解糖系由来代謝物メチルグリオキサールが脂肪細胞の代謝応答に与える影響

京都大学新制・課程博士博士(農学)甲第24914号農博第2577号京都大学大学院農学研究科食品生物科学専攻(主査)教授 井上 和生, 教授 佐々木 努, 准教授 後藤 剛学位規則第4条第1項該当Doctor of Agricultural ScienceKyoto UniversityDFA

Methylglyoxal attenuates isoproterenol-induced increase in uncoupling protein 1 expression through activation of JNK signaling pathway in beige adipocytes

Methylglyoxal (MG) is a metabolite derived from glycolysis whose levels in the blood and tissues of patients with diabetes are higher than those of healthy individuals, suggesting that MG is associated with the development of diabetic complications. However, it remains unknown whether high levels of MG are a cause or consequence of diabetes. Here, we show that MG negatively affects the expression of uncoupling protein 1 (UCP1), which is involved in thermogenesis and the regulation of systemic metabolism. Decreased Ucp1 expression is associated with obesity and type 2 diabetes. We found that MG attenuated the increase in Ucp1 expression following treatment with isoproterenol in beige adipocytes. However, MG did not affect protein kinase A signaling, the core coordinator of isoproterenol-induced Ucp1 expression. Instead, MG activated c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases. We found that JNK inhibition, but not p38, recovered isoproterenol-stimulated Ucp1 expression under MG treatment. Altogether, these results suggest an inhibitory role of MG on the thermogenic function of beige adipocytes through the JNK signaling pathway

Are doctors assessing patients with hypertension appropriately at their initial presentation?

Background: The aim of this study was to determine the extent to which primary care doctors assessed patients newly diagnosed with hypertension for the risk factors of cardiovascular disease (CVD) during the patients’ first clinic visit for hypertension. The study also aimed to examine the trend of assessment for CVD risk factors over a 15-year period. Methods: This retrospective study was conducted between January and May 2012. Data was extracted from the paper-based medical records of patients with hypertension using a 1:4 systematic random sampling method. Data collected included CVD risk factors and a history of target organ damage (TOD), which were identified during the patient’s first visit to the primary care doctor for hypertension, as well as the results of the physical examinations and investigations performed during the same visit. Result: A total of 1,060 medical records were reviewed. We found that assessment of CVD risk factors during the first clinic visit for hypertension was poor (5.4%–40.8%). Assessments for a history of TOD were found in only 5.8%–11.8% of the records, and documented physical examinations and investigations for the assessment of TOD and secondary hypertension ranged from 0.1%–63.3%. Over time, there was a decreasing trend in the percentage of documented physical examinations performed, but an increasing trend in the percentage of investigations ordered Conclusion: There was poor assessment of the patients’ CVD risk factors, secondary causes of hypertension and TOD at their first clinic visit for hypertension. The trends observed in the assessment suggest an over-reliance on investigations over clinical examinations

Development of a web-based insulin decision aid for the elderly: usability barriers and guidelines

In recent years, researchers have attempted to shift patient decision aids (PDAs) from paper-based to web-based to increase its accessibility. Insulin decision aids help diabetes patients, most of whom are elderly to make an informed decision to start insulin. However, the lack of usability guidelines applicable for such target group causes developers to struggle to answer the challenging question ‘How can such web service be made usable, and, ultimately, acceptable and accessible for elderly patients?’. Hence, the purpose of this study is to identify the common usability requirements that may facilitate good practices to empower elderly diabetes patients in utilizing a web-based insulin decision aid for their benefit. We set out an approach to use prototyping and retrospective think-aloud techniques to explore web usability barriers that elderly patients may encounter when using an insulin decision aid web site and use the feedback for improving the prototype. Usability requirements were captured iteratively through scoping, brainstorming, prototype, testing and evaluating. The study suggests that the insights from experts and users are equally important to assure the validity of the identified usability guidelines; they reflect the accessibility needs of the aging community while complementing the key requirements of an insulin decision aid. The study contributes to recommend web usability guidelines backed by a series of expert and user evaluations which could be a proactive resource to improve usability, acceptability and accessibility of online insulin decision aids for elderly with diabetes

What makes efficient circularly polarised luminescence in the condensed phase: aggregation-induced circular dichroism and light emission

In this contribution, we conceptually present a new avenue to construction of molecular functional materials with high performance of circularly polarised luminescence (CPL) in the condensed phase. A molecule (1) containing luminogenic silole and chiral sugar moieties was synthesized and thoroughly characterized. In a solution of 1, no circular dichroism (CD) and fluorescence emission are observed, but upon molecular aggregation, both the CD and fluorescence are simultaneously turned on, showing aggregation-induced CD (AICD) and emission (AIE) effects. The AICD effect is supported by the fact that the molecules readily assemble into right-handed helical nanoribbons and superhelical ropes when aggregated. The AIE effect boosts the fluorescence quantum efficiency (ΦF) by 136 fold (ΦF, ∼0.6% in the solution versus ∼81.3% in the solid state), which surmounts the serious limitations of aggregation-caused quenching effect encountered by conventional luminescent materials. Time-resolved fluorescence study and theoretical calculation from first principles conclude that restriction of the low-frequency intramolecular motions is responsible for the AIE effect. The helical assemblies of 1 prefer to emit right-handed circularly polarised light and display large CPL dissymmetry factors (gem), whose absolute values are in the range of 0.08–0.32 and are two orders of magnitude higher than those of commonly reported organic materials. We demonstrate for the first time the use of a Teflon-based microfluidic technique for fabrication of the fluorescent pattern. This shows the highest gem of −0.32 possibly due to the enhanced assembling order in the confined microchannel environment. The CPL performance was preserved after more than half year storage under ambient conditions, revealing the excellent spectral stability. Computational simulation was performed to interpret how the molecules in the aggregates interact with each other at the molecular level. Our designed molecule represents the desired molecular functional material for generating efficient CPL in the solid state, and the current study shows the best results among the reported organic conjugated molecular systems in terms of emission efficiency, dissymmetry factor, and spectral stability

Assessing catastrophic health expenditure and impoverishment in adult asthma care:a cross-sectional study of patients attending six public health clinics in Klang District, Malaysia

BackgroundIn Malaysia, asthma is a common chronic respiratory illness. Poor asthma control may increase out-of-pocket payment for asthma care, leading to financial hardships Malaysia provides Universal Health Coverage for the population with low user fees in the public health system to reduce financial hardship. We aimed to determine out-of-pocket expenditure on outpatient care for adult patients with asthma visiting government-funded public health clinics. We examined the catastrophic impact and medical impoverishment of these expenses on patients and households in Klang District, Malaysia.MethodsThis is a cross-sectional face-to-face questionnaire survey carried out in six government-funded public health clinics in Klang District, Malaysia. We collected demographic, socio-economic profile, and outpatient asthma-related out-of-pocket payments from 1003 adult patients between July 2019 and January 2020. Incidence of catastrophic health expenditure was estimated as the proportion of patients whose monthly out-of-pocket payments exceeded 10% of their monthly household income. Incidence of poverty was calculated as the proportion of patients whose monthly household income fell below the poverty line stratified for the population of the Klang District. The incidence of medical impoverishment was estimated by the change in the incidence of poverty after out-of-pocket payments were deducted from household income. Predictors of catastrophic health expenditure were determined using multivariate regression analysis.ResultsWe found the majority (80%) of the public health clinic attendees were from low-income groups, with 41.6% of households living below the poverty line. About two-thirds of the attendees reported personal savings as the main source of health payment. The cost of transportation and complementary-alternative medicine for asthma were the main costs incurred. The incidences of catastrophic expenditure and impoverishment were 1.69% and 0.34% respectively. The only significant predictor of catastrophic health expenditure was household income. Patients in the higher income quintiles (Q2, Q3, Q4) had lower odds of catastrophic risk than the lowest quintile (Q1). Age, gender, ethnicity, and poor asthma control were not significant predictors.ConclusionThe public health system in Malaysia provides financial risk protection for adult patients with asthma. Although patients benefited from the heavily subsidised public health services, this study highlighted those in the lowest income quintile still experienced financial catastrophe and impoverishment, and the risk of financial catastrophe was significantly greater in this group. It is crucial to ensure health equity and protect patients of low socio-economic groups from financial hardship.<br/

Feasibility of supported self-management with a pictorial action plan to improve asthma control

Supported self-management reduces asthma-related morbidity and mortality. This paper is on a feasibility study, and observing the change in clinical and cost outcomes of pictorial action plan use is part of assessing feasibility as it will help us decide on outcome measures for a fully powered RCT. We conducted a pre–post feasibility study among adults with physician-diagnosed asthma on inhaled corticosteroids at a public primary-care clinic in Malaysia. We adapted an existing pictorial asthma action plan. The primary outcome was asthma control, assessed at 1, 3 and 6 months. Secondary outcomes included reliever use, controller medication adherence, asthma exacerbations, emergency visits, hospitalisations, days lost from work/daily activities and action plan use. We estimated potential cost savings on asthma-related care following plan use. About 84% (n = 59/70) completed the 6-months follow-up. The proportion achieving good asthma control increased from 18 (30.4%) at baseline to 38 (64.4%) at 6-month follow-up. The proportion of at least one acute exacerbation (3 months: % difference −19.7; 95% CI −34.7 to −3.1; 6 months: % difference −20.3; 95% CI −5.8 to −3.2), one or more emergency visit (1 month: % difference −28.6; 95% CI −41.2 to −15.5; 3 months: % difference −18.0; 95% CI −32.2 to −3.0; 6 months: % difference −20.3; 95% CI −34.9 to −4.6), and one or more asthma admission (1 month: % difference −14.3; 95% CI −25.2 to −5.3; 6 months: % difference −11.9; 95% CI −23.2 to −1.8) improved over time. Estimated savings for the 59 patients at 6-months follow-up and for each patient over the 6 months were RM 15,866.22 (USD3755.36) and RM268.92 (USD63.65), respectively. Supported self-management with a pictorial asthma action plan was associated with an improvement in asthma control and potential cost savings in Malaysian primary-care patients. Trial registration number: ISRCTN87128530; prospectively registered: September 5, 2019, http://www.isrctn.com/ISRCTN87128530

Targeting DNA-PKcs and ATM with miR-101 Sensitizes Tumors to Radiation

Radiotherapy kills tumor-cells by inducing DNA double strand breaks (DSBs). However, the efficient repair of tumors frequently prevents successful treatment. Therefore, identifying new practical sensitizers is an essential step towards successful radiotherapy. In this study, we tested the new hypothesis: identifying the miRNAs to target DNA DSB repair genes could be a new way for sensitizing tumors to ionizing radiation.HERE, WE CHOSE TWO GENES: DNA-PKcs (an essential factor for non-homologous end-joining repair) and ATM (an important checkpoint regulator for promoting homologous recombination repair) as the targets to search their regulating miRNAs. By combining the database search and the bench work, we picked out miR-101. We identified that miR-101 could efficiently target DNA-PKcs and ATM via binding to the 3'- UTR of DNA-PKcs or ATM mRNA. Up-regulating miR-101 efficiently reduced the protein levels of DNA-PKcs and ATM in these tumor cells and most importantly, sensitized the tumor cells to radiation in vitro and in vivo.These data demonstrate for the first time that miRNAs could be used to target DNA repair genes and thus sensitize tumors to radiation. These results provide a new way for improving tumor radiotherapy