs with fewer side effects. Past experimental evidence confirmed the hypoglycemic activity of many indigenous African medicinal plants. S. italica (Fabaceae family) is widely used by traditional healers to treat a number of diseases such as sexually transmitted diseases and other forms of intestinal complications traditionally. The current study was aimed at evaluating the in vitro effects of root and leaf extracts of S. italica on GLUT4 translocation in NIH-3T3-L1 preadipocytes and C2C12 muscle cells. In order to address the aim of the study various methods were undertaken. The roots and leaves of S. italica collected from Zebediela sub-region of the Limpopo province, South Africa, were ground to fine powder and extracted using acetone, methanol, ethyl acetate and n-hexane. The various extracts of the root and leaf material were subjected to fingerprint profiling using TLC plates and different mobile phases (BEA, CEF, EMW and BAW). The chromatograms were visualized with vanillin-H2SO4 reagent, p-anisaldehyde and iodine vapour. The extracts were assayed for the type of secondary metabolites contained in the studied plant parts using chemical text and by TLC analysis. The total phenolic content of the root and leaf material were also evaluated. Evaluation for antioxidant activity was performed using 0.2% DPPH qualitatively and quantitatively with vitamin C as a positive control. Toxicity study was performed on C2C12 muscle cells using the MTT assay, with Curcumin as a positive control and untreated cells as a negative control. The CC50 values of the acetone root and leaf extracts were determined by linear regression. The effect of acetone root and leaf extracts on glucose uptake by C2C12 muscle cells was evaluated, also on western blot and immunofluorescence for NIH-3T3-L1 preadipocytes. The solvents employed for extraction in this study are commonly used to extract various biological active compounds from plants in research settings. Methanol extracted more compounds followed by acetone, then ethyl acetate and n-hexane the least. The constituents extracted by methanol may be mostly sugars, amino acids and glycosides due to the polarity of this solvent. Hydro-alcoholic solvents extract a variety of compounds that are mostly polar. Acetone extracts xxii mostly alkaloids, aglycones and glycosides while n-hexane in general extracts mostly waxes, fats and fixed oils. High yield was obtained with leaf extracts with all the solvent used for extraction as compared to the root. The TLC finger-print showed that good separation was achieved with the methanol and acetone extracts in CEF mobile phase, ethyl acetate extracts in CEF and EMW and n-hexane extracts in BEA respectively, especially with the leaf extract. Most compounds present in S. italica extracts were UV active. Some compounds that were not reactive with vanillin-H2SO4 reagent were shown to be reactive with p-anisaldehyde reagent and iodine vapour which revealed the presence of sugars or aromatic compounds. Chemical analysis for secondary metabolites of the acetone root and leaf extracts revealed the presence of flavonoids, terpenes, tannins, steroids, reducing sugars and alkaloids while glycosides were detected only in the leaf extract. The results obtained using TLC analyses were consistent with the results obtained in the chemical analysis. Thin layer chromatography revealed the presence of glycoflavones in the acetone root extract, alkaloids in the root and leaf extracts; and phytosterols and flavonoid aglycones in root and leaf extracts. The acetone root and leaf extracts revealed the presence of phenols. The leaf extract was shown to contain high total phenolic content as compared to the root. The methanol and acetone root and leaf extracts were shown to possess antioxidant activity. However, the concentration of the activity was higher in the acetone root than in the leaf extract. The least activity was observed with the ethyl acetate root and leaf extracts as compared to other extracts. The n-hexane extracts however, was not shown to contain any antioxidant compounds. Although activity observed with the methanol extracts was comparable to that of the acetone extracts in the quantitative assay, the acetone extracts were shown to possess more antioxidant activity in the qualitative assay. The concentration of extracts increased with increase in scavenging activity. The root extract exhibited a more potent antioxidant activity compared to leaf extract. These extracts were evaluated for their cytotoxicity on normal cells. The highest cytotoxic concentration (CC50) was obtained with the root extract with a CC50 value of 297 635 μg/ml at 48 hrs, followed by CC50 value of 21 544 μg/ml at 24 hrs. The CC50 value of the leaf extract at 24 hrs was 2 904 μg/ml with the least value at 48 hrs. The root extract at 24 and 48 hrs together with the leaf extract at 24 hrs were not toxic to C2C12 muscle cells at the concentration tested in this study. The acetone extracts were shown to possibly enhance proliferation of C2C12 muscle cells at a concentration of 0.001–1000 μg/ml. The non-cytotoxic concentration of 25 μg/ml of the leaf extract in combination with insulin showed more glucose uptake as compared to other extracts as well as the control. Prolonged incubation time was shown to increase glucose uptake with leaf extract while increase in concentration of root extract decreased glucose uptake at 24 hrs. At incubation time of 3 and 24 hrs, glucose uptake results at concentration of 2.5 μg/ml were comparable with that of the root extract, with a similar trend observed at 25 μg/ml, although with decrease in uptake. The qualitative and quantitative fluorescence results showed GLUT4 to be translocated to the cell membrane. The leaf extract at a concentration of 25 μg/ml had more fold as compared to other extracts, indicative that more GLUT4 was translocated at this concentration of the leaf extract. The acetone root and leaf extracts were shown to increase protein expression of GLUT4 at 3 hrs incubation time as compared to other incubation times in insulin-stimulated C2C12 muscle cells. The plant constituents of S. italica was shown to contain a variety of secondary metabolites that maybe be acting alone or in concert with each other to exert the various activities observed in this study. Different solvents used for extraction may be responsible for the extraction of different constituents with antioxidant activity observed in the study. The acetone extracts enhanced proliferation of C2C12 muscle cells at concentrations used in the study. However, there was no significant reduction on viability of normal cells. In addition, the extracts were shown to enhance the differentiation of NIH-3T3-L1 preadipocytes into adipocytes and C2C12 muscle cells into myocytes. These in turn induced the translocation of GLUT4 to the cell membrane and as a consequence facilitate glucose transport. Hence, the differentiation of adipose cells as well as glucose uptake of muscle cells and GLUT4 expression might have been enhanced by constituents contained in the acetone extracts. In conclusion, the acetone leaf extract may have a beneficial role in glucose metabolism of differentiated C2C12 muscle cells. Therefore, further studies are however required to elucidate the molecular mechanism by which the acetone leaf extract of S. italica influences the translocation of GLUT4.
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張子臣 and Zichen Zhang. "Anticancer effects of hexamethylene bisacetamide on human colon carcinoma cells in vitro." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B31239766.
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Lau, Ping-woi Echo, and 劉頻迴. "The anti-cancer effect of berberine in a human nasopharyngeal carcinoma cell line HONE 1." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40687697.
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Kourjian, Georgio. "Effect of HIV antiretroviral drugs on antigen processing and epitope presentation by MHC-I to cytotoxic T cells." Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ027/document.
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L’apprêtement antigénique par les protéases intracellulaires et la présentation des épitopes sont essentiels pour la reconnaissance des cellules infectées par les lymphocytes CD8+. Ici nous avons montré que certains inhibiteurs de la protéase de la VIH (IPs) modulent l’activité de la protéasome et aminopeptidase impliqué dans l’apprêtement antigénique endogène et l’activité cathepsins importante dans l’apprêtement croisée. Deux IPs agissent directement sur les cathepsins et leurs régulateurs en inhibant les activités kinase, NOX2 et en régulant le pH phagolysosomal. Les IPs ont changé la dégradation des protéines viral et la production des épitopes de façon séquence- et cellule-spécifique, ont altéré la présentation direct et croisée des épitopes, et ont partiellement changé l’auto-peptidome des cellules primaires. La modulation par les drogues de l’apprêtement et la présentation des épitopes peut fournir une approche thérapeutique alternative pour moduler la reconnaissance immunitaireAntigen processing by intracellular proteases and peptidases and epitope presentation are critical for recognition of pathogen-infected cells by CD8+ T lymphocytes. Here we show that several HIV protease inhibitors (PIs) prescribed to HIV-infected persons variably modulate proteasome and aminopeptidase activities involved in endogenous antigen presentation and cathepsin activities involved in antigen cross-presentation. Two HIV PIs acted directly on cathepsins and on their regulators by inhibiting kinases, NOX2 and the regulation of phagolysosomal pH, subsequently enhancing cathepsin activities. HIV PIs modified HIV protein degradation and epitope production in a sequence- and cell-dependent manner, altered direct- and cross-presentation and T cell-mediated killing, and partly changed the self-peptidome of primary cells. Drug-induced modulation of antigen processing and peptidome may provide an alternate therapeutic approach to modulate immune recognition
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To, Wing Shu. "Effect of cellular redox and energy states on benzo[a]pyrene induced modes of death in the hepa and the HepG2 cell lines." HKBU Institutional Repository, 2010. http://repository.hkbu.edu.hk/etd_ra/1173.
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Allen, Portia SueAnn. "The effect of drugs and nutraceuticals on the prevention and treatment of non-alcoholic fatty liver disease using rats as a model for humans." [Ames, Iowa : Iowa State University], 2010. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:1476270.
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Zhu, Meifen, and 朱玫芬. "Mir-23a involves in the anti-cancer effect of CRAE and berberine in human hepatocellular carcinoma cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46944771.
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劉汝這 and Yue-huen Thomas Lau. "Ultrastructural and stereological investigation of the effects of hexamethylene bisacetamide on human colon carcinoma LoVo cells invitro." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B29872972.
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Zhang, Jin 1960. "The influence of copper deficiency on the binding and uptake of high-density lipoprotein by rat hepatic parenchymal cells." Thesis, The University of Arizona, 1988. http://hdl.handle.net/10150/276935.
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This study was designed to examine the influence of Cu deficiency on the binding, uptake, and degradation of apolipoprotein E-free high density lipoproteins (apo E-free HDL) in cultured rat hepatic parenchymal cells. The binding of apo E-free HDL during time course studies was slightly but significantly increased in cells derived from Cu-deficient rats. In saturation studies, the amount of surface-bound apo E-free HDL appeared to be saturable, although no difference was observed between Cu-deficient and adequate animals. The amount of total and specific cell-associated uptake of apo E-free HDL was significantly increased in hepatic parenchymal cells of Cu-deficient animals. The present data suggest that hepatic uptake of the HDL protein moiety may be increased in rats fed a diet deficient in copper.
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Okoli, Arinze Stanley Medical Sciences Faculty of Medicine UNSW. "Molecular studies of the response of Helicobacter hepaticus to bile, and the effect of Helicobacter bilis on human hepatoma cells." Publisher:University of New South Wales. Medical Sciences, 2009. http://handle.unsw.edu.au/1959.4/43379.
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Enterohepatic Helicobacter species (EHS) are emerging infectious disease agents. Infection of the enterohepatobiliary tract of several mammals by this group of bacteria results in various pathological disorders. The availability of the Helicobacter hepaticus sequenced and annotated genome, allowed molecular characterisation of the responses of H. hepaticus to host factors such as bile. The adaptation/responses of the bacterium to bovine, porcine and human bile were investigated using proteomics and transcriptomics. Ninety-one different proteins were identified in the responses of H. hepaticus response to the three types of bile. These proteins participate in several key cellular processes including DNA replication; protein transcription, translation and folding; oxidative stress response; motility; virulence; and metabolism. In particular, the bacteria deployed several strategies such as inhibition of the TCA cycle and the electron transport chain as well as iron sequestration to ensure control of the levels of hydroxyl radicals. The results of this study revealed also the modulation by bile of the expression of H. hepaticus genes involved in response to oxidative stress and virulence. The responses of human HEp-2 and Huh7-derived cell-lines to H. hepaticus and Helicobacter bilis, respectively, were investigated employing proteomics and transcriptomics. One-hundred and twenty different proteins were differentially expressed in the responses of the human cells to the presence of Helicobacter spp. in the cell cultures. These proteins are involved in regulation of cell proliferation and structure; metabolism; protein transcription, translation and modification; stress response; and tumour induction. For example, in co-cultures of Huh7-derived cells and H. bilis, the activation of several mitochondrial and endoplasmic reticulum stress-related proteins and the dysregulation of several apoptosis effectors were suggested as mechanisms that could result in the death of the liver cells. Importantly, the differential expression of several tumour-related proteins by the Huh7 cells supported a possible role for Helicobacter spp. in liver cancer.
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Caperna, Thomas J. "Metabolism of supplemental iron by hepatic parenchymal and sinusoidal cells of the neonatal pig." Diss., Virginia Polytechnic Institute and State University, 1986. http://hdl.handle.net/10919/49998.
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Methods were developed to isolate and culture the predominant cell types from porcine liver to investigate hepatic accumulation, distribution and intracellular metabolism of supplemental iron. Hepatocytes were prepared from collagenase perfused livers by differential centrifugation, while Kupffer cells and endothelial cells were isolated by centrifugal elutriation. One day old piglets were injected with iron-dextran (Fe-dextran) and the concentration of accumulated iron was determined in all three cell types 1, 5, and 10 days later. The concentration of iron increased markedly in all three cell types when compared to cells isolated from untreated piglets (Kupffer cells > endothelial cells >> hepatocytes). Accumulated iron was subsequently mobilized from all three cell types.
The role of ferritin in metabolism and storage of accumulated iron was investigated. An antiserum was prepared against porcine liver ferritin and the quantity of cellular ferritin was measured by immunoelectrophoresis. The amount of cellular iron associated with ferritin was assessed by ion exchange chromatography. All three types of liver cells accumulated ferritin in response to Fe-dextran treatment. Higher concentrations of ferritin-iron and ferritin-protein were present in Kupffer and endothelial cells than in hepatocytes at all times after iron treatment. However, at 1 day after treatment 48% of the total iron within hepatocytes was associated with ferritin; ferritin-iron accounted for only 10% of total cell iron by day 10. In contrast, ferritin-iron represented only approximately 9% of the total iron in sinusoidal cells throughout the study period.
The possibility that accumulation of Fe-dextran enhanced peroxidation of membrane lipids was evaluated. Lipids extracted from heart and liver of iron-treated piglets contained increased levels of conjugated dienes. High levels of conjugated dienes were present in endothelial cells and hepatocytes 1 day after treatment and only in endothelial cells by day 5. Although Kupffer cells accumulated substantial quantities of Fe-dextran, conjugated dienes were not detectable. These studies indicate that treatment of piglets with Fe-dextran may selectively impair function of hepatic endothelial cells and perhaps hepatocytes, and define new criteria for evaluating compounds that are used for iron supplementation.Ph. D.
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Zhang, Xiaoyan. "The effect of long-term exposure to transforming growth factor-b1 on the spontaneous transformation of cultured rat liver epithelial cells /." Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=56969.
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In contrast to normal cells, most neoplastic cells are resistant to the growth inhibitory effect of the transforming growth factor-$ beta$(TGF-$ beta$). The neoplastic transformation of cultured rat liver epithelial cells induced spontaneously or by chemical carcinogens and oncogenes is consistently associated with the development of resistance to the mito-inhibitory effect of TGF-$ beta$, suggesting that such phenotype plays an essential role during the transformation of these cells. We have studied the development of this "TGF-$ beta$, resistant" phenotype in a clonal strain of early passage normal cultured rat liver epithelial cells whose proliferation is markedly inhibited by TGF-$ beta$. A continuous control culture of these cells results in a gradual but spontaneous development of TGF-$ beta$ resistance. When the same cells were exposed to step-wise increases of the TGF-$ beta$ concentration in the medium, spontaneous transformation occurred significantly earlier than that in the control cells. After the same number of cumulative population doublings, the TGF-$ beta$ treated cells were much more resistant to the mito-inhibitory effect of TGF-$ beta$ than the control cells, and they exhibited an enhanced constitutive expression of the c-myc mRNA. The results suggest that TGF-$ beta$ facilitates or "promotes" spontaneous transformation. The TGF-$ beta$ resistant cells also showed increased resistance to the cytotoxins Adriamycin and Melphalan. This drug resistance was accompanied by an increase in the MDR-1 mRNA level, the cellular content of the glutathione and the activity of glutathione-S-transferase, thus suggesting a close association between the development of the TGF-$ beta$ resistance and the multidrug resistant phenotypes.
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Cakmak, Gulgun. "The Effects Of Radioprotectant Amifostine On Irradiated Rat Brain And Liver Tissues." Phd thesis, METU, 2010. http://etd.lib.metu.edu.tr/upload/12612591/index.pdf.
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Amifostine is the only approved radioprotective agent by the Food and Drug Administration for reducing the damaging effects of radiation on healthy tissues. In this study, the effects of ionizing radiation on rat liver microsomal membrane and brain tissue and the protecting effects of amifostine on these systems were investigated at molecular level. Sprague-Dawley rats, which were administered amifostine or not, were whole-body irradiated and liver microsomal membranes and different regions of the brain of these rats were analyzed using FTIR spectroscopy, FTIR microspectroscopy and synchrotron FTIR microspectroscopy.
The first part of this study revealed that ionizing radiation caused a decrease in the total lipid content and CH2 groups of lipids, an increase in the carbonyl esters, olefinic=CH and CH3 groups of lipids in the white matter and grey matter regions of the brain, which could be interpreted as a result of lipid peroxidation. In addition, radiation altered the protein structure of the brain. Amifostine caused significant protective effect against all the radiation induced damages in the brain.
In the second part of the study, FTIR results showed that radiation induced a decrease in the lipid/protein ratio and a degradation of lipids into smaller fragments that contain less CH2 and more carbonyl esters, olefinic=CH and CH3 groups in microsomal membranes. In addition, radiation caused an alteration in the secondary structure of proteins, an increase in lipid order and a decrease in the membrane dynamics. Amifostine prevented all the radiation induced compositional, structural and functional damages in the liver microsomal membranes.
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Murata, Toru. "Inhibitory effect of Y-27632,a ROCK inhibitor,on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells." Kyoto University, 2002. http://hdl.handle.net/2433/149343.
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Liao, Ximan, and 廖喜漫. "A study of proteoglycan production during suppressed cell proliferation of a human colon carcinoma cell line." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1999. http://hub.hku.hk/bib/B3123897X.
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Takeda, Yoshihisa. "Morphologic alteration of hepatocytes and sinusoidal endothelial cells in rat fatty liver during cold preservation and the protective effect of hepatocyte growth factor." Kyoto University, 1999. http://hdl.handle.net/2433/181710.
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Li, Jing, and 李靜. "Effects of intrinsic & extrinsic factors on the growth and differentiation of human mesenchymal stem cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37238310.
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Roberts, Lindi. "The effect of quinoline anti-malarial drugs on the endolysosomal and secretory pathways of plasmodium falciparum strain 3D7, dictyostelium discoideum and mammalian A549 cells." Master's thesis, University of Cape Town, 2007. http://hdl.handle.net/11427/3298.
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Includes bibliographical references (leaves 92-109).The precise mechanisms of action of the quinoline anti-malarial drugs are uncertain, although they have been found to influence endocytosis, vesicular processing and secretion in malarial parasites and mammalian cells. In this study, the effects of chloroquine, amadiaquine, halofantrine, mefloquine and quinine on the endolysosomal systems in Plasmodium falciparum 3D7, Dictyostelium discoideum and A549 pulmonary cancer cells were examined.
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Tron, Camille. "Étude des relations entre concentrations sanguines, biliaires, intracellulaires, et effet immunosuppresseur du tacrolimus en transplantation hépatique." Thesis, Rennes 1, 2019. http://www.theses.fr/2019REN1B038.
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Le tacrolimus est la pierre angulaire du traitement préventif du rejet de greffe en transplantation hépatique. Les posologies de tacrolimus doivent être adaptées aux patients en fonction des concentrations résiduelles sanguines mesurées tout au long du traitement. Cependant, ce suivi thérapeutique pharmacologique présente des limites puisque la réponse au tacrolimus n’est pas optimale chez tous les patients. Dans ce contexte, ce travail avait pour objectifs d’évaluer l’intérêt de nouveaux biomarqueurs de suivi pharmacologique du tacrolimus chez les patients transplantés hépatiques. Un premier axe de recherche a permis de montrer que la variabilité intra-individuelle des concentrations sanguines était un facteur de risque de perte de greffon et de survenue de toxicités. Dans la seconde partie du travail, une méthode de dosage du tacrolimus dans la bile a été développée, un métabolite glucuronide direct du tacrolimus a été mis en évidence dans la bile des patients, et la concentration biliaire a été identifiée comme un potentiel biomarqueur prédictif de la neurotoxicité de l’immunosuppresseur. La dernière partie du travail s’est consacrée à l’étude in vitro et in vivo des relations entre l’exposition sanguine, l’exposition intra-cellules mononuclées sanguines et l’effet pharmacodynamique du tacrolimus sur sa cible la calcineurine. L’ensemble de ces travaux de pharmacologie translationnelle ont permis d’améliorer la compréhension de la relation exposition-effet du tacrolimus et d’identifier de nouveaux biomarqueurs qui pourraient permettre de faire un pas en avant dans l’optimisation et la personnalisation du traitement immunosuppresseur des transplantés hépatiquesTacrolimus is the cornerstone of preventive treatment of allograft rejection in liver transplantation. Tacrolimus dosages must be tailored according to trough whole-blood concentrations measured all along the therapy. However, this therapeutic drug monitoring approach has some limitations since tacrolimus response is not optimal for all patients. In this context, this work aimed at evaluating the interest of alternative pharmacological biomarkers of tacrolimus monitoring in liver transplant recipients. The first part of the research led to emphasize that intra-patient variability of tacrolimus trough whole-blood concentrations was a risk factor for graft loss and drug side effects. In the second part of the work, an analytical method of quantification of tacrolimus in bile was developed, evidences of the presence of tacrolimus direct-glucuronide metabolite in bile were provided and tacrolimus bile concentration was found to be a potential predictive biomarker of the drug neurotoxicity onset. The last part of the work was focused on in-vitro and in-vivo studies of the relationships between tacrolimus blood and intracellular exposures and its pharmacodynamic effect on its target calcineurin. Taken together, this translational pharmacology research program led to improve our understanding of tacrolimus exposure-effect relationship and to identify new biomarkers that could allow making a step forward in optimizing and personalizing the immunosuppressive treatment in liver transplant recipients
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Paun, Andrea. "Regulator T cells in murine AIDS." University of Western Australia. Microbiology and Immunology Discipline Group, 2005. http://theses.library.uwa.edu.au/adt-WU2005.0115.
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[Truncated abstract] In the last ten years regulator T (Tr) cells have re-emerged as an integral part of the immune system. Research in this field has rapidly demonstrated the role of these cells in the maintenance of immune homeostasis and their involvement in disease. Tr cells are generated in the thymus as a normal part of the developing immune system. Furthermore, antigen-specific Tr cells are induced in the periphery by a mechanism which is yet to be completely elucidated, but is likely to involve dendritic cells. Tr cells play an important role in autoimmune disease, transplantation tolerance, cancer. Most recently Tr cell involvement has been demonstrated in a growing number of infectious diseases. Tr cell induction was reported in Friend Virus infection at the commencement of this study, and subsequent to publication of our findings have also been identified in FIV and HIV. Murine AIDS (MAIDS) is a fatal chronic retroviral infection induced in susceptible strains of mice by infection with BM5d, a replication defective virus, in a viral mixture which is designated LP-BM5. The manipulation of Tr cells detailed in this thesis and the related publication represent the first reported therapy utilising targeted removal of Tr cells. Chapter 1 summarises the literature relevant to this study up to November 2004. Chapter 2 details the materials and methodologies used in this work. Chapter 3 investigates whether Tr cells are involved in the development of murine AIDS, particularly in the early stages of infection. The data presented in this chapter provides evidence of a population of CD4+ Tr cells which express CD25 on their cell surface and secrete TGF-β, some IL-10 and low levels of IL-4 are induced following infection with LP-BM5. These cells were found to arise by day 12 post infection (pi) by flow cytometry and immunosuppressive cytokine expression was found to peak at day 16 pi indicating a role in the early stages of disease progression. Chapter 4 investigates the effect of therapeutically targeting these induced Tr cells using the antimitotic agent Vinblastine during their induction period. The efficacy of treatment was found to be time dependent and was shown to abrogate disease progression maximally when given at day 14 pi. Treatment with anti-CD4 monoclonal antibody was also found to be efficacious at day 14 pi and confirmed the identity of the Tr cells as being CD4+ T cells. Adoptive transfer studies demonstrated that the return of these cells to a successfully treated host results in renewed MAIDS progression, confirming their role in disease progression
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Nicholls-Grzemski, Felicity April. "The effect of short-term pretreatment with peroxisome proliferators on the acute toxicity of various toxicants, including paracetamol / Felicity April Nicholls-Grzemski." Thesis, 1998. http://hdl.handle.net/2440/19434.
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Erratum tipped in before chapter 1.Bibliography: leaves 226-248.
xv, 248 leaves : ill. (chiefly col.) ; 30 cm.
Shows that pretreatment with peroxisome proliferators protects mice against the acute hepatotoxicity of paracetamol, in addition to a number of other toxicants.
Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1999
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Bruschi, Sam A. (Sam Anthony). "Investigations into mechanisms of paracetamol-induced toxicity using ìn vitro' systems." 1987. http://web4.library.adelaide.edu.au/theses/09PH/09phb192.pdf.
Full text
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Bruschi, Sam A. (Sam Anthony). "Investigations into mechanisms of paracetamol-induced toxicity using in vitro' systems / by Sam A. Bruschi." 1987. http://hdl.handle.net/2440/18564.
Full textAbstract:
Bibliography: leaves 116-138[14], 138 leaves, 5 leaves of plates : ill ; 30 cm.
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical & Experimental Pharmacology, 1988