1α,25-Dihydroxyvitamin D3 enhances cerebral clearance of human amyloid-β peptide(1-40) from mouse brain across the blood-brain barrier

<p>Abstract</p> <p>Background</p> <p>Cerebrovascular dysfunction has been considered to cause impairment of cerebral amyloid-β peptide (Aβ) clearance across the blood-brain barrier (BBB). Further, low levels of vitamin D are associated with increased risk of Alzheimer's disease, as well as vascular dysfunction. The purpose of the present study was to investigate the effect of 1α,25-dihydroxyvitamin D₃(1,25(OH)₂D3), an active form of vitamin D, on cerebral Aβ clearance from mouse brain.</p> <p>Methods</p> <p>The elimination of [¹²⁵I]hAβ(1-40) from mouse brain was examined by using the Brain Efflux Index method to determine the remaining amount of [¹²⁵I]hAβ(1-40) radioactivity after injection into the cerebral cortex. [¹²⁵I]hAβ(1-40) internalization was analyzed using conditionally immortalized mouse brain capillary endothelial cells (TM-BBB4).</p> <p>Results</p> <p>Twenty-four hours after intraperitoneal injection of 1,25(OH)₂D3 (1 μg/mouse), [¹²⁵I]hAβ(1-40) elimination from mouse brain was increased 1.3-fold, and the level of endogenous Aβ(1-40) in mouse brain was reduced. These effects were observed at 24 h after i.p. injection of 1,25(OH)₂D3, while no significant effect was observed at 48 or 72 h. Vitamin D receptor (VDR) mRNA was detected in mouse brain capillaries, suggesting that 1,25(OH)₂D3 has a VDR-mediated genomic action. Furthermore, forskolin, which activates mitogen-activated protein kinase kinase (MEK), enhanced [¹²⁵I]hAβ(1-40) elimination from mouse brain. Forskolin also enhanced [¹²⁵I]hAβ(1-40) internalization in TM-BBB4 cells, and this enhancement was inhibited by a MEK inhibitor, suggesting involvement of non-genomic action.</p> <p>Conclusions</p> <p>The active form of vitamin D, 1,25(OH)₂D3, appears to enhance brain-to-blood Aβ(1-40) efflux transport at the BBB through both genomic and non-genomic actions. Compounds activating these pathways may be candidate agents for modulating Aβ(1-40) elimination at the BBB.</p

日本における小児血友病患者の日本語版KIDSCREEN-52を用いたQOLの自己評価および保護者による評価

Introduction: Assessing health-related quality of life (HRQOL) is critical for providing comprehensive clinical care to patients with haemophilia. HRQOL in individuals with similar cultural backgrounds should be compared using internationally standardized, generic questionnaires. Aim: To evaluate self-/parent-assessed HRQOL in Japanese children and adolescents with haemophilia A or B. Methods: Children and adolescents aged 8-18 years were enrolled. The haemophilia group comprised families with haemophilia, and the control group comprised those without chronic illness. HRQOL was assessed using the self-/parent-reported questionnaire KIDSCREEN-52, the Japanese version. The Oslo 3-Item Social Support Scale was investigated. Results: The questionnaire was completed by 36 families in the haemophilia group and 160 parents and children in the control group. Haemophilia children aged 8-12 years had lower scores for 'moods and emotions' than control children; the parents had lower scores in the haemophilia group than in the control group for 'moods and emotions', 'social support and peers', and 'school environment'. No significant differences in HRQOL were observed between both groups of adolescents aged 13-18 years or their parents. Neck-shoulder pain was associated with a low psychological state, including 'self-perception', but other joint pains did not affect the outcomes of the HRQOL indices. Social support weaknesses were associated with low physical and psychological states, whereas unexpected hospital visits identified low values for 'self-perception', 'autonomy', and 'school environment'. Conclusion: Proactive mental and clinical care in haemophilia families, especially with young children, will foster a better environment for patients and their parents and ease concerns about progress in haemophilia.博士（医学）・甲第747号・令和2年6月30日© 2020 John Wiley & Sons Ltd.This is the peer reviewed version of the following article: [https://onlinelibrary.wiley.com/doi/full/10.1111/hae.13945], which has been published in final form at [https://doi.org/10.1111/hae.13945]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions

SNP (–617C>A) in ARE-Like Loci of the NRF2 Gene: A New Biomarker for Prognosis of Lung Adenocarcinoma in Japanese Non-Smoking Women

<div><p>Purpose</p><p>The transcription factor NRF2 plays a pivotal role in protecting normal cells from external toxic challenges and oxidative stress, whereas it can also endow cancer cells resistance to anticancer drugs. At present little information is available about the genetic polymorphisms of the <i>NRF2</i> gene and their clinical relevance. We aimed to investigate the single nucleotide polymorphisms in the <i>NRF2</i> gene as a prognostic biomarker in lung cancer.</p><p>Experimental Design</p><p>We prepared genomic DNA samples from 387 Japanese patients with primary lung cancer and detected SNP (c.–617C>A; rs6721961) in the ARE-like loci of the human <i>NRF2</i> gene by the rapid genetic testing method we developed in this study. We then analyzed the association between the SNP in the <i>NRF2</i> gene and patients’ overall survival.</p><p>Results</p><p>Patients harboring wild-type (WT) homozygous (c.–617C/C), SNP heterozygous (c.–617C/A), and SNP homozygous (c.–617A/A) alleles numbered 216 (55.8%), 147 (38.0%), and 24 (6.2%), respectively. Multivariate logistic regression models revealed that SNP homozygote (c.–617A/A) was significantly related to gender. Its frequency was four-fold higher in female patients than in males (10.8% female vs 2.7% male) and was associated with female non-smokers with adenocarcinoma. Interestingly, lung cancer patients carrying <i>NRF2</i> SNP homozygous alleles (c.–617A/A) and the 309T (WT) allele in the <i>MDM2</i> gene exhibited remarkable survival over 1,700 days after surgical operation (log-rank p = 0.021).</p><p>Conclusion</p><p>SNP homozygous (c.–617A/A) alleles in the <i>NRF2</i> gene are associated with female non-smokers with adenocarcinoma and regarded as a prognostic biomarker for assessing overall survival of patients with lung adenocarcinoma.</p></div

Frequencies of wild type (–617C) and SNP (–617A) alleles in the <i>NRF2</i> gene among different ethnic groups.

<p>N, the number of subjects.</p>*<p>1000 Genomes. <a href="http://browser.1000genomes.org/Homo_sapiens/Variation/Population?db=corer=2" target="_blank">http://browser.1000genomes.org/Homo_sapiens/Variation/Population?db=corer=2</a>∶178129537–178130537;v = rs6721961;vdb = variation;vf = 4574214.</p

Clinicopathological profiling of 24 patients harboring homozygous SNP alleles (–617A/A) in the <i>NRF2</i> gene.

<p>Abbreviation: Ad, adenocarcinoma; Mix, adenocarcinoma and squamous cell carcinoma; Ple, pleomorphic carcinoma; Sq, squamous cell carcinoma; F, female; M, male; Wt, wild type.</p>†<p>Patient (case 5) died because of primary pancreatic cancer.</p

Kaplan-Meier plots showing the overall survival of patients harboring the WT homozygote (–617C/C), WT/SNP heterozygote (–617C/A), or SNP homozygote (–617A/A) in the <i>NRF2</i> gene.

<p>Patients with p-stages I to IV (<b>A</b>) and p-stage I only NSCLC (<b>B</b>). The number of patients at times 0, 500, 1000, or 1500 days after surgical operation is described along with genotypes of the <i>NRF2</i> gene.</p

Classification of primary lung cancer patients with respect to <i>NRF2</i> genotypes, smoking behavior, adenocarcinoma, and gender.

*<p><i>P</i>-values were calculated by Fisher’s exact test.</p><p>Abbreviation: M, male; F, female.</p

SmartAmp-based detection of SNP (c.–617C>A) in the <i>NRF2</i> gene.

<p>SNP (c.–617C>A) resides in the promoter region of the <i>NRF2</i> gene on chromosome 2q31.2. Panel <b>A</b> presents a schematic illustration of annealing sites of the TP, FP, and OP primers. Panel <b>B</b> shows cDNA encoding a partial sequence of the <i>NRF2</i> gene and primer annealing sites. Panel <b>C</b> depicts the results of SNP detection. a.u. = arbitrary unit.</p

Classification of primary lung cancer patients with respect to genotypes of <i>NRF2</i> and <i>MDM2</i> genes.

<p>N, the number of patients; % in parentheses.</p