京都大学 / 新制・課程博士 / 博士(医学) / 甲第23085号 / 医博第4712号 / 新制||医||1049(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 安達 泰治, 教授 戸口田 淳也, 教授 別所 和久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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CELLULAR MECHANISMS BY WHICH ALCOHOL PROMOTES HIV PROTEASE INHIBITOR-INDUCED HEPATOTOXICITY Michael Hinton, B.S. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University Virginia Commonwealth University, 2019 Major Director: Huiping Zhou Professor, Department of Microbiology and Immunology The development of highly-active-antiretroviral therapy(HAART) has allowed management of HIV and extended the lives of those infected. Alcohol abuse, which is very common in HIV-1 infected patients, is one of the most important co-morbid risk factors for liver injury and has been associated with the occurrence of serious metabolic syndrome and subsequent discontinuation of HAART in HIV patients. We have identified endoplasmic reticulum (ER) stress-induced proapoptotic factor CCAAT-element-binding protein homologous protein (CHOP) as an important mechanism underlying HIV PI-induced inflammation and hepatic lipotoxicity. However, little is known about the mechanistic pathways by which alcohol promotes HIV PI-induced hepatic lipotoxicity. The aim of this study was to determine if inhibition of CHOP expression prevents alcohol- and HIV PI-induced apoptosis and dysregulation of lipid metabolism. We demonstrated that co-administration of alcohol and HIV PIs induced unfolded protein response (UPR) activation, ER stress, and CHOP upregulation in rodent hepatocytes. Both alcohol and HIV PI-induced lipid accumulation and apoptosis were significantly reduced in CHOP-/- hepatocytes. Also, CHOP-/- hepatocytes treated with alcohol and HIV PIs showed inflammation.. Activation of the ER stress-induced proapoptotic factor CHOP is a key cellular mechanism underlying alcohol and HIV PI-induced hepatotoxicity. CHOP expression is key for alcohol and HIV PI-induced dysregulation of key genes involved in lipid metabolism in hepatocytes. Limitations of the study include the usage of global CHOP-/- in lieu of tissue-specific conditional knockout mouse models, nonobservance of the effects of alcohol and HIV PIs on extra-hepatic tissues, and incomplete investigation of the interplay of hepatocytes and resident macrophages.

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Bakgrund: Personer med psykisk ohälsa, och däribland depression, är ett ökande folkhälsoproblem som vanligtvis behandlas med antidepressiva läkemedel och olika former av terapi inom primärvården. Fysisk aktivitet kan erbjudas som behandling vid depression och distriktssköterskan behöver kunskap om fysisk aktivitet och dess användning som sjukdomsprevention och behandling. Detta för att kunna erbjuda individanpassad, evidensbaserad vård till personer med depressionssymtom. Syfte: Syftet med denna litteraturstudie var att beskriva effekten av fysisk aktivitet vid primär depression hos vuxna, samt att undersöka om typen, intensiteten, dosen (frekvensen) eller durationen av den fysiska aktiviteten hade någon betydelse för effekten. Metod: Systematisk litteraturstudie med narrativ syntes, som inkluderar experimentella, randomiserade kontrollerade studier (RCT). Huvudresultat: De flesta av studiernas interventioner utfördes i instruktörsledda grupper och resultatet visade signifikant minskad grad av depression hos majoriteten av deltagarna i interventionerna. Detta samtidigt som all fysisk aktivitet oavsett typ, intensitet och dos (frekvens) gav effekt på depressionssymtom. Dock sågs durationen ha betydelse för effekten av fysisk aktivitet på primär depression och interventioner som pågick under längre tid gav i större utsträckning fördelaktiga signifikanta resultat. Slutsats: All fysisk aktivitet, oavsett typ, intensitet och dos (frekvens) gav effekt vid depression. Interventionernas duration hade betydelse för effekten, och interventioner som pågick under längre tid gav i högre grad signifikanta effekter på depression. Dessa resultat kan vara användbara i distriktssköterskans kliniska arbete och ett stöd när den fysiska aktiviteten ska individanpassas vid behandling av depression, exempelvis vid utbildning och förskrivning av fysisk aktivitet på recept (FaR®). / Background: People with mental illness, including depression, are an increasing public health problem that is usually treated with antidepressants and various forms of therapy in primary care. Physical activity can be offered as a treatment for depression and district nurses need knowledge of physical activity and its use as disease prevention and treatment in order to offer personalised, evidence-based care to people with depressive symptoms. Aim: The aim of this literature review was to describe the effect of physical activity on primary depression in adults, as well as to investigate whether the type, intensity, dose (frequency) or duration of physical activity had any impact on the effect. Method: Systematic literature review with narrative synthesis, including experimental, randomized controlled trials (RCT). Main results: Most of the studies’ interventions were performed in instructor-led groups and the results showed significantly reduced rates of depression in the majority of participants who participated in the interventions. All physical activity, regardless of type, intensity and dose (frequency), had an effect on depressive symptoms. However, the duration was seen to have an impact on the effect of physical activity on primary depression and interventions that lasted for a longer period of time gave more beneficial significant results. Coclusion: All physical activity, regardless of type, intensity and dose (frequency) had an effect on depression. The duration of the interventions had an impact on the effect, and interventions that lasted for a longer period of time had a greater effect on depression. These results can be useful in the district nurse’s clinical work when personalizing physical activity in the treatment of depression, for example in the education of patients and when prescribing physical activity on prescription (FaR®).

The major benefit of geo-referenced exposure modelling tools is the provision of spatially distributed information on expected environmental concentrations. This allows for identifying local and regional concentration differences in the environment which facilitates the development of efficient mitigation strategies. Predicted substance concentrations in the environment are governed by emission rates and representation of the substances' transport and transformation processes on the one hand and by the description of the spatial environmental heterogeneity and temporal variability on the other hand. The shape of river basins and streamflow variability within them is a product of physiographic and climatic factors like e. g. topography, land use, precipitation, or evapotranspiration. These factors are very variable in space and time. This heterogeneity in river basins may have an impact on surface water concentrations of various substances. In this work a hydrological framework for geo-referenced exposure assessment in river networks has been developed which predominantly addresses spatial heterogeneity of river basins. The theoretical background for parameterising a river network for the application of GREAT-ER (Geo-referenced Regional Exposure Assessment Tool for European Rivers) is elaborated and implemented. Quantity of discharge, flow velocity of river water and depth of river bed have to be determined at any location in a river network for the representation of substance dilution, transport and degradation. Temporal variability is handled by a probabilistic approach which demands choice and parameterisation of probability distribution functions to describe the river network characteristics. It is substantiated that discharge and its variation can be described by a lognormal probability distribution. This distribution can be parameterised by spatially distributed information on effective precipitation and specific low flow discharge from the German Hydrological Atlas. Geoprocessing methods are applied to couple information from these maps and the river network. Evaluation of discharge probability distributions by means of gauging data demonstrates good agreement. River depth and flow velocity are estimated on the basis of spatially distributed river structure data and therefore account for actual river morphology more than former approaches do. A comparison with hitherto used flow velocity and depth estimation shows significant differences which trigger perceivable differences in surface water concentration estimates. Identification of the sensitivity of hydrological parameters in terms of chemical fate estimation attaches importance to spatial explicit consideration of river networks. The main benefit of the presented methods is comprehensive incorporation of geo-referenced river basin characteristics into the data basis for the GREAT-ER model because this provides the basis for successful prediction of surface water concentrations by GREAT-ER.

Overweight has become a major health care problem in Western societies and is accompanied by an increasing incidence and prevalence of non-alcoholic fatty liver disease (NAFLD). The progression from NAFLD to non-alcoholic steatohepatitis (NASH) marks a crucial tipping point in the progression of severe and irreversible liver diseases. This study aims to gain further insight into the molecular processes leading to the evolution from steatosis to steatohepatitis. Steatosis was induced in cultures of primary human hepatocytes by continuous five-day exposure to free fatty acids (FFAs). The kinetics of lipid accumulation, lipotoxicity, and oxidative stress were measured. Additionally, ER stress was evaluated by analyzing the protein expression profiles of its key players: PERK, IRE1a, and ATF6a. Our data revealed that hepatocytes are capable of storing enormous amounts of lipids without showing signs of lipotoxicity. Prolonged lipid accumulation did not create an imbalance in hepatocyte redox homeostasis or a reduction in antioxidative capacity. However, we observed an FFA-dependent increase in ER stress, revealing thresholds for triggering the activation of pathways associated with lipid stress, inhibition of protein translation, and apoptosis. Our study clearly showed that even severe lipid accumulation can be attenuated by cellular defenses, but regenerative capacities may be reduced.

Overweight has become a major health care problem in Western societies and is accompanied by an increasing incidence and prevalence of non-alcoholic fatty liver disease (NAFLD). The progression from NAFLD to non-alcoholic steatohepatitis (NASH) marks a crucial tipping point in the progression of severe and irreversible liver diseases. This study aims to gain further insight into the molecular processes leading to the evolution from steatosis to steatohepatitis. Steatosis was induced in cultures of primary human hepatocytes by continuous five-day exposure to free fatty acids (FFAs). The kinetics of lipid accumulation, lipotoxicity, and oxidative stress were measured. Additionally, ER stress was evaluated by analyzing the protein expression profiles of its key players: PERK, IRE1a, and ATF6a. Our data revealed that hepatocytes are capable of storing enormous amounts of lipids without showing signs of lipotoxicity. Prolonged lipid accumulation did not create an imbalance in hepatocyte redox homeostasis or a reduction in antioxidative capacity. However, we observed an FFA-dependent increase in ER stress, revealing thresholds for triggering the activation of pathways associated with lipid stress, inhibition of protein translation, and apoptosis. Our study clearly showed that even severe lipid accumulation can be attenuated by cellular defenses, but regenerative capacities may be reduced.

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No description available.