An Angiotensin II Type 1 Receptor Blocker Prevents Renal Injury via Inhibition of the Notch Pathway in Ins2 Akita Diabetic Mice

Recently, it has been reported that the Notch pathway is involved in the pathogenesis of diabetic nephropathy. In this study, we investigated the activation of the Notch pathway in Ins2 Akita diabetic mouse (Akita mouse) and the effects of telmisartan, an angiotensin II type1 receptor blocker, on the Notch pathway. The intracellular domain of Notch1 (ICN1) is proteolytically cleaved from the cell plasma membrane in the course of Notch activation. The expression of ICN1 and its ligand, Jagged1, were increased in the glomeruli of Akita mice, especially in the podocytes. Administration of telmisartan significantly ameliorated the expression of ICN1 and Jagged1. Telmisartan inhibited the angiotensin II-induced increased expression of transforming growth factor β and vascular endothelial growth factor A which could directly activate the Notch signaling pathway in cultured podocytes. Our results indicate that the telmisartan prevents diabetic nephropathy through the inhibition of the Notch pathway

Novel quantitative immunohistochemical analysis for evaluating PD-L1 expression with phosphor-integrated dots for predicting the efficacy of patients with cancer treated with immune checkpoint inhibitors

IntroductionProgrammed cell death ligand 1 (PD-L1) expression in tumor tissues is measured as a predictor of the therapeutic efficacy of immune checkpoint inhibitors (ICIs) in many cancer types. PD-L1 expression is evaluated by immunohistochemical staining using 3,3´-diaminobenzidine (DAB) chronogenesis (IHC-DAB); however, quantitative and reproducibility issues remain. We focused on a highly sensitive quantitative immunohistochemical method using phosphor-integrated dots (PIDs), which are fluorescent nanoparticles, and evaluated PD-L1 expression between the PID method and conventional DAB method.MethodsIn total, 155 patients with metastatic or recurrent cancer treated with ICIs were enrolled from four university hospitals. Tumor tissue specimens collected before treatment were subjected to immunohistochemical staining with both the PID and conventional DAB methods to evaluate PD-L1 protein expression.ResultsPD-L1 expression assessed using the PID and DAB methods was positively correlated. We quantified PD-L1 expression using the PID method and calculated PD-L1 PID scores. The PID score was significantly higher in the responder group than in the non-responder group. Survival analysis demonstrated that PD-L1 expression evaluated using the IHC-DAB method was not associated with progression-free survival (PFS) or overall survival (OS). Yet, PFS and OS were strikingly prolonged in the high PD-L1 PID score group.ConclusionQuantification of PD-L1 expression as a PID score was more effective in predicting the treatment efficacy and prognosis of patients with cancer treated with ICIs. The quantitative evaluation of PD-L1 expression using the PID method is a novel strategy for protein detection. It is highly significant that the PID method was able to identify a group of patients with a favorable prognosis who could not be identified by the conventional DAB method

Environmental stresses induce transgenerationally inheritable survival advantages via germline-to-soma communication in Caenorhabditis elegans.

獲得形質は遺伝する? : 親世代で受けた環境ストレスが子孫の生存力を高める. 京都大学プレスリリース. 2017-01-11.Hormesis is a biological phenomenon, whereby exposure to low levels of toxic agents or conditions increases organismal viability. It thus represents a beneficial aspect of adaptive responses to harmful environmental stimuli. Here we show that hormesis effects induced in the parental generation can be passed on to the descendants in Caenorhabditis elegans. Animals subjected to various stressors during developmental stages exhibit increased resistance to oxidative stress and proteotoxicity. The increased resistance is transmitted to the subsequent generations grown under unstressed conditions through epigenetic alterations. Our analysis reveal that the insulin/insulin-like growth factor (IGF) signalling effector DAF-16/FOXO and the heat-shock factor HSF-1 in the parental somatic cells mediate the formation of epigenetic memory, which is maintained through the histone H3 lysine 4 trimethylase complex in the germline across generations. The elicitation of memory requires the transcription factor SKN-1/Nrf in somatic tissues. We propose that germ-to-soma communication across generations is an essential framework for the transgenerational inheritance of acquired traits, which provides the offspring with survival advantages to deal with environmental perturbation

DNA double strand break repair under high and low LET radiation

High LET heavy ion radiation has been successfully used for an alternative radiation treatment for cancer and is also an important component for space radiation. The biological effectiveness of high LET radiation (up to 200keV/um) is, in general, higher than that of low LET radiation such as X-rays and r-rays. One of the main causes of this is thought to be the difference in the way how cells process DNA damage, particularly DNA double strand breaks (DSBs). We have recently shown that the repair of DSBs depends on LET values, and DSB repair deficient cells show less dependency on LETs for their cell survival as well as DSB repair process. The inefficient repair of DSB associated with high LET radiation was also confirmed by a sensitive method, rH2AX assay. This inefficiency seems to result in misrejoining of chromosomes, leading to further severe biological consequences such as cell death and mutation. The misrepair/misrejoining could be shown by fluorescence in situ hybridization (FISH) of chromosomes in irradiated cells. \nThe phosphorylation and de-phosphorylation of DNA-PKcs, a key protein for non-homologous end joining (NHEJ), was significantly delayed by irradiation of high LET carbon and iron ions when compared to X-rays. Of interest, this phenomenon was further accentuated in the human NHEJ defective 180BR cells (shown below, Ref.: Radiat. Res. 165: 59-67 (2006))第7回　放射線生物学に関する日仏ワークショッ

Serum 25-hydroxyvitamin D-3 levels and poor sleep quality in a Japanese population : the DOSANCO Health Study

Objective: The present cross-sectional study investigated the relationship between serum 25-hydroxyvitamin D-3 (25[OH]D-3) levels and the presence of poor sleep quality in a community-based Japanese adult population. Methods: Poor sleep quality, defined as poor subjective sleep quality and/or use of sleep medications, was assessed using a self-administered questionnaire. The prevalence of poor sleep quality was compared among 512 Japanese participants aged 35-79 years, based on serum 25(OH) D-3 levels, which were determined using tandem mass spectrometry. A logistic regression model was used to calculate the odds ratios (ORs) for the presence of poor sleep quality in each group with the highest quartile of 25(OH) D-3 serving as the reference group. Results: Poor sleep quality was reported by 33.2% of the total study population. The prevalence of poor sleep quality was higher in the first quartile group (25[OH] D-3: 2.08-18.13 ng/mL) than in the second, third and fourth quartile groups (18.14-23.07 ng/mL, 23.08-28.32 ng/mL, and 28.33-78.83 ng/mL, respectively). The ORs for poor sleep quality were 1.86 (95% confidence interval, 1.08-3.20) for the first quartile group, 0.73 (0.41-1.29) for the second quartile group, and 0.73 (0.42-1.27) for the third quartile group after adjusting for age, sex, and sociodemographic, lifestyle, physical and environmental factors, while the ORs were 1.68 (0.96-2.95), 0.69 (0.39-1.24), and 0.65 (0.37-1.15) after further adjustment for overall health status and depression status. Conclusions: The first quartile group of serum 25(OH) D-3 was associated with the presence of poor sleep quality. (c) 2019 Elsevier B.V. All rights reserved

Single extreme low dose/low dose rate irradiation causes alteration in lifespan and genome instability in primary human cells

To investigate the long term biological effect of extreme low dose ionizing radiation (IR), we irradiated normal human fibroblasts (HFL III) with carbon ions (290 MeV/u, 70 keV/µm) and gamma-rays at 1 mGy (total dose) once at a low dose rate (1 mGy/6-8 h), and observed the cell growth kinetics up to five months by continuous culturing. The growth of carbon irradiated cells started to slow down considerably sooner than that of non-irradiated cells before reaching senescence. In contrast, cells irradiated with gamma-rays under similar conditions did not show significant deviation from the non-irradiated cells. A DNA double strand break (DSB) marker, gammaH2AX foci and a DSB repair marker, phosphorylated DNA-PKcs foci, increased in number when non-irradiated cells reached several passages before senescence. A single low dose/low dose rate carbon ion exposure further raised the numbers of these markers. Furthermore, the numbers of foci for these two markers were significantly reduced after the cells became fully senescent. Our results indicate that high linear energy transfer (LET) radiation (carbon ions) causes different effects than low LET radiation (gamma-rays) even at very low doses and that a single low dose of heavy ion irradiation can affect the stability of the genome many generations after irradiation

Serum 25-hydroxyvitamin D3 Levels and Diabetes in a Japanese Population : The DOSANCO Health Study

Background: Both decreased insulin sensitivity and impaired insulin secretion are common in Asian populations with diabetes, in contrast to Western populations. There is limited evidence regarding the association between insulin response in diabetes in Asian populations and serum 25-hydroxyvitamin D3 (25[OH]D3) insufficiency.Methods: The present cross-sectional study compared the prevalence of diabetes, defined as a fasting plasma glucose level >= 126 mg/dL and/or a HbA1c level >= 6.5%, among 480 participants aged 35-79 years not taking anti-diabetes medications, based on serum 25(OH)D3 levels. A logistic regression model was used to calculate the odds ratios for diabetes in each serum 25(OH)D3 group. Furthermore, this study examined the association between serum 25(OH)D3 levels and the index of homeostasis model assessment of insulin resistance (HOMA-IR) using a linear regression model.Results: The prevalence of diabetes was 7.29% in the study population, and was higher in lower serum 25(OH)D3 quartile groups. The odds ratios for diabetes in the first, second, and third serum 25(OH)D3 quartile groups (25[OH]D3: 28.18 ng/mL) serving as the reference group, after adjusting for sociodemographic, lifestyle, physical and environmental factors. Serum 25(OH)D3 levels showed an inverse association with log-transformed HOMA-IR after adjusting for similar factors (standardized beta = -0.08; 95% CI, -0.14 to -0.02).Conclusion: Serum 25(OH)D3 levels were inversely associated with diabetes prevalence in a general Japanese population, with a slight inverse association between serum 25(OH)D3 levels and HOMA-IR