安静時機能的磁気共鳴画像法を用いた群解析における位相エンコーディング方向の影響

京都大学0048新制・論文博士博士(医学)乙第13387号論医博第2219号新制||医||1048(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 溝脇 尚志, 教授 髙橋 良輔, 教授 渡邉 大学位規則第4条第2項該当Doctor of Medical ScienceKyoto UniversityDFA

TRP Channels as Sensors and Signal Integrators of Redox Status Changes

Proteins are capable of sensing the redox status of cells. Cysteine residues, which react with oxidants, reductants, and electrophiles, have been increasingly recognized as the mediators of this redox sensitivity. Cation channels encoded by the transient receptor potential (trp) gene superfamily are characterized by a wide variety of activation triggers that act from outside and inside the cell. Recent studies have revealed that a class of TRP channels is sensitive to changes in redox status and is notably susceptible to modifications of cysteine residues, such as oxidation, electrophilic reaction, and S-nitrosylation of sulfhydryls. In this review, we focus on TRP channels, which directly sense redox status, and discuss the biological significance of cysteine modifications and the consequences of this chemical reaction for physiological responses

Exhaled Breath Marker in Asthma Patients with Gastroesophageal Reflux Disease

Prevention of acid is important in gastroesophageal reflex disease (GERD)-related asthma therapy. Proton pump inhibitors (PPI) and H2-receptor blockers have been reported as useful therapies for improving asthma symptoms. GERD prevalence is high in asthma; however, methods for validating GERD existence based on questionnaire, endoscopic examination and 24h-pH monitoring do not directly determine GERD influence on the airway. Exhaled breath condensate analysis is a novel and non-invasive tool for assessing information directly from the airway. Breath collected by cooling can be applied to pH, 8-isoprostane and cytokine analysis in patients with GERD-related asthma, and the pH and 8-isoprostane levels have been shown to reflect the effects of PPI therapy in these patients. Although the analysis of cooled breath has not yet been established in a clinical setting, this method is expected to provide a novel tool for monitoring airway acidification associated with GERD

Different gastoroesophageal reflux symptoms of middle-aged to elderly asthma and chronic obstructive pulmonary disease (COPD) patients

Symptomatic differences and the impact of gastroesophageal reflux disease (GERD) have not been clarified in patients with asthma and chronic obstructive pulmonary disease (COPD). The purpose of this study is to assess the differences of GERD symptoms among asthma, COPD, and disease control patients, and determine the impact of GERD symptoms on exacerbation of asthma or COPD by using a new questionnaire for GERD. A total of 120 subjects underwent assessment with the frequency scale for the symptoms of GERD (FSSG) questionnaire, including 40 age-matched patients in each of the asthma, COPD, and disease control groups. Asthma and control patients had more regurgitation-related symptoms than COPD patients (p<0.05), while COPD patients had more dysmotility-related symptoms than asthma patients (p<0.01) or disease control patients (p<0.01). The most distinctive symptom of asthma patients with GERD was an unusual sensation in the throat, while bloated stomach was the chief symptom of COPD patients with GERD, and these symptoms were associated with disease exacerbations. The presence of GERD diagnosed by the total score of FSSG influences the exacerbation of COPD. GERD symptoms differed between asthma and COPD patients, and the presence of GERD diagnosed by the FSSG influences the exacerbation of COPD

Transient receptor potential channels in Alzheimer's disease

AbstractCognitive impairment and emotional disturbances in Alzheimer's disease (AD) result from the degeneration of synapses and neuronal death in the limbic system and associated regions of the cerebral cortex. An alteration in the proteolytic processing of the amyloid precursor protein (APP) results in increased production and accumulation of amyloid β-peptide (Aβ) in the brain. Aβ can render neurons vulnerable to excitotoxicity and apoptosis by disruption of cellular Ca2+ homeostasis and neurotoxic factors including reactive oxygen species (ROS), nitric oxide (NO), and cytokines. Many lines of evidence have suggested that transient receptor potential (TRP) channels consisting of six main subfamilies termed the TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), and TRPA (ankyrin) are involved in Ca2+ homeostasis disruption. Thus, emerging evidence of the pathophysiological role of TRP channels has yielded promising candidates for molecular entities mediating Ca2+ homeostasis disruption in AD. In this review, we focus on the TRP channels in AD and highlight some TRP “suspects” for which a role in AD can be anticipated. An understanding of the involvement of TRP channels in AD may lead to the development of new target therapies

Pathophysiological Role of TRPM2 in Age-Related Cognitive Impairment in Mice

Aging causes various functional changes, including cognitive impairment and inflammatory responses in the brain. Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable channel expressed abundantly in immune cells, exacerbates inflammatory responses. Previously, we reported that TRPM2 on resident microglia plays a critical role in exacerbating inflammation, white matter injury, and cognitive impairment during chronic cerebral hypoperfusion; however, the physiological or pathophysiological role of TRPM2 during age-associated inflammatory responses remains unclear. Therefore, we examined the effects of TRPM2 deletion in young (2–3 months) and older (12–24 months) mice. Compared with young wild-type (WT) mice, middle-aged (12–16 months) WT mice showed working and cognitive memory dysfunction and aged (20–24 months) WT mice exhibited impaired spatial memory. However, these characteristics were not seen in TRPM2 knockout (TRPM2-KO) mice. Consistent with the finding of cognitive impairment, aged WT mice exhibited white matter injury and hippocampal damage and an increase in the number of Iba1-positive cells and amounts of pro-inflammatory cytokines in the brain; these characteristics were not seen in TRPM2-KO mice. These findings suggest that TRPM2 plays a critical role in exacerbating inflammatory responses and cognitive dysfunction during aging

Protection of mice from LPS-induced shock by CD14 antisense oligonucleotide.

CD14 is a pattern recognition receptor on myeloid cells and plays a pivotal role in an innate immune system that is responsible for Gram-negative and Gram-positive bacteria infection. Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, can induce production of a large quantity of proinflammatory cytokines into the circulation mediated by CD14-mediated macrophages and monocytes. These cytokines eventually cause septic shock. Several in vitro and in vivo studies have shown that suppression of a CD14 function by a CD14 antibody led to an inhibition of the production of proinflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-8. In the present study, we found that CD14 antisense oligonucleotide (ODN) can prevent lethal LPS shock in D-galactosamine-sensitized mice. This ODN inhibited CD14 expression in a mouse macrophage cell line, RAW264.7, and suppressed production of TNF-alpha in LPS-stimulated RAW264.7 cells. Furthermore, we designed a consensus antisense ODN that could hybridize human and mouse CD14 RNA, and we evaluated its efficacy. The consensus antisense ODN rescued mice primed with Mycobacterium bovis bacillus Calmette-Guerin (BCG) from the LPS-induced lethal shock. In this model, the CD14 antisense ODN down-regulated LPS-elicited CD14 expression in the liver, resulting in a decrease in LPS-induced TNF-alpha production. These findings suggest that the CD14 antisense ODN is distributed in the liver and efficiently suppresses LPS-induced TNF-alpha production by reducing CD14 expression on Kupffer cells. This CD14 antisense ODN may be useful for the development of a therapeutic agent against sepsis and septic shock.</p