Dissertations / Theses: 'Radiation induced liver disease'

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Boutin, Samuel R. 1952. "Molecular pathogenesis of Helicobacter hepaticus induced liver disease." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/35696.

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Thesis (Ph. D. in Molecular and Systems Bacterial Pathogenesis)--Massachusetts Institute of Technology, Biological Engineering Division, 2005.
This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Includes bibliographical references.
Helicobacter hepaticus infection of A/JCr mice is a model of liver cancer resulting from chronic active inflammation. We monitored hepatic global gene expression profiles and correlated them to histological liver lesions in H. hepaticus infected and control male A/JCr mice at 3 months, 6 months, and 1 year of age. We used an Affymetrix-based oligonucleotide microarray platform on the premise that a specific genetic expression signature at isolated time points would be indicative of disease status. Model based expression index comparisons generated by dChip yielded consistent profiles of differential gene expression for H. hepaticus infected male mice with progressive liver disease versus uninfected control mice within each age group. Linear discriminant analysis and principal component analysis allowed segregation of mice based on combined age and lesion status, or age alone. Up-regulated genes present throughout the 12 month study involved inflammation, tissue repair, and host immune function. Upregulation of putative tumor and proliferation markers correlated with advancing hepatocellular dysplasia. Transcriptionally down-regulated genes in mice with liver lesions included those related to peroxisome proliferator, cholesterol, and steroid metabolism pathways. Transcriptional profiling of hepatic genes documented gene expression signatures in the livers of H. hepaticus infected male A/JCr mice with chronic progressive hepatitis and preneoplastic liver lesions, complemented the histopathological diagnosis, and suggested molecular targets for the monitoring and intervention of disease progression prior to the onset of hepatocellular neoplasia. Our laboratory, in collaboration with Professors Suerbaum and Schauer, recently identified a
(cont.) 70kb genomic island in Helicobacter hepaticus strain ATCC 51488 as a putative pathogenicity island (HhPAI) (Suerbaum et al, PNAS, 2003). This region within H. hepaticus contains genes HH0233-HH0302, a differential GC content, several long tandem repeats but no flanking repeats, and three components of a type IV secretion system (T4SS). A/JCr mice were experimentally infected with three naturally occurring strains of H. hepaticus including the type strain H. hepaticus ATCC 51488 strain (Hh 3B1) isolated from A/JCr mice, MIT 96-1809 (Hh NET) isolated from mice shipped from the Netherlands, and MIT-96-284 (HhG) isolated from mice acquired from Germany.4 HhNET (missing most of the HhPAI) infected male A/JCR mice exhibited a significantly lower prevalence (p<.05) of hepatic lesions at 6 months post infection than Hh 3B1 with an intact HhPAI. Hh G also has a large segment of the genomic island deleted, but not as many genes are deleted as compared to Hh NET. Hh G also demonstrated a lower prevalence of hepatic lesions. This variable pathological effect was evident in male mice only. The severity of chronic active inflammation in the liver of the H. hepaticus infected A/JCr mice depended on H. hepaticus liver colonization levels. The in vivo results support the presence of the HhPAI as a legitimate virulence determinant and predictor of severity of liver lesions in H. hepaticus infected A/JCr male mice. To further determine the differences in virulence of the H. hepaticus strains Hh 3B1, Hh NET, Hh G and an isogenic mutant H. ...
by Samuel R. Boutin.
Ph.D.in Molecular and Systems Bacterial Pathogenesis

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Paun, Mihaela. "Detecting genetic variants in radiation-induced lung disease." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119560.

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Thoracic radiotherapy, a common treatment modality for thoracic cancers, has pulmonary side-effects of either excessive inflammation (alveolitis), or pulmonary fibrosis consisting of uncontrolled deposition of collagen in the lungs, for which no cure exists. Prior knowledge, before radiotherapy, of patients genetically predisposed to fibrosis would improve cancer treatments. Based on the known similarities between human and mouse responses to lung irradiation, we used a murine model to detect molecular pathways, immune mechanisms and genetic variants associated with the development of fibrosis. Through a gene expression study in the lungs of fibrosis-prone C57Bl/6J and alveolitis-prone A/J and C3H/HeJ mice we found that several inflammatory pathways are significantly altered and differentiate between alveolitis- and fibrosis-prone mice and that Cell Adhesion Molecule signaling is the most significantly perturbed pathway in all strains. The differences in fibrosis between inbred mice led us to perform a genome-wide association analysis in a panel of 27 strains. We found several variants in immune genes associated with fibrosis, among which several SNPs upstream of Cell adhesion molecule 1 (Cadm1), a promising potential candidate gene for susceptibility to fibrosis. The role of immunity in lung disease prompted the investigation of mice lacking Tlr2 and/or Tlr4 receptors in response to thoracic irradiation. While Tlr2-/- and Tlr4-/- mice did not differ from C57Bl/6J wildtype, Tlr2,4-/- mice have decreased survival and more severe fibrosis compared to irradiated wildtype animals. Subsequent analyses of lymphocytes infiltrating the lungs after thoracic irradiation revealed the more severe fibrosis in the Tlr2,4-/- strain to be due to increased production of Il6, Tgfβ and Il17 and lack of protective Ifnγ. These studies also showed the pro-fibrotic role of Il17, as Il17-/- mice do not develop the disease. To summarize, in this thesis we identified immune pathways and several candidate genes associated with the presence of fibrosis following thoracic radiation. We also showed that disease development is dictated, in part, by Tlr signaling and disequilibrium between pro- and anti-fibrotic cytokines.
La radiothérapie thoracique, un traitement commun pour les cancers de la cavité thoracique, a des effets secondaires au niveau des poumons: l'inflammation excessive (alvéolite) ou la fibrose pulmonaire qui consiste d'un dépôt incontrôlable de collagène dans les poumons, et pour laquelle aucun traitement n'existe. La connaissance a priori, avant l'administration de la radiothérapie, des patients susceptibles au développement de la fibrose, améliorerait considérablement les traitements du cancer. Étant données les similarités des réponses à la radiation entre l'homme et la souris, nous avons utilisé un modèle murin pour la détection des voies moléculaires, mécanismes immunitaires et des variantes génétiques associés avec le développement de la fibrose pulmonaire. A travers une étude d'expression des gènes sur les poumons des souris susceptibles à la fibrose, C57Bl/6J et à l'alvéolite, A/J and C3H/HeJ, nous avons identifié certaines voies inflammatoires significativement impactées par le traitement et différentient entre les souches susceptibles à la fibrose, et celles succombant à l'alvéolite. Parmi celles-ci, la voie de Signalisation des Molécules d'Adhésion Cellulaire est la plus perturbée dans toutes les souches. Pour déterminer la composante génétique qui détermine les différences en degré de fibrose parmi les souches des souris consanguines, nous avons fait une analyse d'association pan-génomique sur un groupe de 27 souches de souris. Nous avons identifiés plusieurs variants associés à la fibrose, situés dans des gènes immunitaires, parmi lesquels, plusieurs SNPs dans le gène Cadm1 (Cell Adhesion Molecule 1). Étant donné le rôle de l'immunité dans la maladie pulmonaire, nous avons testé la réponse des souris manquant les récepteurs Tlr2 et/ou Tlr4 à la radiation thoracique. Tandis que les souris Tlr2-/- et Tlr4-/- ne diffèrent pas dans leur phénotype de la souche sauvage C57Bl/6J, les souris Tlr2,4-/- succombent plus tôt, a une fibrose plus sévère que les souris sauvages. Des analyses ultérieures sur les lymphocytes qui s'infiltrent dans les poumons à la suite de la radiation, ont démontré que la fibrose plus sévère chez les souris Tlr2,4-/- est due à une production augmentée des cytokines Il6, Il17 et Tgfβ et à l'absence du Ifnγ qui a un rôle protecteur. Ces études ont aussi montré le rôle pro-fibrotique du Il17, étant donné que les souris Il17-/- ne développent pas la maladie. Pour conclure, dans cette thèse nous avons identifié des voies de signalisation immunitaires et plusieurs gènes candidats associés avec la présence de la fibrose suivant la radiation thoracique. Nous avons aussi montré que le développement de la maladie est dicté, en partie, par la voie de signalisation des récepteurs Tlr et aussi par un déséquilibre entre les cytokines pro- et anti-fibrotiques.

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Tomko, Tomasz. "Genetics of radiation-induced lung disease in the mouse." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114227.

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Radiation therapy of the thorax may result in side effects such as alve- olitis and pulmonary fibrosis, both of which limit the efficacy of cancer therapy. Previously, it was determined that mice congenic on chromosomes 2, 4 and 11 succumb to radiation-induced lung disease significantly faster than C57BL/6J mice. Herein we use chromosome 4 and 11 congenic strains and chromosome 4 sub-congenic strains to identify radiation-induced lung response susceptibility loci in C3H/HeJ congenic mice on a C57BL/6J background. Mice were treated with 18-Gy whole-thorax irradiation and their survival, lung histopathology, and BAL cell types were determined. All protein coding genes within the congenic regions were analyzed in silico and a QTL-wide association study was completed for each congenic region using the survival time phenotypes of 27 inbred strains. The C3H/HeJ strain succumbed to radiation-induced lung disease significantly faster than the C57BL/6J strain and exhibited an increase in the percentage of neutrophils combined with a decrease in the percentage of macrophages in the BAL. The survival time phenotype of the chromosome 4 congenic and sub-congenic strains, as well as the chromosome 11 congenic strain, did not differ from the C57BL/6J response. The chromosome 11 congenic strain exhibited a significant increase in alveolitis, fibrosis, and percentage of lymphocytes in the BAL in addition to a decrease in the percentage of macrophages compared to the C57BL/6J strain. Only one of five chromosome 4 sub-congenic strains differed in response from the C57BL/6J strain, these differences included a decrease in the percentage of macrophages and an increase in the percentage of lymphocytes in the BAL. In silico analysis of congenic regions decreased the number of probable candidate genes by 69% and a QWAS on the chromosome 2 congenic region determined a significant association with a SNP located in the first intron of the Wfdc8 gene. In this animal model, a locus on chromosome 2 appears to be associated with the survival time phenotype of whole-thorax irradiated mice.
La radiothérapie du thorax peut entraîner des effets secondaires tels que l'alvéolite et la fibrose pulmonaire, les deux qui limitent l'efficacité de la thérapie du cancer. Auparavant, il a été déterminé que les souris congéniques sur les chromosomes 2, 4 et 11 succombent à la maladie induite par le rayonnement du poumon significativement plus rapide que les souris C57BL/6J. Ici, nous utilisons le chromosome 4 et 11 souches congéniques et le chromosome 4 sous-souches congéniques pour identifier les radio-induites loci de susceptibilité dans pulmonaires réponse des souris C3H/HeJ congéniques sur un fond C57BL/6J. Les souris ont été traitées avec 18 Gy d'irradiation du thorax entier et leur survie, du poumon histopathologie et types de cellules BAL ont été déterminées. Toutes les gènes codant des protéines à l'intérieur des régions congéniques ont été analysés in silico et une étude de QTL à l'échelle association a été effectuée pour chaque région congéniques utilisant les phénotypes de temps de survie de 27 souches consanguines. La souche C3H/HeJ succombé à la maladie pulmonaire induite par un rayonnement beaucoup plus rapidement que la souche C57BL/6J et présentaient une augmentation du pourcentage de neutrophiles et de la baisse du pourcentage de macrophages dans la BAL. Le phénotype temps de survie des 4 chromosomes souches congéniques et sous-congéniques, ainsi que le chromosome 11 souches congéniques, ne diffère pas de la réponse C57BL/6J. Le chromosome 11 souche congénique a montré une augmentation significative de l'alvéolite, fibrose, et le pourcentage de lymphocytes dans le LBA en plus d'une diminution du pourcentage de macrophages par rapport à la souche C57BL/6J. Seulement l'un des cinq sous-chromosome 4 souches congéniques différente en réponse à partir de la souche C57BL/6J, ces différences inclus une diminution du pourcentage de macrophages et une augmentation du pourcentage de lymphocytes dans la BAL. Une analyse in silico des régions congéniques diminué le nombre de gènes candidats probables de 69% et un QWAS sur le chromosome 2 congéniques région déterminée une association significative avec un SNP situé dans le premier intron du gène Wfdc8. Dans ce modèle animal, d'un locus du chromosome 2 semble être associé avec le phénotype de toute la durée de survie des souris irradiées-thorax.

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Barnes, Mark Aaron Jr. "MACROPHAGE MIGRATION INHIBITORY FACTOR AND LIVER DISEASE: THE ROLE OF MIF IN ALCOHOL-INDUCED LIVER INJURY AND CARBON TETRACHLORIDE (CCI4)-INDUCED LIVER FIBROSIS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396429556.

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Alghamdi, Shareefa. "Consequences of non-alcoholic fatty liver disease on drug-induced hepatocytoxicity." Thesis, University of Surrey, 2015. http://epubs.surrey.ac.uk/808210/.

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Non-alcoholic fatty liver disease (NAFLD) is characterised by the accumulation of lipid in liver. Liver is the principal organ involved in drug biotransformation. The central hypothesis of this project is that alterations in the liver environment due to lipid accumulation aggravate sensitivity of hepatocytes to toxicity of some commonly prescribed drugs (paracetamol, alcohol, phenobarbital, cisplatin or doxorubicin). The aim of this study was to investigate the effect of lipid overloading (steatosis) on drug cytotoxicity in the liver model Huh7 cell line. Hepatic steatosis was induced in Huh7 cells by exposing cells to 300 μM FFA mixture or 1 mM oleic acid. Impact of steatosis on drug toxicity was examined by co-treating the cells with FFA and paracetamol, alcohol, phenobarbital, cisplatin or doxorubicin. Cell viability MTT assay showed that neither 300 μM FFA mixture nor 1 mM OA caused significant reduction in cell viability after 24 h incubation. However, a significant reduction seen after incubation for 48 h, therefore for the subsequent experiments the time frame chosen was 24 h. The results showed that 300 μM FFA mixture did not induce a significant amount of intracellular lipid, whereas 1 mM OA induced significant amount of intracellular lipid. The subsequent experiments were carried out to test the hypothesis that lipid-loaded Huh7 cells are more sensitive to drug toxicity. Co-treatment with FFA and either paracetamol, ethanol or doxorubicin resulted in further reduction in cell viability. Phenobarbital resulted in enhanced cell viability, and no significant changes in cell viability observed after co-treatment with cisplatin. To investigate mode of cell death, caspase3/7 activity was measured as mediator of apoptosis. Generally, an advance apoptosis was observed in steatotic cells treated with the different drugs. Reactive oxygen species were measured as a possible trigger of apoptosis. A significant amount of ROS were generated by FFAs, and generally, drug treatment induced a higher significant amount of ROS in the steatotic Huh7 cells. To elucidate the specific changes observed upon treatment of steatotic cells with hepatotoxic drugs, a single FFA dose (300 μM FFA mixture) and a single drug (doxorubicin) were selected to identify major alterations in gene expression. The microarray data confirmed alterations in oxidative stress-related genes. Such changes were functionally relevant as confirmed by cellular assay and In-Cell Western blot. In conclusion, the hypothesised effect of steatosis on drug toxicity has been confirmed and steatosis may enhance drug toxicity through changing cellular oxidative state and activating the apoptotic pathway.

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Bégin, Michelle Anne. "Identifying quantitative trait loci involved in radiation-induced lung disease in mice." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=99321.

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The goal of this thesis was to identify genetic loci involved in radiation-induced lung disease in mice. Phenotypic analysis was completed for alveolitis, pulmonary fibrosis, survival time, mast cells/mm2 and cell counts in bronchoalveolar lavage (BAL) to assess lung damage. Genome scans and linkage analysis were completed for two backcross cohorts (75%C3H/HeJ-25%C57Bl/6J or 25%C3H/HeJ-75%C57BU6J) using each of the phenotypes measured. Putative susceptibility loci were identified for alveolitis on chromosomes 12 (LOD=3.35), 14 (LOD=2.22) and 19 (LOD=1.7) in the mostly C3H/HeJ backcross cohort and on chromosome 14 (LOD=2.7) in the mostly C57BI/6J backcross cohort. Linkage using the pulmonary fibrosis scores provided supportive evidence for a quantitative trait loci (QTL) on chromosome 17 (LOD=2) in the mostly C57BI/6J background, and two unique putative linkage regions were localized on chromosome 2 (LOD=2.2) in the mostly C3H/HeJ cohort and 14 (LOD=2) in the mostly C57BI/6J cohort. Supporting evidence for linkage on chromosomes 12 and 14 in the mostly C3H/HeJ background and chromosome 14 in the mostly C57BI/6J background was obtained using cellular markers. Additionally, survival time mapped to the linkage regions isolated for alveolitis and pulmonary fibrosis, suggesting that the development of radiation-induced lung disease influences the survival time of the mice. Within each cohort there were sex dependent linkage intervals, indicating that male and female mice may possess different factors involved in the development of alveolitis and/or pulmonary fibrosis. These results suggest that there are multiple genetic loci involved in the development of radiation-induced lung disease in mice.

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Martin, Daniel Richard. "The Role of Phosphohistidine Phosphatase 1 in Ethanol-induced Liver Injury." Scholar Commons, 2018. http://scholarcommons.usf.edu/etd/7194.

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Chronic liver diseases, which includes alcoholic liver disease (ALD), are consistently among the top 15 leading causes of death in the United States. ALD is characterized by progression from a normal liver to fatty liver disease (hepatic steatosis), which can lead to cirrhosis, alcoholic hepatitis, and liver failure. We have identified a novel role of phosphohistidine signaling, mediated through phosphohistidine phosphatase 1 (PHPT1), in the onset of hepatic steatosis. We have identified PHPT1 as a target of selective oxidation following acute ethanol exposure as well as being downregulated following chronic ethanol exposure. We mapped the oxidative modification site and developed a mass-spectrometry based phosphohistidine phosphatase assay to determine the impact of PHPT1 oxidative modification during acute ethanol exposure. To further understand the role of PHPT1 and phosphohistidine signaling during chronic ethanol exposure, we have developed PHPT1 overexpression and knockout mouse models. These mouse models were characterized using mass spectrometry-based proteomics. They were then utilized in a 10-day chronic ethanol plus binge model to determine the impact of PHPT1 expression on the onset of ethanol-induced hepatic steatosis. In addition, advanced mass spectrometry-based phenotypic characterization was performed on the treated liver tissues to determine the key regulators and canonical pathways influencing phosphohistidine signaling during chronic ethanol exposure. We have evidence to suggest that PHPT1 overexpression plays a protective role in the onset of hepatic steatosis, the PHPT1 heterozygous model is more susceptible to liver damage, and the complete knockout model is embryonically lethal. Additionally, we have identified novel pathways and regulators involved in phosphohistidine signaling during the development of ethanol-induced hepatic steatosis.

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Schultes, Klaus. "Ultrastructural characterization of ultraviolet induced corneal disease : an animal model." Master's thesis, University of Cape Town, 1994. http://hdl.handle.net/11427/27046.

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The majority of ancient people worshipped the sun and viewed it as a health - bringing deity. During the eighteenth and nineteenth century therapeutic benefits of sunlight exposure were beginning to be understood and by the end of the nineteenth century the importance of ultraviolet radiation was being realized. Danish physician Niels Finsen, whom many regard as the father of ultraviolet phototherapy, also stressed that it was ultraviolet radiation in the solar spectrum which cause sunburn. We now recognize that the small portion of ultraviolet radiation which reaches the earth's surface is not necessarily therapeutic, but in fact could be harmful to humans. There are numerous accounts of the harmful effects of UV radiation to the skin and the eye as a whole. These effects may be caused by either acute or chronic exposure to UV radiation. For example, some acute effects of UV-B radiation include conjunctivitis and photokeratitis. "Snow blindness" and "arc welders eye" are further examples of acute ultraviolet damage specifically to the surface of the cornea. On the other hand, chronic exposure to ultraviolet radiation is thought to be responsible for pterygia, climatic droplet keratopathy Hill and Maske (1989), cancers of the external eye, cataracts and various types of retinal diseases. The present study is an extension of ongoing studies on ultraviolet radiation damage to the cornea in the Department of Ophthalmology, University of Cape Town and Groote Schuur Hospital. Their specific interest lies in the causes and treatment of climatic droplet keratopathy. The aims of the present study are: 1) Establish a possible role of ultraviolet B radiation in human corneal diseases such as climatic droplet keratopathy and pterygium using the rabbit as an animal model. 2) Determine by means of SEM the initial effects and subsequent recovery of the epithelium after a 3-hour dose of ultraviolet B radiation. We refer to this study as "acute" response to ultraviolet B radiation. 3) To try and confirm the effects observed by SEM with ultrastructural studies using TEM. 4) In addition, we are also looking at the possible effects after exposing rabbit cornea to a daily dose of low level ultraviolet B radiation, over a long period of time. We refer to this as chronic exposure to ultraviolet B radiation. It is hoped that by exposing rabbits to ultraviolet light, principally ultraviolet B radiation, diseases similar to those found in humans could be simulated and disease progression studied. People are generally exposed to substantial amounts of UV radiation for a very long time. Since people generally live longer they will be exposed to an ever-increasing amount of solar UV radiation and subsequently, there is an increasing risk of developing corneal diseases. The possible threat to the ozone is also a real possibility and could lead to increased levels of ultraviolet radiation reaching the earth's surface. This will require a greater understanding of the very nature of corneal damage due to acute and chronic exposure. This study focusses mainly on the acute response to UV-B radiation since most studies have investigated effects of prolonged exposure to UV light. Accordingly, much less is known about acute exposure. Many people suffering from acute UV B radiation effects probably never visit the ophthalmologist or wait for a couple of days. This could also contribute to the fact that effects of short-term damage is not well documented.

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Taylor, Carolyn W. "Breast cancer radiotherapy and heart disease." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:c9dda3ca-8cb3-4a38-938d-0b75b4f6471d.

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Introduction: Some past breast cancer radiotherapy regimens led to an increased risk of death from heart disease. Although heart dose from breast cancer radiotherapy has generally reduced over the past few decades, there may still be some cardiac risk. Estimation of future risk for women irradiated today requires both measurement of their cardiac dose and dose-response relationships, which depend on cardiac dosimetry of past regimens, in conjunction with long-term follow-up data. Methods: Virtual simulation and computed tomography 3-dimensional treatment planning on a representative patient were used to estimate mean heart and coronary artery doses for women irradiated since 1950 in 71 randomised trials in the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) overview. Patient-to-patient variability in cardiac dose was assessed. Heart and coronary artery doses were also calculated for breast cancer radiotherapy regimens used since the 1950s in Sweden. Cardiac doses from contemporary (year 2006) radiotherapy were assessed for 55 patients who received tangential breast cancer irradiation at a large UK radiotherapy centre. The maximum heart distance (i.e. the maximum distance between the anterior cardiac contour and the posterior tangential field edges) was measured for the left-sided patients, and its value as a predictor of cardiac doses assessed. Results: Mean heart dose for women irradiated in the EBCTCG trials varied from <1 to 18 Gray, and mean coronary artery dose from <1 to 57 Gray. Patient-to-patient variability was moderate. Mean heart dose for women irradiated in Sweden since the 1950s varied from <1 to 24 Gray, and mean coronary artery dose from <1 to 46 Gray. Heart dose from tangential irradiation has reduced over the past four decades. However, mean heart dose for left-sided patients irradiated in 2006 was 2 Gray and around half of them still received >20 Gray to parts of the heart and left anterior descending coronary artery. For these patients, maximum heart distance was a reliable predictor of cardiac doses. For the other patients, mean heart dose varied little and was usually less than 2 Gray. Conclusions: Cardiac doses from breast cancer radiotherapy can be estimated reliably and are now available for use in deriving dose-response relationships in the EBCTCG data and in a Scandinavian case-control study. Cardiac dose has reduced over the past four decades. Therefore the cardiac risk is also likely to have reduced. Nevertheless, for some patients, parts of the heart still receive >20 Gray in the year 2006.

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Sethi, Mieran Kaur. "Xeroderma pigmentosum : a disease model for clinical, cellular and molecular consequences of ultraviolet radiation-induced damage." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/xeroderma-pigmentosum(e3241e71-b997-4830-826c-06c898c76a59).html.

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XP is considered a disease of failed repair of direct UVR-induced DNA photoproducts, leading to severe sunburn, extremely high rates of skin cancer, and death in young adulthood from complications relating to malignancy and neurodegeneration. Most experiments in the literature on XP cells, both for diagnosis and interpretation of photobiological processes, have used non-solar UVC radiation. Discernable differences in clinical phenotype have emerged from long-term follow-up of XP patients in the UK National XP clinic. The development of a sunburn severity score revealed that XP-C, XP-E and XP-V patients have normal sunburn reactions; a cohort of milder XP-A patients has been identified, arising from a likely founder mutation yielding less than 5% read-through of normal XPA protein. Deep phenotyping, including the development of ocular and neurological severity scores, has resulted in precise correlation of XP phenotype with the causal mutation, enabling the development of personalized prognostic advice for XP patients worldwide. Based on XP phenotype patterns, molecular experiments were conducted on skin fibroblasts from a range of XP complementation groups using environmentally relevant 385nm UVA-1 compared with 254nm UVC. UVA-1 was a more effective inducer of MMP mRNA and protein than UVC, by a mechanism independent of CPD. MMP upregulation was proportional with ROS generation, and this effect was attenuated when vitamin E was added to cell culture, providing indirect evidence that UVA-1-induced ROS was the main cause of MMP upregulation. The effects of UVA in XP literature have been largely ignored; studies here highlight that XP is a disease of impaired defenses against direct and indirect UVR-induced damage, which may explain sunburn, photoageing, skin cancer and neurological phenotype. These studies demonstrate the importance of translational research in this rare genetic disease. Photoprotection from solar-UVA, together with antioxidants, may provide a future gold standard for photoageing in the general population.

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Jemail, Leila. "Pivotal roles of Kupffer cells in the progression and regression of DDC-induced chronic choangiopathy." Kyoto University, 2019. http://hdl.handle.net/2433/242350.

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Lee, Matthew L., and Jonathan M. Peterson. "CTRP3 Protects Liver Cells From Alcohol-Induced Damage, But Not Through Enhanced Akt Signaling Type." Digital Commons @ East Tennessee State University, 2014. https://dc.etsu.edu/etsu-works/70.

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Alcoholic fatty liver disease (AFLD) is a significant public health concern. Excessive alcohol (ethanol) consumption causes liver cell damage and death, which results in eventual failure of the liver and death. AFLD is the number one cause of liver-related mortality in the United States. Our lab works with the novel protein C1q TNF Related Protein 3 (CTRP3), which inhibits non-alcoholic fatty liver disease, however the effects on AFLD are unknown. Therefore, the purpose of this experiment is to determine if CTRP3 prevents ethanol-induced liver cell death. The H4IIE rat hepatoma cell line was chosen for experimentation as a cell culture model of liver tissue. To determine a suitable alcohol level H4IIE cells were treated with 50, 100, and 200 mmol of ethanol for 18-24 hours. Trypan Blue was used to identify the dead/damaged cells, as only dead/damaged cells will be stained blue with this protocol. We observed that 100 mmol of ethanol consistently induced ~10% mortality rate in these cells. Next, we tested the ability of CTRP3 to reduce ethanol-induced mortality. We added purified CTRP3 protein to the cell media along with the 100 mmol ethanol treatment. The addition of CTRP3 reduced the amount of alcohol-induced cell death/damage in the H4IIE cell line by approximately 60%. Our next goal was to determine how CTRP3 reduces ethanol-induced death. The Akt signaling pathway is a well-known inhibitor of cell death. Therefore, to determine if CTRP3 attenuated ethanol-induced cell damage/death through activation of the Akt signaling pathway, another set of cells was treated with 100 mmol of ethanol and CTRP3 (with or without insulin). Western blots were used to compare the amount of active Akt (phosphorylated) in the CTRP3-treated and non-treated cells. A Western blot utilizes an electric current to separate denatured protein samples on a SDS-page gel, separating the proteins based on size. The smaller the protein the faster it migrates across the gel. The proteins are then transferred to a membrane for analysis, through exposure to commercial antigens and chemiluminescence imaging. There was no change in the amount of total or active Akt between the samples treated with or without CTRP3. We conclude that CTRP3 protects liver cells from ethanol-induced damage/death, but not through activation of the Akt pathway.

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Bellos, Damien A. "The Protective Role of Specifically-Sized Hyaluronan in Ethanol-Induced Liver Injury and Gastrointestinal Permeability." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1504885141094526.

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Nilsson, Kenneth. "Radiation induced pneumonitis : clinical and experimental studies with special emphasis on the effect of smoking." Doctoral thesis, Umeå universitet, Onkologi, 1992. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-100545.

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Bronchoalveolar lavage (BAL) is an established method providing diagnostic support and evaluation of disease activity in interstitial lung disease (ILD). The aims of the present investigation were 1) to study the inflammatory response in pneumonitis evoked by irradiation. 2) to evaluate how well lung tissue inflammation is reflected in BAL findings. 3) to study the effect of smoking on radiation-induced pneumonitis. BAL was performed in 21 patients (11 smokers, 10 non-smokers) who were treated for breast cancer, stage 1 (TjMaNq) by post-surgery irradiation to an accumulated target dose of 56 Gy. It was founa that irradiation induced an alveolitis in the non-smoking patient group while the smoking patients did not differ from their smoking controls. The alveolitis in non-smokers was characterized by an increase in lymphocytes, mast cells and elevated concentrations of hyaluronan (HA), and fibronectin (FN). Three of the non-smoking patients had chest X-ray infiltrates indicating the presence of pneumonitis. An animal experimental model for radiation-induced pneumonitis and fibrosis was established in rats, allowing comparative analysis of BAL fluid and morphology. In the rat model a divergence was noted between the differential cell counts in BAL and cells observed in the interstitial tissue, which was most notable for neutrophils (PMN) and mast cells whereas there was a good correlation between HA content in BAL and HA deposition in the lung tissue. A marked infiltration of intraseptally-located mast cells occurred during the pneumonitis-phase, and this increase was paralleled by a deposition of HA in the interstitial tissue. Histochemical fixation and staining properties of the mast cells revealed that the majority of these cells were of connective tissue mast cell type (CTMC). Compound 48/80, a mast cell secretagogue, significantly altered the HA content both in BAL and in lung tissue in the irradiated animals. Regular treatment throughout the whole experimental period induced depletion of mast cell granules and a decrease in HA deposition whereas 48/80 treatment during the pneumonitis phase enhanced HA deposition. A rat model with smoke exposure was developed, and the effect of cigarette smoke on radiation-induced inflammation was studied. Rats that smoked 3 weeks prior to irradiation and continued to smoke throughout the observation period (7 weeks) had a significantly reduced inflammatory response compared to irradiated non-smoking rats. The most prominent BAL findings in the smoke-exposed rats were a decrease in PMN, mast cells and a decrease in HA. In conclusion, irradiation induces an alveolitis characterized mainly by mononuclear cells. Mast cells seem to be of importance in the remodelling of the connective tissue in the radiation-induced inflammatory response. Hyaluronan is an important component in the early connective tissue response preceding later collagen deposition, and its interstitial deposition is very well reflected in BAL. Moreover, tobacco-smoke suppresses the radiation-induced inflammation with a decreased recruitment of effector cells including mast cells.

Diss. (sammanfattning) Umeå : Umeå universitet, 1992, härtill 5 uppsatser.

digitalisering@umu

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Sharma, Vishakha. "Aging and Gender Effects in Diet-Induced Obesity and its Metabolic Sequelae." University of Cincinnati / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1522320845867142.

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Neeb, Zachary P. "Diet-induced dyslipidemia drives store-operated Ca2+ entry, Ca2+ dysregulation, non-alcoholic steatohepatitis, and coronary atherogenesis in metabolic syndrome." Thesis, Connect to resource online, 2010. http://hdl.handle.net/1805/2209.

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Thesis (Ph.D.)--Indiana University, 2010.
Title from screen (viewed on July 21, 2010). Department of Cellular and Integrative Physiology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Michael Sturek, Jeffrey A. Breall, Robert V. Considine, Alexander Obukhov, Johnathan D. Tune. Includes vitae. Includes bibliographical references (leaves 212-240).

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Neves, Christian André Fernandes. "Methylglyoxal-induced glycation changes liver lipid content in high-fat diet-fed rats, causing glucose and lipid systemic dysmetabolism." Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/14597.

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Mestrado em Biomedicina Molecular
Fatty liver disease is simultaneously a cause and a consequence of type 2 diabetes. Hepatic lipid metabolism is altered in obese patients, causing insulin resistance. More, inhibition of insulin signaling may also affect hepatic lipid metabolism, causing a feedback that may lead to hepatic steatosis, common in such patients. In this work, we intended to assess the role of glycation (methylglyoxal-induced) in the hepatic lipid metabolism of high-fat diet-fed rats, using lipidomic approaches and magnetic resonance imaging, which identify hepatic lipid species, including phospholipids (PL), triglycerids (TG), diacylglycerols (DAG) and fatty acids (FA). Wistar rats were maintained during 4 months with methylglyoxal (MG) supplementation (100mg/Kg/day) (MG group), a high-fat diet rich in TG (HFD group) or both (HFDMG group) and compared with controls feeding a standard diet (n=6/ group). Lipidomic approaches, namely liquid chromatography - mass spectrometry (LC-MS) and gas chromatography (GC) were used to determine liver composition in PL, TG and FA. Non-invasive 1H nuclear magnetic resonance (NMR) spectroscopy (9 Tesla) of liver tissues in vivo was used to determine lipid species, such as TG and DAG. The total and phosphorylated levels of the mediators of the insulin receptor pathway and lipid oxidation were determined by western blotting. High-fat diet-fed (HFD) rats showed increased body weight in relation to controls, but this effect was partially inhibited by MG supplementation (HFDMG group). Moreover, HFDMG group showed increased plasma free fatty acid levels, hyperinsulinemia, insulin resistance and glucose intolerance. In liver, lipidomic techniques and 1H NMR showed increased fat mass in the liver of HFD and HFDMG rats. HFD rats, but not HFDMG, showed increased total levels of the 18:1 fatty acid (common in high-fat diets). Despite no differences were observed for HFD group, HFDMG rats showed decreased fraction of unsaturated lipids and increased fraction of saturated lipids. This difference was obtained due to a decrease in monounsaturated FA. Regarding lipid esterification, HFDMG group showed lower percentage of esterified glycerol carbons, suggesting an increased concentration of DAG in relation to TG. In accordance, this group showed higher fatty acids/glycerol ratio, suggesting increased liver non-esterified fatty acid levels. Western Blotting analyses showed decreased activation of insulin pathway, especially HFDMG group, as well as decreased activation of the insulin receptor in HFDMG group. Data suggest that glycation changes lipid metabolism in a context of hyperlipidemia, possibly contributing to hepatic lipotoxicity and to accelerate progression of insulin resistance and fatty liver disease.
O fígado gordo é simultaneamente uma causa e consequência da diabetes mellitus tipo 2. O metabolismo lipidico-hepático (MLH) encontra-se alterado em obesos, causando insulino-resistência. A diminuição da sinalização da via da insulina pode igualmente afetar o MLH, estimulando o desenvolvimento de esteatose hepática, comum nos doentes. Neste trabalho, pretende-se analisar o papel da glicação (induzida por metilglioxal) no MLH em ratos com dieta gorda, através de técnicas de lipidómica e ressonância magnética, para identificar as espécies lipídicas hepáticas, tais como fosfolípidos (FL), triglicéridos (TG), diacilgliceróis (DAG) e ácidos gordos (AG). O modelo animal usado foi o rato Wistar, mantido nos últimos 4 meses, antes de completar 1 ano de idade, com metilglioxal (100mg/Kg/dia) (grupo MG), com dieta gorda rica em TG (grupo HFD) ou com ambas (grupo HFDMG) e comparados com os controlos com dieta normal (n=12/grupo). As técnicas de lipidómica usadas foram cromatografia líquida com espetrometria de massa e cromatografia gasosa para determinar a composição hepática de PL, TG e AG. Usou-se também espectroscopia (9 Tesla), não invasiva, de ressonância magnética nuclear 1H (NMR) nos ratos vivos para determinar os TG e DAG hepáticos. Os mediadores proteicos totais e fosforilados da via da insulina e da oxidação lipídica no fígado também foram analisados por western blot. Os ratos, com dieta gorda (HFD), aumentaram o peso corporal, mas o efeito foi parcialmente inibido pelo metilglioxal (HFDMG). Além disso, o grupo HFDMG apresenta um aumento dos ácidos gordos livres no plasma, hiperinsulinemia, insulino-resistência e intolerância à glicose. No fígado, as técnicas de lipidómica e NMR mostraram um aumento da massa gorda no fígado nos grupos HFD e HFDMG, mas apenas no grupo HFD se verifica o aumento do AG 18:1 (comum na dieta). Apesar de não haver diferença significativa no grupo HFD, o grupo HFDMG apresenta uma diminuição dos AG insaturados e aumento dos saturados; isto deve-se à diminuição dos monoinsaturados neste grupo. Quanto à esterificação dos glicerolípidos, o grupo HFDMG apresenta uma menor percentagem da total esterificação dos gliceróis, sugerindo o aumento dos DAG, em relação aos TG. Também, este grupo apresenta um ratio AG/glicerol aumentado, ou seja, com aumento de AG não esterificados. A análise por western blot mostrou uma diminuição da via do receptor da insulina especialmente no grupo HFDMG. Em suma, estes resultados sugerem que a glicação causa alterações do metabolismo lipidico-hepático num contexto de hiperlipidemia, contribuindo possivelmente para a lipotoxicidade hepática, progressão acelerada de insulino-resistência e patologia do fígado gordo.

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Kriss, Crystina Leah. "Investigation of Alcohol-Induced Changes in Hepatic Histone Modifications Using Mass Spectrometry Based Proteomics." Scholar Commons, 2018. http://scholarcommons.usf.edu/etd/7185.

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Alcohol liver disease (ALD) is a major health concern throughout the world. Currently, in the United States, 17 million people suffer from alcoholism, of which 1.4 million people are receiving treatment [1, 2]. The link between ethanol metabolism, reactive oxygen species (ROS) and liver injury in ALD has been well characterized over the last couple decades [3-10]. Ethanol metabolism relies on the availability of the cofactor NAD+ for the oxidation of ethanol into acetate, consequently causing alterations in redox potential. Redox dysfunction within the mitochondria can affect multiple pathways important in maintaining cellular homeostasis. Chapter 1 provides an introduction to the role of ethanol metabolism in oxidative stress and alcohol liver injury (ALI). During ethanol metabolism, both the cytochrome bc1 and NADH dehydrogenase complexes within the mitochondria have been demonstrated to be major contributors to ROS formation and “leak” free radicals [11-13]. As a result, the free radicals superoxide (O2-) and hydrogen peroxide (H2O2) is diffused into the cytoplasm where they can react with other molecules, proteins and DNA and cause tissue injury [4, 14]. Chapter 1 aims to introduce the link between ethanol metabolism and histone post-translational modifications (PTM) such as tyrosine nitration and lysine acetylation using proteomics techniques. Chapter 2 uses a global proteomic study to identify links between gender and ALI. A 10-day chronic-binge mouse model was employed in order to identify gender-specific proteins that may influence the development of ALD. It has previously been established that females are more susceptible to developing ALD, however, the cause is still unknown. This study identifies gender differences in the family of cytochrome P450 proteins using a mouse model for chronic-binge alcohol exposure. The cytochrome P450 family of proteins are important in the metabolism of toxic compounds, such as acetaldehyde, a byproduct of ethanol metabolism. Interestingly, I also identified that female mice expressed naturally higher levels of histone acetylation prior to alcohol exposure when compared to males. Following alcohol exposure, the female mice did not show much change in acetylation, whereas male acetylation levels were raised to similar levels of the female mice. These acetylation changes raised the question, how does alcohol influence epigenetic marks on histone proteins? Recently, new evidence has emerged that supports the role of epigenetics in the pathophysiology of ALD [4, 14-27]. Ethanol metabolism will promote shifts in redox potential and mitochondrial dysfunction, the result is the formation of reactive oxygen and/or nitrogen species (ROS/RNS) [4, 5, 7, 10, 14, 28]. As ethanol is metabolized, the accumulation of ROS/RNS species such as NO- and O2- can induce the post-translational modification nitrotyrosine. Shifts in redox potential will cause the electron transport chain to “leak” the free radical O2-. Another free radical known as nitric oxide (NO-) has been shown to be elevated during times of ethanol consumption [29, 30]. Traditionally, NO has a protective role within the cell at low concentrations, however, in surplus can lead to tissue damage. Ethanol-induced increases in NO- and O2- can instigate to peroxynitrite (ONOO-) formation; a potent oxidant and nitrating agent of tyrosine residues [29, 31-34]. Chapter 3 examines the indirect effect of alcohol metabolism and ROS/RNS formation on histone tyrosine nitration. This project used mass-spectrometry to identify novel targets of histone tyrosine nitration using a mouse-model of chronic-binge alcohol exposure. Interestingly, histone H3 was found to be nitrated on the hinge-region of the N-terminal tail at tyrosine 41. Molecular dynamics of the nitrated and unmodified proteoforms revealed that the DNA prefers a change in conformation upon H3Y41 nitration. Further studies using an antibody synthesized against the nitrated H3y41 region of the protein revealed potential targets within the genome important in fatty acid synthesis and metabolism. Chapter 4 looks at the direct influence of alcohol metabolism and its contribution to histone acetylation via acetate production and acetyl-CoA. Alcohol metabolism has traditionally been thought influence acetylation through the sirtuin family of deacetylase proteins. Sirtuin deacetylases are NAD+-dependent and have been shown to be a regulate protein acetylation within the mitochondria, cytoplasm, and nucleus during times of ethanol exposure [35-37]. Shifts in redox potential attributed to ethanol metabolism can inhibit sirtuin deacetylase activity by out-competing the enzymes for available NAD+, ultimately leading to mitochondrial and nuclear hyperacetylation [17, 28, 38-42]. Currently, there is evidence that ethanol increases acetylation of histone 3 lysine 9, which then targets activation of the alcohol dehydrogenase gene (ADH) [17, 18, 43]. Moreover, Shukla et.al. (2008) support the idea that ethanol can alter epigenetic transcriptional activation based on which modification is selected for a site during times of stress when it can be occupied by more than one modification [22]. Chapter 4 demonstrates the use of mass-spectrometry to metabolically trace 13C2-labeled ethanol in vivo. These new data show clear evidence of 13C2 heavy-labeled ethanol being incorporated into known sites of acetylation on the N-terminal tails of histone H3 and H4. Incorporation of heavy-label was calculated using extracted ion chromatograms (XIC) for the double and singly acetylated and unmodified peptides belonging to H3K9-R17 and H3K18-R23. Total change in acetylation was also assessed for each peptide using the ratio of ratios of total acetylation to unmodified peptide over the fold change in ethanol- to control-fed groups. An interesting observation was observed in that the incorporation of heavy-label suggests site-selectivity of lysine residues over time. Histone 4 contains multiple sites of acetylation on the peptide H4K5-R17, making it hard to quantify manually. MaxQuant evidence files in conjunction with R were used to calculate the 13C2 incorporation on the multiple H4 acetyl-sites over 24-hours. Ethanol-heavy label incorporation at multiple acetyl-sites occurred as a mixture suggesting a role in transcriptional regulation. These new data establish a link between alcohol metabolism and known epigenetic marks on histone proteins. These studies have now established that alcohol metabolism is indirectly linked to histone tyrosine nitration through increased ROS/RNS and directly through acetate production. Understanding how these epigenetic marks fluctuate as ALD progresses will provide potential targets for the development of new drug therapies. The epigenetic marks identified in these studies have previously been established to be important activators in transcription. These data provide novel techniques using proteomics-based metabolic tracing in vivo. Future studies will assess how these marks change after chronic ethanol exposure and whether the changes in epigenetics are heritable. Understanding hereditary of alcoholism will provide insight to those predisposed to the disease.

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Kanuri, Giridhar [Verfasser], and Stephan C. [Akademischer Betreuer] Bischoff. "Role of plasminogen activator inhibitor (PAI-1) in the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD) / Giridhar Kanuri. Betreuer: Stephan C. Bischoff." Hohenheim : Kommunikations-, Informations- und Medienzentrum der Universität Hohenheim, 2012. http://d-nb.info/1027354297/34.

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Patton, Ashley. "Characterization of the Very Early Development of High Fat Diet-induced Non-alcoholic Fatty Liver Disease (NAFLD) and Efficacy of Novel Therapeutics for its Treatment." Ohio University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1521811677550828.

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Subramanian, Vikram [Verfasser], Michael J. [Akademischer Betreuer] Atkinson, Gabriele [Gutachter] Multhoff, and Michael J. [Gutachter] Atkinson. "The role of the Peroxisome Proliferator-Activated Receptor alpha in radiation-induced cardiovascular disease / Vikram Subramanian ; Gutachter: Gabriele Multhoff, Michael J. Atkinson ; Betreuer: Michael J. Atkinson." München : Universitätsbibliothek der TU München, 2019. http://d-nb.info/1189815486/34.

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Le, Guillou Dounia. "Altérations de l'homéostasie de l'ADN mitochondrial par les médicaments et modulation par la stéatose hépatique." Thesis, Rennes 1, 2017. http://www.theses.fr/2017REN1B039/document.

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Il est estimé aujourd’hui que plus de 350 médicaments peuvent induire des lésions hépatiques entraînant différentes manifestations cliniques telles qu’une hépatite cytolytique, une stéatose voire une cirrhose. Bon nombre de médicaments hépatotoxiques induisent un dysfonctionnement mitochondrial. Cependant, les mécanismes induisant de tels effets délétères ne sont pas tous élucidés, en particulier ceux concernant l’ADN mitochondrial (ADNmt) et son homéostasie, qui ne sont pas souvent explorés. De plus, il existe peu d’informations concernant l’hépatotoxicité médicamenteuse dans un contexte de stéatose induite par l’obésité. Ainsi, l’objectif de ce travail a été tout d’abord de mettre au point un modèle de stéatose dans les cellules de la lignée hépatocytaire humaine HepaRG afin d’étudier ensuite, les effets de neuf médicaments hépatotoxiques et vraisemblablement mitochondriotoxiques – l’amiodarone, l’atorvastatine, la carbamazépine, l’imipramine, la lovastatine, la perhexiline, le ritonavir, la terbinafine et la troglitazone – sur l’homéostasie de l’ADNmt dans un contexte ou non de stéatose. En utilisant des concentrations peu ou non cytotoxiques, nous avons trouvé que parmi les neuf médicaments étudiés, le ritonavir et l’imipramine ont induit des effets mitochondriaux suggérant une altération de la traduction mitochondriale. De façon notable, la toxicité du ritonavir était plus importante dans les cellules non-stéatosées. De plus, aucun des neuf médicaments n’a induit de diminution des quantités d’ADNmt. Cependant, les quantités accrues d’ADNmt ont été retrouvées avec six des neuf médicaments, et notamment dans les cellules non-stéatosées. Cela était par ailleurs accompagné d’une modulation de l’expression des différents facteurs impliqués dans la biogenèse mitochondriale (PGC-1α, PGC-1β, AMPK, etc.). Ainsi, ces données laissent supposer qu’une altération de la traduction mitochondriale peut ne pas être une événement rare et que l’augmentation des quantités d’ADNmt et la modulation de la biogenèse mitochondriale pourraient être une réponse adaptative fréquente à des altérations mitochondriales pouvant être amoindrie par la stéatose
It is currently estimated that more than 350 drugs can induce liver injury with different clinical presentations such as hepatic cytolysis, steatosis, even cirrhosis. Many hepatotoxic drugs can induce mitochondrial damage and dysfunction. However, not all mechanisms that lead to such deleterious effects are clarified, especially those concerning mitochondrial DNA (mtDNA) and its homeostasis, which are not often investigated. Moreover, there is little information regarding the impact of non alcoholic fatty liver disease (NAFLD) on drug-induced liver injury. Thus, the aim of this work was, first of all, to develop a model of NAFLD in the hepatic cell line HepaRG in order to study further effects of nine hepatotoxic and presumably mitochondriotoxic drugs – amiodarone, atorvastatin, carbamazepine, imipramine, lovastatin, perhexiline, ritonavir, terbinafine and troglitazone –, on mtDNA homeostasis in the context of NAFLD or not. By using drug concentrations that did not induce major cytotoxicity, we found that, among the nine drugs, studied, ritonavir and imipramine induced mitochondrial effects suggesting alteration of mtDNA translation. Notably, ritonavir toxicity was stronger in non-steatotic cells. Furthermore, none of the nine drugs decreased mtDNA levels. However, increased mtDNA was observed with six drugs, especially in non-steatotic cells. This result was also accompanied by a modulation of the expression of various factors involved in mitochondrial biogenesis (e.g. PGC-1α, PGC-1β, AMPK).Therefore, this data suggests that drug-induced impairment of mtDNA translation may not be a rare event and increased mtDNA levels and modulation of mitochondrial biogenesis could be a frequent adaptive response to mitochondrial impairments, which could be dampened by steatosis

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Paiva, Adriene Alexandra 1985. "Severidade da esteatose hepática não alcoólica induzida por super expressão da apolipoproteína CIII é associada à inflamação e morte celular = Severity of nonalcoholic fatty liver disease induced by apolipoprotein CIII overexpression is associated with inflammation and cell death." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/314291.

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Orientador: Helena Coutinho Franco de Oliveira
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
Made available in DSpace on 2018-08-27T08:22:09Z (GMT). No. of bitstreams: 1 Paiva_AdrieneAlexandra_D.pdf: 2285275 bytes, checksum: e9d86e12d4ac3d041953799c130a314a (MD5) Previous issue date: 2015
Resumo: A doença hepática gordurosa não alcoólica (Nonalcoholic fatty liver disease - NAFLD) é a principal manifestação hepática na obesidade e síndrome metabólica. A história natural da doença envolve a esteatose, estresse oxidativo, inflamação, fibrose e morte celular. Níveis plasmáticos elevados de lipoproteínas ricas em triglicérides são fatores de risco independentes para doenças cardiovasculares. Estudos clínicos e experimentais mostram forte correlação entre triglicérides plasmáticos (TG) e os níveis de apolipoproteína CIII. A apolipoproteína CIII também é aumentada no plasma de pacientes diabéticos. Ao comparar camundongos apoCIII transgênicos com controles não transgênicos irmãos (NTg), mostramos aqui que a super-expressão de apoCIII, independentemente da dieta rica em gordura (High fat diet - HFD), resulta em características NAFLD, ou seja, aumento do conteúdo de lípidos no fígado, diminuição poder antioxidante, aumento da expressão de TNF'alfa', receptor de TNF'alfa', caspase-1 clivada e interleucina-1'beta', diminuição do receptor de adiponectina-2 e aumento da morte celular. Além disso, os indicadores de inflamação sistêmica de TNF'alfa' e a proteína C-reactiva estão também elevados em camundongos apoCIII. Esse quadro é agravado e características adicionais da NAFLD são diferencialmente induzidas por HFD em camundongos apoCIII. A HFD induziu intolerância à glicose, juntamente com aumento da gliconeogênese, evidenciando a resistência hepática à insulina, induziu um aumento significativo da TNF'alfa' (8 vezes) e IL-6 (60%) no plasma em camundongos apoCIII comparados aos NTg. Os outros indicadores de inflamação (proteína C reativa plasmática e TNF?, TNFr, caspase-1 e IL-1'beta' hepática) mantiveram-se superiores em camundongos apoCIII em HFD. A ativação da via intrínseca (Bax / Bcl-2) e a proteina efetora (caspase-3) de apoptose foram aumentados em ambos os camundongos apoCIII com low fat diet (LFD) e HFD. Como esperado, o tratamento com fenofibrato reverteu vários dos efeitos da dieta e da apoCIII. No entanto, o fibrato não normalizou o padrão inflamatório nos animais apoCIII, tais como o aumento do TNF'alfa', TNFr, IL1'beta' e redução do adiponectina-R2, mesmo com total correção do teor de lipídios no fígado. Estes resultados indicam que a superexpressão apoCIII desempenha um papel importante na inflamação hepática e na morte celular e aumenta a suscetibilidade e a gravidade da esteatose hepática induzida pela dieta
Abstract: Nonalcoholic fatty liver disease (NAFLD) is the principal liver manifestation in obesity and metabolic syndrome. The natural history of the disease involves steatosis, oxidative stress, inflammation, fibrosis and cell death. Elevated plasma levels of triglyceride-rich remnant lipoproteins are independent cardiovascular disease risk factors. Clinical and experimental studies show strong correlation and causal links between plasma triglycerides (TG) and apolipoprotein CIII levels. Apolipoprotein CIII is also increased in the plasma of diabetic patients. By comparing apolipoprotein (apo) CIII transgenic mice with control non-transgenic (NTg) littermates, we show here that the overexpression of apoCIII, independently of high fat diet (HFD), results in NAFLD features, namely, increased liver lipid content, decreased antioxidant power, increased expression of TNF'alfa', TNF'alfa' receptor, cleaved caspase-1 and interleukin-1'beta', decreased adiponectin receptor-2 and increased cell death. In addition, systemic indicators of inflammation TNF? and C-reactive protein are also elevated in apoCIII mice. This picture is aggravated and additional NAFLD features are differentially induced by HFD in apoCIII mice. HFD induced glucose intolerance together with increased gluconeogenesis, evidencing hepatic insulin resistance. Marked increases in plasma TNF'alfa' (8-fold) and IL-6 (60%) were induced by HFD in apoCIII mice compared to NTg mice. The other inflammatory indicators (plasma C reactive protein, liver TNF'alfa', TNFr, caspase-1 and IL1 'beta') remained higher in HFD apoCIII mice. Cell death signaling (Bax/Bcl2), effector (caspase-3) and apoptosis were augmented in both low and HFD apoCIII mice. As expected, fenofibrate treatment reversed several of the diet and apoCIII effects. However, fibrate did not normalize apoCIII inflammatory traits, such as increased TNF'alfa1, TNFr, IL1'beta' and reduced adiponectin-R2, even under fully corrected liver lipid content. These results indicate that apoCIII overexpression play a major role in liver inflammation and cell death increasing susceptibility to and the severity of diet induced NAFLD
Doutorado
Fisiologia
Doutora em Biologia Funcional e Molecular

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Panta, Utsab, Adam chan, and Debalina Das. "Osteonecrosis of Jaw: Common etiologies, uncommon treatments." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/201.

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Introduction First described in 2002, osteonecrosis of the jaw (ONJ, or avascular necrosis of the jaw) is an uncommon but potentially serious side effect of treatment with bisphosphonates. Although typically identified in patients with multiple myeloma and other malignancies, a few cases have been reported in patients taking bisphosphonates - a potent drug class used in the treatment of osteoclast-mediated bone resorption issues, including postmenopausal osteoporosis, Paget's disease, multiple myeloma, and malignant hypercalcemia. The clinical diagnosis of ONJ can be obscured by jaw pain, abscess, swelling, and fistulas, but exposed bone is a distinctive sign. This reports a case of ONJ secondary to bisphosphonate use in a 65-year-old woman and clinical management complications. Case Presentation A 65-year-old lady with history of age-related osteoporosis and compression fractures on alendronate for 4 years, squamous cell carcinoma of neck status post excision and radiotherapy 11-years prior, Sjogren's syndrome and discoid lupus on hydroxychloroquine, diabetes, hypertension, stroke and multiple dental abscesses presents with persistent neck pain. Initial CT neck with contrast showed diffuse fat stranding. Subsequently, alendronate was discontinued due to jaw necrosis suspicion. Eight months later, repeat CT scan showed new non-mass-like soft tissue thickening in the subcutaneous fat abutting the right anterior mandible with mandibular teeth cavities and periapical lucencies, likely to be periodontal cellulitis versus radiation osteonecrosis. Later, patient complained of a piece of bone penetrating the skin of her chin and presented with continuous drainage from sinus tract in her mandible, which was diagnosed as osteonecrosis attributed to bisphosphonates, previous radiation therapy, and dental abscesses. Patient was started on abaloparatide, an osteo-anabolic medication for osteoporosis and enrolled in hyperbaric oxygen therapy which immensely helped in controlling sinus drainage. Patient is currently awaiting mandibular reconstruction surgery. Discussion ONJ, often associated with pain, swelling, exposed bone, local infection, and pathologic fracture of the jaw, is a rare complication of bisphosphonate therapy. Currently, no prospective data exists to advise the benefits of therapy discontinuation however most clinical practices tend to discontinue at least temporarily. The incidence increases with longer treatment duration, particularly when therapy exceeds four years. Risk factors for developing ONJ while taking bisphosphonates include IV administration, anticancer therapy, dose and duration of exposure, dental extractions/implants, glucocorticoids, smoking, diabetes, and preexisting dental disease. Case reports and series suggest benefit from hyperbaric oxygen therapy in wound healing, pain, and quality of life at three months, however no significant differences exist with outcomes beyond three months. Patients being considered for therapy with a bisphosphonate should be thoroughly evaluated for dental issues, prior to initiating therapy. Conservative management with limited debridement, antibiotic therapy as needed, and topical mouth rinses rather than aggressive surgical resection are recommended. Conservative therapy may result in healing in a significant proportion of patients. Surgical resection of necrotic bone should be reserved for refractory or advanced cases. Providers should remain cautious while prescribing high doses of bisphosphonates in patients with increased risk factors to prevent, timely diagnose and treat this condition. References Edwards BJ, Gounder M, McKoy JM, et al. Pharmacovigilance and reporting oversight in US FDA fast-track process: bisphosphonates and osteonecrosis of the jaw. Lancet Oncol 2008; 9:1166. Khosla S, Burr D, Cauley J, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007; 22:1479. Hoff AO, Toth BB, Altundag K, et al. Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 2008; 23:826.

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Fleming, Christina Katelyn, and Jonathan M. Peterson. "Ethanol Feeding Reduces Circulating CTRP3 Levels." Digital Commons @ East Tennessee State University, 2016. https://dc.etsu.edu/etsu-works/128.

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26

Remes, T. (Tiina). "Signs of radiation-induced accelerated ageing in survivors of childhood brain tumors:the incidence of cerebrovascular disease, neurocognitive impairment, secondary neoplasms, and low bone mineral density after 18 years of follow-up." Doctoral thesis, Oulun yliopisto, 2019. http://urn.fi/urn:isbn:9789526224305.

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Abstract Background: Childhood brain tumors (CBTs) are the most common solid tumors in childhood. CBT survivors have a high risk of several late-effects, including cerebrovascular disease (CVD), neurocognitive impairment, secondary neoplasms, and low bone mineral density; however, only a few studies have clinically investigated the late-sequelae in young-adult CBT survivors. Aim: To determine the prevalence of CVD, neurocognitive impairment, secondary neoplasms, and bone mineral density in a national cohort of radiotherapy-treated long-term survivors of CBT. Subjects and Methods: Radiotherapy-treated CBT survivors diagnosed between 1970–2008 were selected based on the following inclusion criteria: follow-up ≥5 years since the cessation of therapy and age of ≥16 years at the time of the study. Survivors were clinically and neuropsychologically examined, and investigated by magnetic resonance imaging (MRI), bone mineral densitometry, and laboratory analysis. Results: We included 74 survivors after a mean follow-up time of 18.9 ± 6.1 years. The mean age at follow-up was 28.4 ± 6.8 years and at diagnosis 8.3 ± 4.3 years. At the 20-year follow-up, the cumulative prevalence of CVD, along with small- and large-vessel disease was 52%, 38%, and 16%, respectively. Ischemic infarcts or transient ischemic attacks were diagnosed in 11% of the survivors, lacunar infarcts in 10%, and cerebral hemorrhage in 3%. White matter lesions (WMLs) were noted in 49% of the survivors. Higher blood pressure was associated with CVD, large-vessel disease, WMLs, and lacunar infarcts. Survivors had lower cognitive performance in all neuropsychological domains than controls. Mean verbal intelligence quotient was 89 ± 14 and mean performance intelligence quotient 87 ± 19. Executive functions (Z-score -5.0 ± 5.3 SD) and processing speed (Z-score -4.3 ± 5.4 SD) were extensively impaired. Executive functions and processing speed were associated with everyday life skills. Cumulative incidence of secondary meningiomas was 10.2% at the 25-year follow-up using the clinical data, and that of secondary neoplasms was 2.4% using the Finnish Cancer Registry data. We observed low bone mineral density in 23.6% of the survivors, which was associated with fractures in long bones. Conclusions: Young adult CBT survivors experienced late-consequences typically associated with ageing
Tiivistelmä Taustaa: Suomessa sairastuu vuosittain 46-60 lasta aivokasvaimeen, joka on lapsuusiän yleisin, kiinteä kasvain. Selviytyneillä on todettu lisääntynyt hoitojen myöhäisvaikutuksien riski. Kuitenkin nuorten aikuisten haittavaikutuksia on toistaiseksi tutkittu melko vähän. Tutkimuksen tarkoitus: Tarkoituksena oli selvittää sädehoidon jälkihaittoina esiintyvien sairauksien, kuten aivoverisuonisairauksien, älyllisten ongelmien, sekundaaristen kasvainten ja luustonhaurastumisen yleisyyttä ja riskitekijöitä suomalaisessa, kansallisessa kohortissa. Aineisto ja Menetelmät: Tutkimukseen kutsuttiin kaikki Suomessa lapsuusiällä aivokasvaimen sairastaneet aikuiset, jotka oli hoidettu sädehoidolla vuosina 1970-2008. Tutkittavat olivat yli 16-vuotiaita ja hoitojen päättymisestä oli yli 5 vuotta. Osallistuneille tehtiin kliininen ja neuropsykologinen tutkimus, pään magneettikuvaus, luustontiheysmittaus ja laboratoriotutkimuksia. Tulokset: Tutkimukseemme osallistui 74 nuorta aikuista 18,9 ± 6,1 vuotta hoitojen päättymisen jälkeen. Tutkittavat olivat iältään 28,4 ± 6,8 -vuotiaita osallistuessaan, ja 8,3 ± 4,3 -vuotiaita diagnoosihetkellä. Aivoverisuonisairaus todettiin 52% tutkimukseen osallistuneella 20 vuoden seurannan jälkeen, pienten suonten tauti oli 38 %:lla ja suurten suonten tauti 16 %:lla. Aivoinfarktin oli sairastanut 9 % tutkituista, lakuunainfarktin 10 % ja aivoverenvuodon 3 % tutkituista. Valkean aivoaineen muutoksia todettiin 49 %:lla magneettikuvauksessa. Korkea verenpaine lisäsi aivoverisuonisairauden, suurten suonten taudin, valkoisen aivoaineen muutoksien sekä lakuunainfarktien riskiä. Selviytyjien keskimääräinen kielellinen älykkyysosamäärä oli 89 ± 14 ja ei-kielellinen 87 ± 19. Suurimmat vaikeudet todettiin toiminnanohjauksessa (Z-luku -5,0 ± 5,3 SD) ja prosessointinopeudessa (Z-luku -4,3 ± 5,4 SD). Toiminnanohjauksen ja prosessointinopeuden vaikeudet olivat yhteydessä arkielämän haasteisiin. Sekundaaristen aivokalvokasvainten kumulatiivinen esiintyvyys oli 25 vuoden seuranta-aikana 10,2 % kliinisessä tutkimuksessa ja sekundaaristen kasvainten 2,4 % Syöpärekisteriaineistossa. Matala luustontiheys todettiin 23,6%:lla selviytyneistä. Johtopäätökset: Nuorilla aikuisilla, jotka ovat lapsena aivokasvaimen vuoksi saaneet sädehoitoa, esiintyy useita sellaisia jälkihaittoja, jotka yleensä liittyvät ikääntymiseen

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27

Moreira, Maria Margarida Miranda. "Efeitos hepatotóxicos e nefrotóxicos dos antibacterianos." Master's thesis, [s.n.], 2012. http://hdl.handle.net/10284/3566.

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Trabalho apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
Os antibióticos são medicamentos etiotrópicos sem ação farmacológica sobre as células eucarióticas do Homem, tendo como alvo os locais específicos da célula procariótica. Contudo, apesar desta especificidade de ação, os antibióticos podem exibir efeitos tóxicos nas células humanas, muito embora o risco potencial é baixo tendo em conta o seu elevado número de prescrições. Assim, a nível hepático a lesão induzida pelas penicilinas (ampicilina, benzilpenicilina, fenoximetilpenicilina, amoxicilina) é rara, mas no caso da flucloxacilina e da associação de amoxicilina com ácido clavulânico há um aumento da sua incidência. As cefalosporinas raramente causam reações hepatotóxicas, sendo o efeito mais relatado a colestase. A administração de elevadas doses de tetraciclinas por via intravenosa pode causar esteatose microvesicular e elevação das enzimas hepáticas, podendo mesmo conduzir, em casos mais graves a falha hepática fulminante. Nas quinolonas, a trovafloxacina tem maior potencial hepatotóxico. A telitromicina, um macrólido de nova geração, é o mais preocupante dentro dos macrólidos, devido ao número de casos descritos num curto período de tempo. Nos fármacos para o tratamento da tuberculose, os efeitos adversos variam desde aumentos assintomáticos das enzimas hepáticas a hepatite aguda ou falha hepática fulminante. Relativamente à nefrotoxicidade, os aminoglicosídeos podem causar necrose tubular aguda, uma vez que têm capacidade para interagir com muitos alvos intracelulares. A vancomicina, que é quase exclusivamente eliminada por via renal, também tem a capacidade de causar necrose das células do túbulo renal proximal. Das cefalosporinas, a cefaloridina e a cefaloglicina são as únicas capazes de causar danos renais quando administradas em doses terapêuticas. Também existem alguns casos de toxicidade renal com as polimixinas B e E, observando-se necrose tubular aguda e nefrite intersticial aguda. Nas penicilinas, a meticilina é a mais tóxica causando nefrite intersticial aguda. Por fim, nos carbapenemos, o imipenem e o panipenem apenas são comercializados em combinação com agentes nefroprotectores, uma vez que são hidrolisados a nível renal originando metabolitos tóxicos. Antibiotics are etiotropic drugs without pharmacologic action in human eucaryotic cells, and so their targets are specific sites of prokaryote cell. However, in spite of this specific action, antibiotics can exhibit toxic effects in human cells, but this potential risk is low considering count their high number of prescriptions. Thus, in hepatic level the lesion induced by penicillins (ampicillin, benzylpenicillin, phenoxymethylpenicillin and amoxicillin) is rare, but in the case of flucloxacillin and the association of amoxicillin with clavulanic acid there is an increase of this incidence. Cephalosporins rarely cause hepatotoxic reactions, and thus the must related effect is cholestasis. Administration of high doses of tetracyclines via intravenous route can cause microvesicular steatosis and elevation of hepatic enzymes, and can even lead, in more severe cases, to fulminant liver failure. In quinolones, trovafloxacin has more potential to induce hepatotoxic effects. Telithromycin, a macrolide of second generation, is the most worring of all macrolides, due to the number of cases related in a short time. In drugs for tuberculosis treatment, the adverse effects vary from assintomatic hepatic enzymes elevation to acute hepatitis or fulminant liver failure. In the case of nephrotoxicity, aminoglycosides can cause tubular acute necrosis, because they have the capacity to interact with many intracellular targets. Vancomycin, which is almost exclusively eliminated by the kidneys, also has the capacity to cause necrosis of proximal renal tubule cells. In all cephalosporins, cephaloridine and cephaloglycine are the ones capable of causing renal damage when administered in therapeutic doses. There are some cases of renal toxicity with polymyxins B and E, noting acute tubular necrosis and acute interstitial nephritis. In penicillins, methicillin is the most toxic drug causing acute interstitial nephritis. Lastly, in carbapenems the imipenem and panipenem are only marketed in combination with nephroprotectors agents, because they are hydrolyzed in kidneys originating toxic metabolites.

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28

Pacheco, Patricia Soares. "Estudo do metabolismo energético hepático e da via de sinalização da grelina na obesidade induzida por dieta ocidental." Universidade do Estado do Rio de Janeiro, 2015. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=9378.

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Fundação Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro
A obesidade é um dos maiores problemas de saúde pública que cresce em todo o mundo, resultante de um desequilíbrio entre ingestão alimentar e gasto energético. Pode-se dizer que a obesidade é o principal fator de risco para o desenvolvimento de doenças crônicas de maior prevalência como dislipidemias, doenças cardiovasculares, diabetes do tipo 2 e esteatose hepática não alcóolica, acarretando na redução da qualidade e expectativa de vida. A Grelina é um hormônio sintetizado pelo estômago, que atua em diferentes tecidos através de um receptor específico (GHS-R1a), incluindo hipotálamo e tecidos periféricos, como o fígado. Esse hormônio está envolvido no comportamento alimentar e adiposidade, modulando o armazenamento ou utilização dos substratos energéticos no coração, músculo esquelético, adipócitos e fígado, além disso, revela-se de grande importância na manutenção do metabolismo energético hepático. Estes dados suportam a hipótese de que as vias de sinalização responsivas à grelina são um importante componente da regulação do metabolismo energético hepático e da homeostase glicêmica. O objetivo deste trabalho, foi estudar o metabolismo energético hepático e a sinalização da grelina em camundongos Swiss adultos obesos submetidos a dieta ocidental rica em gordura saturada e carboidratos simples. Avaliamos o efeito desta dieta a partir do 21 dia de idade (desmame) até o 133 dia destes animais, através de parâmetros biométricos e bioquímicos, avaliação histomorfológica, respirometria de alta resolução, conteúdo de glicogênio hepático e conteúdo de algumas proteínas envolvidas na sinalização de insulina e grelina, além do metabolismo energético hepático. Baseado em nossos resultados observamos que o consumo de dieta ocidental rica em gordura saturada e carboidrato simples durante 16 semanas causa hiperfagia, levando ao quadro de obesidade na idade adulta e prejuízo nas vias de sinalização dos hormônios insulina e grelina, que são importantes moduladores do metabolismo energético hepático, favorecendo o desenvolvimento de esteatose hepática não alcoólica.
Obesity is a major public health problem growing around the world, resulting from an imbalance between food intake and energy expenditure. Obesity is one of the main risk factor for developing the most prevalent chronic diseases as dyslipidemia, cardiovascular disease, type 2 diabetes and non-alcoholic fat liver disease, resulting in lower life expectancy and quality of life. Ghrelin is a hormone synthesized into the stomach, which has an important role in different tissues by a specific receptor (GHS-R1a), including the hypothalamus and peripheral tissues such as the liver. This hormone is involved in feeding behavior and adiposity by modulating storage or use of energy substrates in heart, skeletal muscle, adipocytes and liver. Moreover, Ghrelin is important in maintaining liver energy metabolism. These data support the hypothesis that ghrelin signaling pathways is a key component in the regulation of energy metabolism and hepatic glucose homeostasis. The aim of this study was to investigate the hepatic energy metabolism and signaling of ghrelin in obese adults Swiss mice fed the Western diet, rich in saturated fat and simple carboidrate. We analyzed the effect of this diet starting from 21 days of age (weaning) up to 133 days, using biometric and biochemical parameters, histomorphological assessment, high resolution respirometry, hepatic glycogen content and proteins content involved in insulin and ghrelin signaling besides the hepatic energy metabolism. Based on our results we found that the consumption of rich Western diet for 16 weeks promoves overeating leading to obesity in adulthood, metabolic desorders and impairment in signaling pathways of hormones insulin and ghrelin, which are important metabolic modulators of liver energy, contributing to the development of NAFLD.

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29

Liu, Hua-Shan, and 劉華姍. "Analysis of Radiation-Induced Liver Disease Using the Parallel Architecture NTCP Model." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/86299079364054085619.

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碩士
國立臺灣大學
電機工程學研究所
92
An optimized treatment plan procedure of radiation therapy (RT) is done by delivering a sufficient dose of radiation to eradicate cancerous cells without having severe complication in healthy organs. For this reason, radiobiological models should be introduced to quantify the radiobiological response of normal tissues to radiotherapy. To predict the incidence of radiation-induced disease in parallel organs, the parallel architecture normal tissue complication probability (NTCP) model hypothesizes that a complication would be caused if the damaged fraction of the organ volume (f) exceeds the threshold of a critical one, ft (the “ functional reserve”). This study analyzed data of normal liver function from 4 patient subgroups with the parallel NTCP model to investigate the tolerance of the partial liver irradiation by evaluating the value of f. The calculated f from maximum likelihood estimated (MLE) parameters shows that cases of radiation-induced liver disease (RILD) have been reported in patients with a value of f larger than 0.4.

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30

Cheng, Chia-Hsien. "Probability Model for Biology Integrated Normal Tissue Complication Based on Radiation-Induced Liver Disease." 2005. http://www.cetd.com.tw/ec/thesisdetail.aspx?etdun=U0001-1001200514234200.

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31

Cheng, Chia-Hsien, and 成佳憲. "Probability Model for Biology Integrated Normal Tissue Complication Based on Radiation-Induced Liver Disease." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/06887570882134127601.

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博士
國立臺灣大學
電機工程學研究所
93
Radiotherapy has been one of the most important treatment modalities in cancer patients. The scientific method to estimate the risk of radiation-induced organ complication is using the dose-volume data from the computerized treatment planning system to perform calculations with certain thresholds and criteria. The current commonly used dosimetric parameters have the defects of non-volumetric criteria and the lack of volume effect integrated into the radiation-related organ damage. Normal tissue complication probability (NTCP) model has been proposed as a more comprehensive way to calculate the risk of complication by the use of the serial dose-volume data with a few parameters to weigh the risk between low-dose and high-dose damage. In our past patients with radiation-induced liver disease (RILD) after three-dimensional conformal radiotherapy (3DCRT), we found that the NTCP was more useful than the conventionally used parameters. However, the risk of RILD in Taiwan seemed underestimated with the NTCP model parameters developed in the Unites States. This means the tolerance of liver to radiation for patients in Taiwan different from the patients’ tolerance in the western countries, and the indication of generating the unique model parameters based on the biological features of RILD in Taiwanese patients. Our first step was to establish the biology-integrated NTCP in the two different databases, 89 patients with hepatocellular carcinoma (HCC) and 62 patients with gastric carcinoma (GC) undergoing 3DCRT. Hepatitis B viral (HBV) carriers have been the unique feature of Taiwanese patients in their liver tolerance as compared to the western countries. We first used the three-parameter Lyman NTCP model to recalculate the NTCP of RILD in 89 HCC patients by their original dose-volume data retrieved from the conformal design of 3DCRT. Logistic regression was used for significant factors of RILD. Maximal likelihood analysis was conducted to obtain the best estimates of NTCP model parameters based on the true occurrence of RILD in 17 of 89 HCC patients. In multivariate analysis, HBV carrier remained statistically significant as the susceptible factor to RILD. The best estimates of NTCP parameters (n, m, TD50(1)) were 0.35, 0.39, and 49.4 Gy. The parameters specifically estimated from HBV carriers were 0.26, 0.40, and 50.0 Gy, as compared to 0.86, 0.31, and 46.1 Gy for non-carrier patients. The main difference in volume effect parameter (n) between the two subgroups indicated the impact of this biological factor (HBV carrier) on modeling NTCP. The second step was to apply the Lyman NTCP model in 62 GC patients. HBV carrier status was the only independent factor associated with RILD. The parameters (n, m, TD50(1)) specifically estimated from HBV carriers were 0.11, 6.88, and 20.5 Gy, as compared to 1.99, 0.09, and 21.5 Gy for non-carrier patients. The difference in volume effect parameter similarly described the biological integration of HBV carrier into the NTCP model. The third step was to use the four-parameter parallel-architecture NTCP model, specifically designed for the organ with parallel feature like liver, in a combined group of 151 patients with either HCC or GC. HBV carrier was the only independent factor with statistically significant susceptibility to RILD in multivariate test. The NTCP model parameters, mean functional reserve (v50), width of functional reserve distribution ( ), dose at which half of liver subunits are damaged (d1/2), slope parameter for subunit dose response (k), were 0.54, 0.14, 50Gy, 0.13 (whole group); 0.53, 0.07, 50Gy, 4.6 10-7 (HBV carriers); 0.59, 0.12, 25Gy, 59.8 (non-HBV carriers), respectively. The main difference in slope parameter demonstrated the biological influence of HBV carrier on RILD. The threshold effect of fraction of liver damaged (f) became evident after integrating biological factor (HBV carrier) into the modeling process. We concluded the effectiveness of the two NTCP models in RILD, and the unique importance of HBV carrier in estimating the two NTCP model parameters. It is emphasized that physical and mathematical NTCP methods should be cautiously used with appropriate integration of biological factors. The biology integrated NTCP models are extremely important for HBV carrier patients undergoing 3DCRT or the other new technology of radiotherapy to the liver. Such importance of biological factor in radiation-induced liver damage also implies the corresponding biological pathogenesis and warrants the ongoing basic cellular or molecular research on RILD.

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32

Reuter, Felix. "Strahleninduzierte Expression von pro-inflammatorischen Zytokinen nach selektiver Ganzleberbestrahlung in vivo (Ratte)." Doctoral thesis, 2017. http://hdl.handle.net/11858/00-1735-0000-0023-3F8D-B.

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33

Jhih-YunLiu and 劉芷妘. "Investigating the role of PTX3 in radiation-induced liver fibrosis." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/4w4849.

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Liu, I.-Li, and 劉以立. "Prevention of Radiation Induced Liver Damage by Human Hepatocyte Growth Factor Electro-gene Therapy." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/80461263015879403816.

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碩士
國立臺灣大學
獸醫學研究所
90
Abstract In vivo electrogene therapy by using electric pulse to increase cell membrane permeability, and facilitating DNA into cell is a promising new method of gene therapy. The primary aim of this study is: Transferring hHGF gene into muscle or liver by electrogene therapy (EGT) to prevent radiation induced liver damage in rats. Rats received whole liver irradiation in different doses (20~65Gy) with cobalt machine to establish radiation induced liver damage model. We found that a LD50 was 40~50Gy, and only a quarter of rats survived after 65Gy of radiation at 12 weeks. hHGF gene 200μg was electroporated into the hind leg’s muscle or liver of rats 48 hrs before rats received a whole liver irradiation of 65Gy. No therapeutic effect was observed in the muscle hHGF-EGT group. There are only limited amount of hHGF expressed on muscle and no plasma hHGF was detected. It is likely that the amount of hHGF protein secreted from EGT-transfected muscle is too low to promote liver regeneration. On the contrary, markedly decrease of apoptotic liver cells was observed in the liver hHGF-EGT group. The anti-fibrosis effect of hHGF on liver TGF-β1 expression and collagenase activity in irradiated rats is worthy of future study. In conclusion, we have proved hHGF gene therapy would protect liver from radiation induced apoptosis by liver-EGT. The dual effects of hHGF on the anti-apoptosis and anti-fibrosis activity on hepatocytes suggest that hHGF may play an important role in the prevention and treatment of radiation induced liver damage.

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LEE, YAU-KER, and 李曜閣. "Licochalcone A Ameliorated Obese And Nonalcoholic Fatty Liver Disease In High-Fat Diet-Induced Mice." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/40178946529503329122.

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36

Li, Yi-Chieh, and 李宜潔. "The Regulatory Effect of Lactoferrin on High-Fructose Induced Nonalcoholic Fatty Liver Disease in Murine Model." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/89276179927449272658.

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碩士
東海大學
畜產與生物科技學系
101
The increase in fructose consumption is paralleled by a higher incidence of obesity and associate to metabolic syndrome including hypertriglyceridemia, fatty liver, hypertension, insulin resistance and diabetes mellitus. In recent years, several studies had been published that implicate subclinical chronic inflammation as an important pathogenic factor in the development of fatty liver. The most important reasons will be the hyperglycemia, high blood glucose, causes oxidative stress and leading inflammation. High fructose diet modulated the distribution of gut microbes and increased Gram negative bacteria proliferation further increased lipopolysaccharide (LPS) releasing. Lactoferrin, an iron-binding glycoprotein, regulated several physiological functions such as antimicrobial activity, especially in Gram negative bacteria. Previous studies indicated lactoferrin reduced serum triglyceride and down-regulated inflammation in rat. The purpose of this study was to investigate that lactoferrin protects against the onset of non-alcoholic fatty liver disease via anti-inflammation in high-fructose administered murine model. Our results indicated high-fructose diet stimulated intestinal bacterial overgrowth and increased intestinal permeability, subsequently leading to endotoxin in blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 (TLR-4) indicated lactoferrin could modulate LPS mediated inflammatory cascade. These inflammatory response in adipokines include interleukin-1β (IL-1β), IL-6, IL-33, tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), thymic stromal lymphopoietin (TSLP) and adiponectin. Furthermore, lactoferrin could reduce serum and hepatic triglycerides, and lipid accumulation in liver, finally reduced hepatic damage and decreased serum alanine aminotransferase (ALT) release. These beneficial effects of lactoferrin were related to the decreased LPS induced inflammatory cascade in liver and also significantly lowered liver weight that ameliorated fatty liver by decrease of triglyceride and cholesterol syntheses in activating hepatic steatosis. These findings suggest that lactoferrin had the potential to improve nonalcoholic fatty liver disease in murine model.

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37

Chang, Ching-He, and 張靜合. "Functional Study of MicroRNA-7a Depletion Induced Zebrafish Early Onset of Non-alcoholic fatty liver disease." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/88680702450712827170.

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碩士
國立臺灣海洋大學
生命科學暨生物科技學系
104
MicroRNAs (miRNAs) are short non-coding RNAs of 20-24 nucleotides that play key roles in the regulation of gene expression. Recently, several researchers have reported that miRNA we links to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and the progression to non-alcoholic steatohepatitis (NASH). NASH may progress to advanced-stages of hepatic fibrosis, cirrhosis and liver failure, and then causes of death and hepatocellular carcinoma (HCC). However, there is rarely known about specific therapies for NASH. To development of new target therapy is urgently needed. MicroRNA-7 (miR-7) plays an important role in the occurrence and development of tumors as a key tumor suppressor. Previous research indicated that mir-7a is down-regulated in ob/ob mouse liver and HNF4a-NF-jB feedback circuit including mir-7 is identified in HCC, miR-7 directly inhibits a number of oncogenic targets and impedes cancer progression in vitro and in vivo. Therefore, we designed a miR-7a sponge expression vector drove by liver specific promoter L-FABP combined fluorescent gene to establish transgenic fish. We show that miR-7-silencing activity is specifically knocked down in the transgenic fish liver. As the insights into our research aims for studying NAFLD, feeding these transgenic fish with high fat diet (HFD) and low fat diet (LFD) . We observed the accrual of fat in hepatocytes with Oil Red O staining. Our data shows that miR-7a sponge transgenic fishs have more lipid droplet accumulation in liver than WT with HFD and LFD. In the future, we will plan to analyze miR-7 target genes and of cell proliferation and cell apoptosis in transgenic fish, it can be expected to activities help the study of NAFLD.

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38

Liaw, Bor-Song, and 廖柏松. "Combination of Recombinant Human Hepatocyte Growth Factor and Bone Marrow Cells for the Elimination of Radiation-Induced Liver Damage." Thesis, 2003. http://ndltd.ncl.edu.tw/handle/42312828287404660741.

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碩士
國立臺灣大學
獸醫學研究所
91
Introduction: Recombinant human hepatocyte growth factor (rhHGF) is a stem cell growth factor with great clinical implication potential. There are evidences of bone marrow cells are capable source of stem cells for specific organ damage repair. The primary aim of the study is to evaluate the protective effects of combination HGF and bone marrow cells in radiation-induced liver damage. Methodology: We have set up rat radiation-induced liver damage model by delivering 65 Gy whole liver irradiation with cobalt irradiation under exploratory laparatomy. Female rats were allocated into groups of RT alone, RT + BM (whole bone marrow cells), RT + rhHGF and RT + rhHGF + BM. rhHGF (20μg/kg) was infused into portal vein just before irradiation and followed by tail vein injection with dose of 50μg/kg from day 1 to 4 after irradiation in HGF-assigned group. 3×107 whole bone marrow cells from male rats were also infused into portal vein immediately after irradiation in BM and rhHGF + BM-assigned groups. The TUNEL assay and trichrome staining were used to evaluate early and subacute complication of liver damage. The Y-chromosomes in female rats liver tissues were identified with fluorescence in situ hybridization (FISH). Results: We found that HGF was able to increase survival rate. The 120th day survival rate were 83%, 66.7%, 0%, 0% in rhHGF + BM group, rhHGF alone group, BM alone group and RT alone group, respectively (p<0.05). rhHGF + BM seemed to be the most effective modality to prevent radiation-induced liver damage. With HGF infusion, median survival time (MST) was prolonged from 23 days to 120 days with reduce of jaundice, ascites, and hepatomegaly. Bone marrow cells may not be able to protect liver cells from radiation injury, however, prolonged MST from 23 days to 37.5 days can be observed. rhHGF + BM is also more effective than BM alone that MST prolonged from 37.5 days to 120 days. The TUNEL assay proved the direct anti-apoptotic effect of HGF from radiation damage. Trichrome staining also showed decreased liver fibrosis. FISH stain confirmed that bone marrow cells from male donors did engraft in the female liver. Conclusion: We have demonstrated that rhHGF effectively protects the rat liver from radiation-induced apoptosis, subsequent fibrosis and facilitates the engraftment of bone marrow cells in liver. The bone marrow cells can improve the liver regeneration from radiation damaged but not the prevention of apoptosis. It is synergistic of combination rhHGF and BM therapy than BM alone. The strategy has great potential in the prevention of radiation-induced liver damage.

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39

Cheng, Lu Chieh, and 鄭輅婕. "The pathological mechanisms of high cholesterol and high cholesterol-fructose diets-induced non-alcoholic fatty liver disease." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/8em2dn.

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WANG, CHIA-LING, and 王嘉鈴. "Ginkgolide Regulated Hepatic Lipid Metabolism and Reduced Nonalcoholic Fatty Liver Disease in High-Fat Diet-Induced Obese Mice." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/15802727958000192025.

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碩士
長庚科技大學
健康產業科技研究所
104
In China and Taiwan, the fruit of ginkgo is used to treat asthma, and the leaf of ginkgo extract is used to treat dementia, cardiovascular, and cerebrovascular diseases. Ginkgo extract also inhibited platelet aggregation and promoted free radical scavenging in mice. Several compounds was isolated from Ginkgo, including ginkgolides A, B, and C. Ginkgolides B was found that could reduce ROS production for improving the damage of hepatocytes by alcohol. In this study, we would investigate whether ginkgolide B modulate lipogenesis, lipolysis in hepatocytes. HepG2 cells incubated with oleic acid for 24 h, then the cells treated with various concentrations of of ginkgolide B. We found that ginkgolide B significantly suppressed fatty acids intake in the hepatocytes. Ginkgolide B also increased adipose triglyceride lipase and perilipin for lipolysis and enhanced phosphorylation of AMPK and SIRT-1 expression, resulting in inhibited activity of acetyl-CoA carboxylase for fatty acid synthesis. Consistently, intraperitoneal administration of ginkgolide B to high fat diet-induced obese mice significantly ameliorated body weight gain, decreased hepatic steatosis and adiposity. The results suggest that ginkgolide B is an effective flavone for improved obesity and nonalcoholic fatty liver disease by inhibiting adipogenesis and increasing lipolysis.

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WEI, CIAO-HAN, and 魏巧涵. "Fisetin Suppresses Adipogenesis in FL83B Hepatocytes and Alleviates High-Fat Diet-Induced Nonalcoholic Fatty Liver Disease in Mice." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/26506504056766937164.

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碩士
長庚科技大學
健康產業科技研究所
104
Fisetin is a bioactive flavonoid, and fisetin widely distributes in vegetables and fruits. It has been shown that fisetin has antioxidant, anti-inflammatory and anti-tumor effects. Fisetin could suppress the proliferation and metastasis of cancer cells. Fisetin also inhibited lipid accumulation of 3T3-L1 by blocked mTOR-C/EBP α pathway. However, the anti-obesity effects and mechanism of fisetin remain unclear. This study aimed to evaluate whether fisetin has an anti-obesity effects of in FL83B cells and if fisetin can improve non-alcoholic fatty liver disease in mice. FL83B incubated in medium contained 0.5 mM oleic acid in absence or presence of fisetin (10-100 μM) for 24 hours. Fisetin significantly inhibited lipid accumulation and lipid peroxidation. Fisetin also increased the enzyme of lipolysis and enhance the enzyme of fatty acid β-oxidation. We also found that fisetin decreased fatty acid synthase for lipogenesis. Next, we evaluated the protective effect of fisetin against nutritional steatohepatitis in mice. C57BL/6 mice fed with high fat diet for induced non-alcoholic fatty liver disease. We found that fisetin could decrease body weight, epididymal fat pad weight in the obese mice. Fisetin also suppressed lipid accumulation of liver tissue. Our study suggested that fisetin may have a potential therapeutic effect to regulate lipid metabolism in improved non-alcoholic fatty liver disease.

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Wun, Sheng-Fa, and 温勝發. "Exosome-carried YTH methyladenosine RNA binding domain family 2 (YTHDF2) protein Induced Inflammatory Signaling in nonalcoholic fatty liver disease." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/2jen74.

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碩士
國立陽明大學
臨床醫學研究所
107
Hepatocyte cellular dysfunction and pro-inflammtion by lipid induced release of exosomes(EXO) from hepatocytes, which activate an inflammatory phenotype are characteristics of nonalcoholic steatohepatitis (NASH).Exosomes are extracellular vesicles responsible for communication between cells. However, the regulatory mechanism of YTH domain methyladenosine RNA binding family 2 (YTHDF2) protein is not understand. In this study, it was shown that incubation with lysophosphatidylcholine (LPC), a central player for hepatic fat accumulation and inflammation, resulted in dose-dependent increase in fatty acid accumulation assessed by Oil Red O staining. We have found that treatment of LPC-induced lipotoxicity promoted the expression of m6A reader YTHDF2. Interestingly, the LPC treatment at the concentration of 20 µM shown to significantly increase nanoparticles secretion compared vehicle control based on nanoparticle tracking analysis (NTA). Moreover, these isolated exosomes were positively stained CD63 and YTHDF2 by using super-resolution fluorescence microscopy and co-localization is confirmed. We investigated the effect of the exosomes-carried YTHDF2 protein derived from overexpression YTHDF2 of human hepatocytes (HepG2) on human hepatocytes in vitro. In vitro data showed that EXO could be uptake and exert paracrine effect in the human hepatocytes exposing to different doses. Quantitative PCR detection showed that EXO treatment significantly induced the upregulated expression of pro-inflammatory genes in the human hepatocytes. Intriguingly, western blotting detection demonstrated that YTHDF2 overexpression recovered the phosphorylation levels of p38, suggesting the involvement of the YTHDF2-mediated p38 signaling pathway in injured livers. In conclusion, our findings demonstrate that EXO derived from LPC-induced human hepatocytes aggravate nonalcoholic fatty liver disease and the mechanism may involve an EXO carried YTHDF2 protein-triggered p38 Inflammatory Signaling pathway.

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DAI, YI-WEN, and 戴逸玟. "Maslinic Acid Ameliorated Nonalcoholic Fatty Liver Disease and Regulated Hepatic Lipid Metabolism in High-Fat Diet-Induced Obese Mice." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/36002830558639001427.

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Lin, Wei-Hsiang, and 林煒翔. "To establish the animal models for alcohol liver disease and nanoparticles-induced lung injuries in rat/mice and related researches." Thesis, 2006. http://ndltd.ncl.edu.tw/handle/48796166470854999412.

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碩士
國立中興大學
生命科學系
94
Abstract(Part I. The effects of catechin alcohol on alcohol liver disease) Liver is an important detoxifying and metabolic organ in the human body. Drinking and viral infection are two of the main causes of liver diseases. Obvious correlation was observed between the increasing global alcohol consumption and the rising incidence of the alcohol liver diseases. Aumulating evidence indicated that reactive oxygen species (ROS) contribute to alcohol-induced liver diseases. Therefore, We test whether adding antioxidant ingredients, like catechins, in the 36% alcohol may prevent or reduce alcohol liver damage. Our results showed that catechin alcohol can significantly scavenge O2-‧, H2O2 and HOCl in vitro. Furthermore, in our acute liver damage animal model, catechin alcohol (0.25 ml/250g) reduced the value of ROS from the liver surface and bile and blood. We also found that the occurrence of chronic alcoholic liver disease was significantly reduced after one month of oral catechin alcohol when compared to 36% alcohol. We found the levels of blood, bile, and liver ROS were reduced in the catechin alcohol treated high fat-feeding rats, also , the level of VLDL and LDL in blood, the contents of 4- hydroxynonenal/4HNE in liver and the number of Kupffer cells (ED-1 positive stains) decreased and sparse alcohol fatty liver were observed.. Western blot analysis showed an up-regulation of CuZn-superoxide dismutase (CuZn-SOD) and Bcl-2 protein and a down-regulation of Bax and SREBP-1 protein in the catechin alcohol treated livers. In conclusion, catechin alcohol with antioxidant O2-‧,H2O2 and HOCl offers a protection against alcohol induced oxidative injury via the up-regulation of anti-apoptotic and antioxidant proteins. Abstract(Prat II. To Study the Pulmonary Toxicity of Nano-Particles(UF-TiO2 and Single-Wall Carbon Nanotubes) in mice after intratracheal instillation.) Nanotechnology has important scientific, industrial, and bio-medical applications,however, its effects on human health and and environmental safetyare still uncertain. In fact, a lot of studies have suggested that nano-particle inhalation might induce pulmonary injuries in several animal models. Previous studies have shown that ultra fine-titanium dioxide (UF-TiO2), carbon nanotube, and colliery dust might induce chronic pulmonary inflammation, pulmonary fibrosis, and lung cancer in rat . The macrophages thatactivated by UF-TiO2produce lots of oxygen free radicals and some growth factors, that lead to chronic inflammation. Inhalation of nanoparticles could induce more severe pulmonary toxicity than microparticles. Nanoparticle inhalation can induce pulmonary toxicity, however its pathogenic mechanism is not fully understood. In this study, UF-TiO2 R type and Single-Wall Carbon Nanotubes (SWCNT) were used to investigate their pulmonary toxicity and molecular mechanisms of pathogenesis . Mice were intratracheally instilled with 0.1 or 0.5 mg of fine-TiO2 R type (F-TiO2 R type), UF-TiO2 R type and SWCNT in 3 days or 7 days. UF-TiO2 R type and SWCNT induced epithelioid granulomas, pulmonary emphysema with extensive disruption of alveolar septa, type II pneumocyte hyperplasia, foamy macrophage accumulation, pulmonary cell proliferation and alveolar septa cells apoptosis. We also utilize cDNA microarray and Affymetrix GeneChip to detect the gene expression profiles of mice's lung with UF-TiO2 R type treatment. We found that hundreds of distinct genes were differentially expressed, including cytokines, chemokines (vEGFc, PlGF, Flt-3, MIP-1, MIP-2, MCP-1, IL-1, C-C and C-X-C), and cell cycle regulators (cdk2, cyclin A, and B).Furthermore, We used the KEGG and BioCata databases to address how these genes might involve in pulmonary pathogenesis.. According to the arrays’ data and pathway analysis, we found that placenta growth factor (PlGF), cell cycle, apoptosis, chemokine and complement pathways might involve in UF-TiO2 R type-induced pulmonary pathological changes. In conclusion, our study has not only pointed out that nano-particle could induce pulmonary injury, but also setup a platform of animal model to examine the pulmonary toxicity of nanoparticles in vivo. We also provide possible pathogenic pathways that might be involved.

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Shyu, Ming-Huan, and 徐明煥. "Assessments of Hsian-tsao (Mesona procumbens Hemsl.) and its active compounds, olenaolic acid and ursolic acid, on improvements of chemical-induced liver injury and nonalcoholic fatty liver disease (NFALD)." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/06781461071684756075.

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博士
國立中興大學
食品暨應用生物科技學系所
101
Oleanolic acid (OA) and ursolic acid (UA) are triterpenoids in chinese herbal medicine plants (e.g. Mesona procumbens Hemsl, Hsian-tsao) and have beneficial effects on antioxidant capacity, anti-inflammation, hepatoprotection and induction of cancer cells apoptosis. The aim of study was to evaluate the potential protective effects of OA and UA on different risk factor-induced liver diseases. The previously study indicated that water extract of Hsian-tsao could decrease acute liver damage in SD rats induced by t-BHP (tert-butyl hydroperoxide) through enhancing antioxidant capacity in rats. First, the protective effects of EHT (extracts of Hsian-tsao) and its active compounds (OA and UA) on chronic liver damage and fibrosis in vivo and in vitro were evaluated. The results showed that EHT decreased the relative liver weight in carbon tetrachloride (CCl4)-treated SD rats. Serum aspartate aminotransferase (AST) and alanine aminotranferease (ALT) levels in rats with EHT treatment were significantly lower than that in rats by CCl4-induced only (p < 0.05). Histological examination expressed EHT had significantly protective against liver fibrosis (p < 0.05). These data showed that EHT could decrease liver fibrosis in rats induced by CCl4. When rats fed EHT could also significantly increase total antioxidant capacity (TEAC) and decease malondialdenhyde (MDA) in liver than only CCl4-induced rats (p < 0.05). In antioxidant enzymes, orally treated EHT raised glutathione peroxidase (GPx), glutathione S-transfertase (GST), catalase activity and total glutathione (GSH) content (p < 0.05). These data showed that EHT could increase the antioxidant enzymes and decrease lipid peroxidation to enhance total antioxidant capacity in CCl4-induced rats. EHT also diminished the protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and decreased the protein level smooth muscle α-actin (α-SMA) and the activities of matrix metalloproteinase (MMP)-2 and -9 in CCl4-induced rats. These data showed that EHT could inhibit inflammation and liver fibrosis in CCl4-induced rats. Rat hepatic stellate HSC-t6 cells activation induced by phorbol-12-myristate-13-acetate (PMA) was uesd to study the anti-fibrotic effects of OA and UA in vitro. Treating these cells with OA or UA caused a decrease in the protein level of α-SMA and the activity of MMP-2. These data suggested that OA and UA might be the anti-fibrotic compounds in Hsian-tsao. OA and UA are commonly found in plants and herbs, and have been reported to prossess hepatoprotective, anti-inflammatory and anticancer activitires. The effects of OA and UA on induction of apoptosis in human hepatocellular carcinoma HuH 7 cells and the related mechanisms were investigated. The results demonstrated that OA and UA could inhibit the growth of HuH 7 cells with IC50 values of 100 and 75 μM, respectively. Cell cycle analysis using flow cytometry indicated that OA and UA progressively increased the fraction of HuH 7 cells in sub-G1 phase in dose-dependent manner. These data showed that OA and UA could induce HuH 7 cell apoptosis to inhibit HuH 7 cell growth. Treatment with OA or UA induced a dramatic loss of the mitochondria membrane potential and interfered with the ratio of expression levels of pro- and antiapoptotic Bcl-2 family members in HuH 7 cells. OA and UA-induced apoptosis involved the release of mitochondria cytochrome c into the cytosol and subsequently induced the activation of caspase-9 and caspase-3, followed by cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, HuH 7 cells treated with OA and UA also suppressed the activity of nuclear factor-κB (NF-κB) to modulate the mRNA expression of X-linked inhibitor of apoptotic protein (XIAP) as compared with untreated cells. These results demonstrated that OA and UA induce HuH 7 cells apoptosis through a mitochondria-mediated pathway and regulation of the activity of NF-κB and the mRNA expression of its downstream protein, XIAP. Insulin resistance could promote triglyceride (TG) lipolysis in the adipose tissue to release a number of free fatty acids into blood, and fre fatty acids could transfer into liver. But excess free fatty acids in liver could promote a large amount of TG synthesis to cause nonalcoholic fatty liverdisease (NAFLD). Palmitic acid (PA) and Oleic acid (OLA) are the main type of free fatty acids in human blood, and the ratio of saturated fatty acid and unsaturated fatty acid is 1 : 2. We established the fatty acid mixture (FFA mixture, PA : OA = 1 : 2)-induced nonalcoholic fatty liver disease in HepG2 cells as the in vitro model for the study of NAFLD. The results showed that 1 mM of PA or FFA mixture could significantly inhibit HepG2 cells growth (p < 0.05), but OLA was no cytotoxicity. In addition, the results showed that PA could increase the intracellular Ca2+ concentration and the gene expressions of endoplasmic reticulum (ER) stress related proteins, 78-kDa glucose-regulated protein (GRP78) and C/EBP homologous protein (CHOP), and the activities of cathepsin B and caspase-3. Moverover, OLA and FFA mixture could slightly increase organelles damage. These results suggested that PA was the main type of free fatty acid to induce organelles damage. PA, OLA and FFA mixture also increased intracellular reactive oxygen species (ROS) production in HepG2 cells, suggesting ROS plays a role in free fatty acid induced liver damage. Besides, PA, OLA and FFA mixture could increase the gene expressions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Oil Red O-stained material (OROSM) was used to investigate the effects of free fatty acids on fat-droplet formation in HepG2 cells. The results showed that OLA and FFA mixture significantly increased fat-droplet formation in HepG2 cells (p < 0.05), but PA could slightly increase fat-droplet formation. The data suggested that OLA was the main type of free fatty acid to increasing triglyceride (TG) synthesis in HepG2 cells. In addition, The results showed that PA, OLA and FFA mixture cloud increase the gene expressions of stearoyl-CoA desaturase 1 (SCD-1), fatty acid synthase (FAS), acetyl-CoA carboxylase α (ACCα), HMG-CoA reductase (HMGCoAR), low-density lipoprotein receptor (LDLR), sterol regulatory element binding proteins-1 (SREBP-1) and peroxisome proliferator-activated receptor γ (PPARγ), and these fatty acids also slightly increased the gene expression of carnitine palmitoyltransferase 1 (CPT-1), but free fatty acids could not influence the gene expressions of uncoupling protein 2 (UCP2) and peroxisome proliferator-activated receptor α (PPARα). The data suggested that FFA mixture-induced HepG2 cells could be the in vitro model for the study of NAFLD. Previously study showed that palmitic acid (PA) and oleic acid (OLA) are the main type of free fatty acids to promote the formation of nonalcoholic fatty liver disease, and free fatty acid mixture (FFA mixture, PA : OLA = 1 : 2) could induce organelles damage and lipid-droplet formation to promote the formation of nonalcoholic fatty liver disease (NAFLD) in HepG2 cells. The potential protective effects of OA and UA on NAFLD in FFA mixture-induced HepG2 cells were further determined. The results showed that OA and UA could decrease ROS production, and increase the gene expressions of glutathione peroxidase 1 (GPx1), γ-glutamylcysteine synthetase (γGCS), CuZn superoxide dismutase (CuZnSOD), Mn superoxide dismutase (MnSOD) and catalase in FFA mixture-induced HepG2 cells. Besides, OA and UA could decrease the intracellular Ca2+ concentration, the gene expressions of GRP78 and CHOP, and the activities of caspase-3 and cathepsin B in FFA mixture-induced HepG2 cells. These data suggested that OA and UA could decrease ER stress, lysosome and mitochondria damage through decreasing ROS production and increasing the gene expressions of antioxidant enzymes in HepG2 cells induced by FFA mixture. Besides, OA and UA could decrease the gene expressions of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in FFA mixture-induced HepG2 cells. Moreover, OA and UA could decrease fat-droplet formation in FFA mixture-induced HepG2 cells. These results showed that OA and UA could decrease the expressions of SCD-1, FAS, ACCα, HMGCoAR, LDLR, SREBP-1 and PPARγ, and increase the gene expressions of CPT-1, UCP2 and PPARα in FFA-mixture induced HepG2 cells. These data suggested that OA and UA could decrease fat-droplet formation by decreasing fat and cholesterol synthesis-related gene expression and increasing fatty acid oxidation-related gene expression in HepG2 cells induced by FFA mixture. In conclusion, the potential effects of OA and UA could be inhibition of liver fibrogenesis, depletion of NAFLD induced by FFA and induction of hepatoma cell apoptosis to protect against liver diseases.

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Chang, Ting-Xuan, and 張庭瑄. "Hepatoprotective activity of garlic essential oil and its active compound diallyl disulfide in high fructose-induced nonalcoholic fatty liver disease mice." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/j8u53h.

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碩士
國立臺灣大學
食品科技研究所
105
Due to the change of eating habits, people tend to consume more sugar-containing food in Taiwan as well as worldwide. Excessive fructose consumption resulted in the development of non-alcoholic fatty liver disease (NAFLD). A recent study found that prevalence of NAFLD in Taiwan is around 11.4-41%. Typically, NAFLD is defined as lipid accumulation in the liver more than 5% by weight. Garlic (Allium sativum L.) is a traditional food ingredient and it has been reported as the liver protective food. A recent study found that the garlic essential oil (GEO) protects the liver from high fat diet-induced NAFLD by reducing the hepatic lipid accumulation and inflammation. However, the effect of GEO in high fructose-induced NAFLD and its mechanism are still unknown. The aims of this study were to investigate the hepatoprotective effect of GEO and its active compound diallyl disulfide (DADS) in the high fructose-induced NAFLD mice model and to explore its mechanism via hepatic lipogenesis pathway. Ten week-old male C57BL/6J mice were divided into six groups: (1) control group, (2) 30% fructose-induced NAFLD group, (3) 30% fructose + low dosage of GEO group (25 mg/kg bw), (4) 30% fructose + high dosage of GEO (50 mg/kg bw), (5) 30% fructose + low dosage of DADS group (10 mg/kg bw), and (6) 30% fructose + high dosage of DADS (20 mg/kg bw). The treatment groups were daily gavaged with GEO or DADS for 8 weeks, then the mice were sacrificed. In this study, the results indicated that GEO and DADS significantly exhibited hepatoprotective activity against high fructose-induced NAFLD by reducing approximately 44-56% serum aspartate aminotransferase (AST) and 36-46% hepatic triglyceride (TG) (p < 0.05). In addition, the dose of 10 mg/kg bw DADS significantly reduced 20% serum cholesterol and 8% liver cholesterol levels (p < 0.05), and the dose of 20 mg/kg bw DADS significantly reduced serum 57% alanine transaminase (ALT), 30% TG and 31% free fatty acid (p < 0.05) compared with 30% fructose-induced NAFLD group. Moreover, liver histopathological analysis indicated the accumulation of hepatic glycogen in mice with high fructose diet, but the high dosage of DADS significantly reduced glycogen accumulation in the liver (p < 0.05). Since DADS exhibited higher anti-NAFLD activity than GEO, thus, this study we further investigated the effect of DADS on the hepatic de novo lipogenesis and β-oxidation related protein. DADS supplementation prevented the hepatic lipogenesis by suppressing acetyl-CoA carboxylase (ACC), carbohydrate-responsive element-binding protein (ChREBP) and sterol regulatory element-binding protein-1c (SREBP-1c) in NAFLD mice. Moreover, DADS improved the hepatic β-oxidation by enhancing carnitine palmitoyl transferase-1 (CPT-1). In conclusion, our results suggested that supplementation of GEO or DADS for 8 weeks could prevent the development of the NAFLD and the potential mechanism was through suppressing de novo lipogenesis and enhancing lipid β-oxidation.

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47

Ding-Bang, Shu, and 舒定邦. "The Modulation of Lactobacillus plantarum, Lactobacillus rhamnosus, Prebiotics and Synbiotics on High-Fructose induced Nonalcoholic Fatty Liver Disease in Murine Model." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/22633581304638286690.

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碩士
東海大學
畜產與生物科技學系
102
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver injuries ranging from steatosis to steatohepatitis that has become the most common liver disease and is frequently associated with obesity and hepatic manifestation of the metabolic syndrome. The prevalence of fatty liver disease is about 30% in Taiwan, and the obese individuals (80%) are in higher risk of NAFLD. Over-intake of fructose in daily brewages is the risk factors for the development for NAFLD. In this study, male C57BL/6 mice were divided into six groups, the control group, LP group, LCR group, prebiotics group, synbiotics group and the fructose control group (30% of fructose in drinking water), respectively. The purpose of this study imitated to explore these treatment in the NAFLD induced by fructose and monitor area under curve of glucose (AUCG), adiponectin, thymic stromal lymphopoietin (TSLP), interleukin-6 (IL-6), tumor necrosis factor (TNF-) in liver tissue homogenates by ELISA, and serum aspartate aminotransferase (sAST), alanine aminotransferase (sALT), triglycerides (sTG) and cholesterol (sCHOL),. The results shows all the treatment could significant alleviate the serum TG, CHOL , AST and ALT. In histological evaluation of H&E stain and Oil-Red-O stain liver specimens demonstrated massive panlobular microvesicular and macrovesicular steatosis in mice fed with high fructose corn syrup. Immunohistochemistry stain we examined 4-hydroxynonenal, TSLP and TLR-4 in liver sections. Both probiotic and synbiotic plays an important role in regulate inflammation effect and decrease adipose tissue infiltration in liver. Keywords: High-fructose syrup, Inflammation, Nonalcoholic fatty liver disease, Probiotics, Prebiotics, Synbiotics.

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Zhang, Wen-Juan, and 張文娟. "Study on the improvement of high-fat/high-fructose diet-induced nonalcoholic fatty liver disease by mycelium glycoprotein (Antrodan) of Antrodia cinnamomea." Thesis, 2019. http://ndltd.ncl.edu.tw/handle/skbkux.

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碩士
弘光科技大學
營養醫學研究所
107
Obesity is one of the important factors to cause the nonalcoholic fatty liver disease (NAFLD), and increasing trends in the prevalence of NAFLD have being resulted from the obesity. The Food and Drug Administration (FDA) currently doesn't have an approved drug for specific treatment of NAFLD, thus seeking the complementary and alternative medicine (CAM) is currently considered as one of the strategies. According to previous reports, the glycoprotein (Antrodan) isolated from the mycelium of Antrodia cinnamomea (ACM) has been indicated with significant anti-inflammatory biological activity, especially for liver protection has been the most interested to people. The aims of this study were to explore the effects of Antrodan in improving the symptoms of NAFLD in mice. NAFLD was induced by high-fat high-fructose diet (HFD) in the male 5-week-old C57BL / 6 mice and was investigated from the oral administration of Antrodan (20 and 40 mg/Kg) in simultaneously compared with the treatment of the weight loss drug Orlistat (10 mg/Kg). The results showed that the HFD diet significantly caused obesity and fatty liver symptoms. In blood biochemical parameters, low dose of Antrodan reduced the triglyceride (TG), blood glucose, uric acid, and liver index (GOT and GPT) by 1.87%, 1.71%, 1.45%, 2% and 1.45 % respectively, and high dose Antrodan reduced the TG, blood glucose, uric acid, GOT and GPT by 2.00%, 1.37%, 1.07%, 1.09 and 1.22% respectively, while regardless of dose in Antrodan reduced the total cholesterol (T-CHO) by 1.16%, compared with the HFD group. In the results of enzyme immunoassay, low doses of Antrodan reduced the insulin by 1.17%, adiponectin by 0.87%, and leptin by 1.30%, and high dose Antrodan reduced insulin by 1.22%, adiponectin by 0.85%, and leptin by 0.28%, compared with HFD group. The expression of the lipid metabolism associated proteins SIRT1, p-AMPK and PGC-1α were up-regulated by 0.94, 0.83 and 1.59% respectively in low dose Antrodan group, while the increasing by 0.84, 0.88 and 1.48%, respectively were shown in high dose Antrodan group. In addition, the expression of PPARr and SREBP1 proteins were down-regulated by 1.04 and 1.09% respectively in low dose Antrodan group. While there were down-regulated by 1.30 and 1.17% respectively in high dose Antrodan group. Oral Antrodan showed the better effects in the expressions of Sirt1, p-AMPK, PPAR, SREBP1 and PGC-1α proteins than those of Orlistat. Overall, it can be concluded that the Antrodan has the partial effects in the improvement of lipid metabolism and accumulation in the liver even at low dosage. The improved effects of Antrodan on NAFLD symptoms were proposed from the regulation of SIRT1/AMPK/PGC-1α pathway, which was reported firstly that the Antrodan isolated from ACM could be one of the candidate of CAM in the improvement of the symptoms of NAFLD. Keywords: nonalcoholic fatty liver disease, Antrodia cinnamomea, glycoprotein, mouse, SIRT1, AMPK

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Nocon, Allison. "Resveratrol stimulation of SIRT1 & exogenous delivery of FGF21 mimics metformin's ability to alleviate non-alcoholic fatty liver disease caused by diet-induced obesity." Thesis, 2015. https://hdl.handle.net/2144/13942.

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Metformin has been used clinically since 1957 for its efficacy and safety as therapy for type 2 diabetes. Besides ameliorating hyperglycemia without risk of hypoglycemia, metformin also lowers plasma triglyceride levels. Furthermore, a wealth of data shows that metformin facilitates weight loss in mice as well as humans. Due to its numerous metabolic benefits, researchers and clinicians are interested in the possibility of using metformin as treatment to combat obesity and other metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). Despite being the most commonly prescribed anti-diabetic, metformin’s complete mechanism(s) for weight loss or for lowering glucose and lipids remains an enigma. Our studies show that metformin-treated mice exhibited decreased caloric intake, providing a viable mechanism for metformin to bring about weight loss. Intriguingly, we found that metformin induces PRDM16 to promote browning of iWAT and increase expression of thermogenic genes such as UCP1 and DIO2. However, metformin did not appear to increase energy expenditure. It’s possible that metformin’s effect on energy expenditure was masked since energy expenditure measurements were taken when metformin-treated mice were still losing weight and were in a state of negative energy balance. Recently, there has been much attention given to AMPK activators as exercise mimetics. Metformin is known to activate AMPK and similarly brings about many beneficial effects as exercise such as alleviation of obesity-induced NAFLD. SIRT1 stimulation by resveratrol and delivery of exogenous FGF21 mimics metformin’s ability to combat obesity and improve NAFLD. Collectively, these results implicate metformin, resveratrol, and exogenous administration of FGF21 as beneficial therapies for weight loss and amelioration of NAFLD.

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Vemuri, Madhuri. "Effect of omega-3 fatty acids on t10, c12-conjugated linoleic acid induced insulin resistance, non alcoholic fatty liver disease and tissue fatty acid composition." Diss., 2009. http://proquest.umi.com/pqdweb?did=1987416851&sid=1&Fmt=2&clientId=48051&RQT=309&VName=PQD.

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Dissertations / Theses on the topic 'Radiation induced liver disease'

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