Philosophiae Doctor - PhD / The blood-brain barrier (BBB) is a critical interface between the blood circulation and brain tissue which performs critical selection of circulating molecules that gain access to the brain tissue. Its unique ability to adjust to changes in the constituents of the blood circulation confer in the BBB a dynamic nature enabling changes in its properties to suit the homeostatic needs of the brain. Dysfunction of the BBB has been established to be pivotal to the initiation and/or maintenance of an array of neurological disorders, most of which involve the production of excess reactive oxygen species (ROS) and oxidative stress in their pathophysiology. Thus, clinical trials of exogenous antioxidant agents have been proposed and initiated, with most results being inconclusive. Extensive studies of the impact, capacity and plasticity of endogenous antioxidants in the cells that constitute the blood-brain barrier, especially the brain endothelial cells, therefore, became necessary for the rational choice, timing, and the mode of application of antioxidants in the management of oxidative stress-mediated neurological diseases.

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The gut microbiota and its metabolites – namely short chain fatty acids (SCFAs) – interact with the digestive, immune, and nervous systems. Microbiota with disrupted composition are highly associated with obesity, gastrointestinal symptoms, and chronic inflammation. Levels of SCFAs in the feces can represent dynamics of the microbiota, and they represent one mechanism by which the microbiota interacts with its host. This study aimed to further our understanding of associations between microbiota bacterial diversity and SCFAs, immune markers, BMI, and GI symptoms and to identify bacteria that are differentially abundant in different BMI groups and with synbiotic supplementation. Data (SCFAs, immunoglobulins, body mass index, fecal fiber, fecal protein, measures of GI symptoms, and 16s RNA sequences, n=11) was extracted from a randomized control trial investigating the effects of synbiotic supplementation in non-celiac gluten-sensitive participants. QIIME2 was used to process 16s RNA data, analyze quantitative, qualitative, phylogenetic quantitative, and phylogenetic qualitative measures of alpha and beta diversity and to perform an analysis of composition of microbiomes (ANCOM) for identification of differential abundances. Multiple metrics of alpha diversity were found to significantly correlate with IgG4, IgM, IL-2, acetate, propionate, isobutyrate, valerate, isovalerate, caproate, heartburn, urgent need to defecate, and feelings of incomplete evacuation. Multiple metrics of beta diversity were significantly different between normal and overweight, normal and obese, and overweight and obese BMI classification groups. Beta diversity was also found to significantly correlate with IgG1, IgG3, IgG4, IgA, IL-6, IL-8, fecal fiber, propionate, butyrate, heartburn, acid regurgitation, nausea and vomiting, bloating, abdominal distension, increased gas, and eructation. The synbiotic intervention did not significantly alter alpha or beta diversity. An ANCOM identified bacterial taxa differentially abundant with BMI shifts and synbiotic supplementation, though these taxa were not those included in the synbiotic. Findings demonstrate alpha and beta diversity associations with various SCFAs, GI symptoms, immune markers, and BMI, and the results of the placebo-controlled intervention suggest careful consideration of placebo contents moving forward. This research supports plans to apply analysis to larger sample sizes to elucidate changes microbial profiles that are associated with clinically relevant biomarkers and symptoms.

The ability of fungal-derived β-glucan particles to induce leukocyte activation and the production of inflammatory mediators, such as tumor necrosis factor (TNF)-α, is a well characterized phenomenon. Although efforts have been made to understand how these carbohydrate polymers exert their immunomodulatory effects, the receptors involved in generating these responses are unknown. Here we show that Dectin-1 mediates the production of TNF-α in response to zymosan and live fungal pathogens, an activity that occurs at the cell surface and requires the cytoplasmic tail and immunoreceptor tyrosine activation motif of Dectin-1 as well as Toll-like receptor (TLR)-2 and Myd88. This is the first demonstration that the inflammatory response to pathogens requires recognition by a specific receptor in addition to the TLRs. Furthermore, these studies implicate Dectin-1 in the production of TNF-α in response to fungi, a critical step required for the successful control of these pathogens.

2-Chloroethyl ethyl sulfide (CEES) or half-mustard gas, a sulfur mustard (HD) analog, is a genotoxic agent that causes oxidative stress and induces both apoptotic and necrotic cell death. Sodium pyruvate induced a necrosis-to-apoptosis shift in HaCaT cells exposed to CEES levels ≥ 1.5 mmol/L and lowered markers of DNA damage, oxidative stress, and inflammation. This study provides a rationale for the future development of multicomponent therapies for HD toxicity in the skin. We hypothesize that a combination of pyruvates with scavengers/antioxidants encapsulated in liposomes for optimal local delivery should be therapeutically beneficial against HD-induced skin injury. However, the latter suggestion should be verified in animal models exposed to HD.

RATIONALE: Transgenic mice with cardiac specific overexpression of mutated αB-crystallin (CryABR120G) display Desmin-related myopathy (DRM) with dilated cardiomyopathy and heart failure. Our previous studies showed the presence of progressive mitochondrial abnormalities and activation of apoptotic cell death in CryABR120G transgenic hearts. However, the role of mitochondrial dysfunction and apoptosis in the overall course of the disease was unclear. OBJECTIVE: We tested the hypothesis that prevention of apoptosis would ameliorate CryABR120G pathology and decrease morbidity. METHODS AND RESULTS: We crossed CryABR120G mice to transgenic mice with cardiac specific overexpression of Bcl-2. Sustained Bcl-2 overexpression in CryABR120G hearts prolonged CryABR120G transgenic mice survival by 20%. This was associated with decreased mitochondrial abnormalities, restoration of cardiac function, prevention of cardiac hypertrophy, and attenuation of apoptosis. CryABR120G misfolded protein aggregation was significantly reduced in the double transgenic. However, inhibition of apoptotic signaling resulted in the upregulation of autophagy and alternative death pathways, the net result being increased necrosis. CONCLUSION: Although Bcl-2 overexpression prolonged life in this DRM model, in the absence of apoptosis, another death pathway was activated.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21632号 / 医博第4438号 / 新制||医||1034(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 生田 宏一, 教授 上本 伸二, 教授 竹内 理 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Acute esophageal necrosis, commonly known as black esophagus, is a serious clinical condition that requires prompt diagnosis and management to improve morbidity and mortality. We present a 47-year-old woman who had this potentially lethal condition. The patient initially presented with hematemesis, and esophagogastroduodenoscopy at presentation showed diffuse esophageal ulcerations, erosions, and necrosis. During her admission, she required multiple blood transfusions for active bleeding, after which her clinical condition stabilized. Repeat esophagogastroduodenoscopy showed near-complete resolution of the earlier findings.