Hyperbaric Oxygen Exposure Reduces Age-Related Decrease in Oxidative Capacity of the Tibialis Anterior Muscle in Mice

The effects of exposure to hyperbaric oxygen on the oxidative capacity of the skeletal muscles in mice at different ages were investigated. We exposed 5-, 34-, 55-, and 88-week-old mice to 36% oxygen at 950 mmHg for 6 hours per day for 2 weeks. The activities of succinate dehydrogenase (SDH), which is a mitochondrial marker enzyme, of the tibialis anterior muscle in hyperbaric mice were compared with those in age-matched mice under normobaric conditions (21% oxygen at 760 mmHg). Furthermore, the SDH activities of type IIA and type IIB fibers in the muscle were determined using quantitative histochemical analysis. The SDH activity of the muscle in normobaric mice decreased with age. Similar results were observed in both type IIA and type IIB fibers in the muscle. The decrease in the SDH activity of the muscle was reduced in hyperbaric mice at 57 and 90 weeks. The decreased SDH activities of type IIA and type IIB fibers were reduced in hyperbaric mice at 90 weeks and at 57 and 90 weeks, respectively. We conclude that exposure to hyperbaric oxygen used in this study reduces the age-related decrease in the oxidative capacity of skeletal muscles

Activation of microRNA-596 induced by DNA demethylation and interferon in malignant melanoma cells

Dysregulation of microRNA has been implicated in melanoma, although the mechanism is not fully understood. We aimed to examine the epigenetically silenced miRNAs and its involvement in the antitumor effect of DNA demethylation and interferon in melanoma. Growth suppressive effects of 5-aza-2’deoxycytidine plus interferon-β were assessed in 20 melanoma cell lines, and the highest effect was observed in TXM18 cells. A screen for miRNAs induced by 5-aza-2’deoxycytidine plus IFN-β in TXM18 cells identifi ed a set of miRNAs including miR-7, miR-203, miR-215 and miR-596. The CpG island of the miR-596 gene was highly methylated in all melanoma cell lines tested (n = 20) whereas levels of methylation were limited in normal melanocytes. Methylation levels of miR-596 were signifi cantly higher in clinical specimens of melanoma than in benign melanocytic nevi (40.6% vs. 30.1%, P= 0.018). Furthermore, transfection of a precursor of miR-596 into melanoma cells induced growth suppression, indicating that the effect of 5-aza-2’deoxycytidine plus interferon-β is in part due to induction of miR-596. Our data suggest that miR-596 is a novel tumor suppressor frequently silenced by DNA methylation in melanoma; that modulation of miRNAs may be involved in the antitumor effect of DNA demethylation plus interferon in melanoma.departmental bulletin pape

骨格筋線維、表皮基底細胞、及び皮膚色素斑に対する軽度高気圧酸素への曝露の影響

京都大学0048新制・論文博士博士(人間・環境学)乙第12883号論人博第40号新制||人||169(附属図書館)26||論人博||40(吉田南総合図書館)31601(主査)教授 石原 昭彦, 教授 船橋 新太郎, 教授 林 達也, 准教授 神﨑 素樹, 准教授 久代 恵介学位規則第4条第2項該当Doctor of Human and Environmental StudiesKyoto UniversityDFA

Single Molecule Energetics of F(1)-ATPase Motor

Motor proteins are essential in life processes because they convert the free energy of ATP hydrolysis to mechanical work. However, the fundamental question on how they work when different amounts of free energy are released after ATP hydrolysis remains unanswered. To answer this question, it is essential to clarify how the stepping motion of a motor protein reflects the concentrations of ATP, ADP, and P(i) in its individual actions at a single molecule level. The F(1) portion of ATP synthase, also called F(1)-ATPase, is a rotary molecular motor in which the central γ-subunit rotates against the α(3)β(3) cylinder. The motor exhibits clear step motion at low ATP concentrations. The rotary action of this motor is processive and generates a high torque. These features are ideal for exploring the relationship between free energy input and mechanical work output, but there is a serious problem in that this motor is severely inhibited by ADP. In this study, we overcame this problem of ADP inhibition by introducing several mutations while retaining high enzymatic activity. Using a probe of attached beads, stepping rotation against viscous load was examined at a wide range of free energy values by changing the ADP concentration. The results showed that the apparent work of each individual step motion was not affected by the free energy of ATP hydrolysis, but the frequency of each individual step motion depended on the free energy. This is the first study that examined the stepping motion of a molecular motor at a single molecule level with simultaneous systematic control of ΔG(ATP). The results imply that microscopically defined work at a single molecule level cannot be directly compared with macroscopically defined free energy input

Severe cytokine release syndrome resulting in purpura fulminans despite successful response to nivolumab therapy in a patient with pleomorphic carcinoma of the lung: a case report

Abstract Background Immune checkpoint inhibitors (ICIs) have provided more options in the treatment of lung cancer. However, ICIs can cause several unfavorable reactions generally referred to as immune-related adverse effects. Case presentation In this report, we present the case of a 52-year-old woman with successful regression of pleomorphic carcinoma of the lung following nivolumab therapy. She developed purpura fulminans (PF) ultimately resulting in amputation of both lower extremities. Blood tests revealed thrombocytopenia with increased serum soluble IL-2 receptor, ferritin, and triglyceride levels suggesting hemophagocytic lymphohistiocytosis (HLH). In addition, serum A disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 activity was decreased, suggesting thrombotic thrombocytopenic purpura (TTP). Further detailed analysis revealed severe hypercytokinemia including increased levels of IL-1β, IL-6, IL-10, TNFα, IFNγ, and G-CSF. Conclusion The severe systemic inflammatory reaction and impaired peripheral circulation in this patient was attributed to excessive immunological effect induced by nivolumab resulting in cytokine release syndrome (CRS). This is the first report of a patient with multiple pathological conditions including HLH, TTP-like condition, and PF presumably arising from ICI-induced CRS. Further accumulating thoroughly investigated cases would lead to better understanding of the disease and development of reliable cancer immunotherapy