ヒト白血病K562細胞におけるアドリアマイシン作用のクレモフォールELによる修飾

Adriamycin and paclitaxel are simultaneously used for cancer treatment in some cases. The formula of paclitaxel contains cremophor EL as a solvent. Since this solvent exerts diverse biological actions, the modification of adriamycin action by cremophor EL has been studied on human leukemia K562 cells. Cremophor EL did not significantly affect the concentration-response relation for antiproliferative action of adriamycin and the cell cycle changed by adriamycin. However, the induction of morphological change by adriamycin was significantly augmented by cremophor EL. The simultaneous application of cremophor EL increased the intensity of fluorescence from adriamycin trapped inside the cells in a concentration-dependent manner, suggesting an increase in intracellular concentration of adriamycin by cremophor EL. Adriamycin alone at concentrations higher than those to completely inhibit the growth induced morphological change in K562 cells. Therefore, cremophor EL may potentiate some of actions induced by adriamycin when adriamycin and paclitaxel are simultaneously applied

フォン・ヴィレブランド因子の機能を調節することで、マウスの急性腎虚血再灌流障害を緩和できる

Acute kidney injury (AKI), an abrupt loss of renal function, is often seen in clinical settings and may become fatal. In addition to its hemostatic functions, von Willebrand factor (VWF) is known to play a role in cross-talk between inflammation and thrombosis. We hypothesized that VWF may be involved in the pathophysiology of AKI, major causes of which include insufficient renal circulation or inflammatory cell infiltration in the kidney. To test this hypothesis, we studied the role of VWF in AKI using a mouse model of acute ischemia-reperfusion (I/R) kidney injury. We analyzed renal function and blood flow in VWF-gene deleted (knock-out; KO) mice. The functional regulation of VWF by ADAMTS13 or a function-blocking anti-VWF antibody was also evaluated in this pathological condition. Greater renal blood flow and lower serum creatinine were observed after reperfusion in VWF-KO mice compared with wild-type (WT) mice. Histological analysis also revealed a significantly lower degree of tubular damage and neutrophil infiltration in kidney tissues of VWF-KO mice. Both human recombinant ADAMTS13 and a function-blocking anti-VWF antibody significantly improved renal blood flow, renal function and histological findings in WT mice. Our results indicate that VWF plays a role in the pathogenesis of AKI. Proper functional regulation of VWF may improve the microcirculation and vessel function in the kidney, suggesting a novel therapeutic option against AKI.博士（医学）・甲第744号・令和2年3月16日© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

Effects of Zn2+ chelators, DTPA and TPEN, and ZnCl2 on the cells treated with hydrogen peroxide: a flow-cytometric study using rat thymocytes

Recently, we have revealed that trace Zn2+ partly attenuates Ca2+-dependent cell death induced by A23187, a calcium ionophore, in rat thymocytes. In this study, to see if Zn2+ attenuates the H2O2-induced cell death that is also Ca2+-dependent, the effects of ZnCl2 and chelators for Zn2+ have been examined by using a flowcytometer with propidium iodide. The incubation with H2O2 increased the cell lethality. Simultaneous application of ZnCl2 greatly augmented the H2O2-induced increase in lethality. DTPA, a chelator for extracellular Zn2+, did not affect the increase in cell lethality by H2O2. However, the H2O2-induced increase in cell lethality was greatly attenuated by TPEN, a chelator for extracellular and intracellular Zn2+. Taken together, it may be likely that intracellular Zn2+ modifies the H2O2-induced cytotoxicity. However, it cannot be ruled out the possibility that TPEN chelates intracellular Fe2+, resulting in inhibiting the formation of hydroxyl radical from H2O2 that leads to an attenuation of H2O2 cytotoxicity

Pulmonary blood flow evaluation using a dynamic flat-panel detector: Feasibility study with pulmonary diseases

金沢大学医薬保健研究域保健学系Purpose: Pulmonary ventilation and circulation dynamics are reflected on fluoroscopic images as changes in X-ray translucency. The purpose of this study was to investigate the feasibility of non-contrast functional imaging using a dynamic flat-panel detector (FPD). Methods: Dynamic chest radiographs of 20 subjects (abnormal, n = 12; normal, n = 8) were obtained using the FPD system. Image analysis was performed to get qualitative perfusion mapping image; first, focal pixel value was defined. Second, lung area was determined and pulmonary hilar areas were eliminated. Third, one cardiac cycle was determined in each of the cases. Finally, total changes in pixel values during one cardiac cycle were calculated and their distributions were visualized with mapping on the original image. They were compared with the findings of lung perfusion scintigraphy. Results: In all normal controls, the total changes in pixel value in one cardiac cycle decreased from the hilar region to the peripheral region of the lung with left-right symmetric distribution. In contrast, in many abnormal cases, pulmonary blood flow disorder was indicated as a reduction of changes in pixel values on a mapping image. The findings of mapping image coincided with those of lung perfusion scintigraphy. Conclusions: Dynamic chest radiography using an FPD system with computer analysis is expected to be a new type of functional imaging, which provides pulmonary blood flow distribution additionally. © CARS 2009

Development of pulmonary blood flow evaluation method with a dynamic flat-panel detector: quantitative correlation analysis with findings on perfusion scan

金沢大学医薬保健研究域保健学系Pulmonary blood flow is reflected in dynamic chest radiographs as changes in X-ray translucency, i.e., pixel values. Thus, decreased blood flow should be observed as a reduction of the variation of X-ray translucency. We performed the present study to investigate the feasibility of pulmonary blood flow evaluation with a dynamic flat-panel detector (FPD). Sequential chest radiographs of 14 subjects were obtained with a dynamic FPD system. The changes in pixel value in each local area were measured and mapped on the original image by use of a gray scale in which small and large changes were shown in white and black, respectively. The resulting images were compared to the findings in perfusion scans. The cross-correlation coefficients of the changes in pixel value and radioactivity counts in each local area were also computed. In all patients, pulmonary blood flow disorder was indicated as a reduction of changes in pixel values on the mapping image, and a correlation was observed between the distribution of changes in pixel value and those in radioactivity counts (0.7 ≤ r, 3 cases; 0.4 ≤ r < 0.7, 7 cases; 0.2 ≤ r < 0.4, 4 cases). The results indicated that the distribution of changes in pixel value could provide a relative measure related to pulmonary blood flow. The present method is potentially useful for evaluating pulmonary blood flow as an additional examination in conventional chest radiography. © 2009 Japanese Society of Radiological Technology and Japan Society of Medical Physics

胎盤増殖因子の可溶性Fms様チロシンキナーゼ-1に対する血中濃度比の上昇は安定冠動脈疾患患者における有害事象発症の予測因子である

OBJECTIVE: To investigate the predictive values of placental growth factor (PlGF) and its endogenous antagonist, soluble fms-like tyrosine kinase-1 (sFlt-1), for the long-term prognosis of patients with stable coronary artery disease (CAD). Both PlGF and sFlt-1 play important roles in the pathological mechanisms of atherosclerosis. We recently demonstrated that the plasma levels of these molecules are correlated with the severity of coronary atherosclerosis. METHODS: We enrolled 464 patients with stable CAD who consecutively underwent coronary angiography. Baseline blood samples were collected from the femoral artery immediately before coronary angiography (after the administration of 20 units of heparin), and the plasma levels of PlGF and sFlt-1 were measured. A Cox proportional hazard regression analysis was performed to evaluate the relationship between these parameters and the occurrence of all-cause death (ACD) and total cardiovascular events (TCVE) during a median follow-up of 3.3 years. RESULTS: A total of 31 ACDs and 51 TCVEs occurred. Patients with higher PlGF/sFlt-1 ratios (>4.22×10(-2)) had a significantly higher risk of both ACD and TCVE than patients with lower ratios (<4.22×10(-2)) (hazard ratio [HR]: 3.32, 95% confidence interval [CI]: 1.43 to 7.72, p=0.005, and HR: 2.23, 95% CI: 1.23 to 4.03, p=0.008, respectively). A multivariate analysis showed the PlGF/sFlt-1 ratio to be an independent predictor for ACD, but not TCVE.博士（医学）・甲615号・平成26年3月17日発行元の規定により、本文の登録不可。本文は以下のURLを参照 "http://dx.doi.org/10.2169/internalmedicine.52.9073

可溶性Flt-1産生低下は、心筋リモデリングおよび心不全増悪に寄与する

Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti–placental growth factor–neutralizing antibody prevented pressure overload–induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart.博士（医学）・乙第1384号・平成28年11月24日© 2016 American Heart Association, Inc.The definitive version is available at " https://doi.org/10.1161/HYPERTENSIONAHA.116.07371