Biological evaluation of double point modified analogues of 1,25-Dihydroxyvitamin D₂ as potential anti-leukemic agents

Structurally similar double-point modified analogues of 1,25-dihydroxyvitamin D2 (1,25D2) were screened in vitro for their pro-differentiating activity against the promyeloid cell line HL60. Their affinities towards human full length vitamin D receptor (VDR) and metabolic stability against human vitamin D 24-hydroxylase (CYP24A1) were also tested. The analogues (PRI-1730, PRI-1731, PRI-1732, PRI-1733 and PRI-1734) contained 5,6-trans modification of the A-ring and of the triene system, additional hydroxyl or unsaturation at C-22 in the side chain and reversed absolute configuration (24-epi) at C-24 of 1,25D2. As presented in this paper, introduction of selected structural modifications simultaneously in two distinct parts of the vitamin D molecule resulted in a divergent group of analogues. Analogues showed lower VDR affinity in comparison to that of the parent hormones, 1,25D2 and 1,25D3, and they caused effective HL60 cell differentiation only at high concentrations of 100 nM and above. Unexpectedly, introducing of a 5,6-trans modification combined with C-22 hydroxyl and 24-epi configuration switched off entirely the cell differentiation activity of the analogue (PRI-1734). However, this analogue remained a moderate substrate for CYP24A1, as it was metabolized at 22%, compared to 35% for 1,25D2. Other analogues from this series were either less (12% for PRI-1731 and PRI-1733) or more (52% for PRI-1732) resistant to the enzymatic deactivation. Although the inactive analogue PRI-1734 failed to show VDR antagonism, when tested in HL60 cells, its structure might be a good starting point for our design of a vitamin D antagonist

Long-term monitoring of the short period SU UMa-type dwarf nova, V844 Herculis

We report on time-resolved CCD photometry of four outbursts of a short-period SU UMa-type dwarf nova, V844 Herculis. We successfully determined the mean superhump periods to be 0.05584(64) days, and 0.055883(3) for the 2002 May superoutburst, and the 2006 April-May superoutburst, respectively. During the 2002 October observations, we confirmed that the outburst is a normal outburst, which is the first recorded normal outburst in V844 Her. We also examined superhump period changes during 2002 May and 2006 April-May superoutbursts, both of which showed increasing superhump period over the course of the plateau stage. In order to examine the long-term behavior of V844 Her, we analyzed archival data over the past ten years since the discovery of this binary. Although photometry is not satisfactory in some superoutbursts, we found that V844 Her showed no precursors and rebrightenings. Based on the long-term light curve, we further confirmed V844 Her has shown almost no normal outbursts despite the fact that the supercycle of the system is estimated to be about 300 days. In order to explain the long-term light curves of V844 Her, evaporation in the accretion disk may play a role in the avoidance of several normal outbursts, which does not contradict with the relatively large X-ray luminosity of V844 Her.Comment: 10 pages, 11 figures, accepted for PAS

Human NINEIN polymorphism at codon 1111 is associated with the risk of colorectal cancer

NINEIN serves an essential role in centrosome function as a microtubule organizing center, and in the reformation of the interphase centrosome architecture following mitosis. In the present study, the association between NINEIN Pro1111Ala (rs2236316), a missense single nucleotide polymorphism, and the risk of colorectal cancer (CRC), related to smoking and alcohol consumption habits in 200 patients with CRC and 1,141 cancer‑free control participants were assessed in a case‑control study performed in Japan. The results showed that the NINEIN Ala/Ala genotype compared with the Pro/Pro genotype was significantly more associated with an increased risk of CRC, and the males with the Ala/Ala genotype exhibited a significantly increased risk of CRC compared with those with Pro/Pro and Pro/Ala genotypes. Stratified analyses of the Ala/Ala genotype with CRC risk further showed an increased association in never/light drinkers (<23 g of ethanol/day), in male never/light drinkers and in male patients with rectal cancer. These findings suggest that the genetic variant of the NINEIN Pro1111Ala polymorphism has a significant effect on CRC susceptibility in the Japanese population

Home-based aerobic exercise and resistance training

Background The potential effects of aerobic and resistance training in patients with severe chronic kidney disease (CKD) are not fully elucidated. This study investigated the effects of a home-based exercise programme on physical functioning and health-related quality of life (HRQOL) in patients with Stage 4 CKD, equivalent to estimated glomerular filtration rate of 15–30 mL/min/1.73 m2. Methods Forty-six patients with Stage 4 CKD (median age, 73 years; 33 men) were randomly assigned to exercise (n = 23) and control (n = 23) groups. Exercise group patients performed aerobic exercise at 40–60% peak heart rate thrice weekly and resistance training at 70% of one-repetition maximum twice weekly at home for 6 months. Control patients received no specific intervention. Primary outcomes were distance in incremental shuttle walking test and HRQOL assessed using the Kidney Disease Quality of Life—Short Form questionnaire. Secondary outcomes included kidney function assessed with combined urea and creatinine clearance, urinary biomarkers, and anthropometric and biochemical parameters associated with CKD. Results Improvement in incremental shuttle walking test was significantly greater in the exercise group compared with controls (39.4 ± 54.6 vs. −21.3 ± 46.1; P < 0.001). Among Kidney Disease Quality of Life domains, significant mean differences were observed between the exercise group and the control group in work status, quality of social interaction, and kidney disease component summary outcomes (12.76 ± 5.76, P = 0.03; 5.97 ± 2.59, P = 0.03; and 4.81 ± 1.71, P = 0.007, respectively). There were greater reductions in natural log (ln)-transformed urinary excretion of liver-type fatty acid-binding protein, ln serum C-reactive protein, and acylcarnitine to free carnitine ratio in the exercise group compared with controls, with significant between-group differences of −0.579 ± 0.217 (P = 0.008), −1.13 ± 0.35 (P = 0.003), and −0. 058 ± 0.024 (P = 0.01), respectively. Conclusions Our 6 month home-based exercise programme improved aerobic capacity and HRQOL in patients with Stage 4 CKD, with possible beneficial effects on kidney function and CKD-related parameters

Replication study of the association of SNPs in the LHX3-QSOX2 and IGF1 loci with adult height in the Japanese population; wide-ranging comparison of each SNP genotype distribution

Adult height is a highly heritable trait involving multiple genes. Recent genome-wide association studies have identified that SNP rs12338076 in the LHX3-QSOX2 locus, and rs1457595 and rs17032362 in the IGF1 locus are associated with human height in the Japanese population (Okada et al. (2010)[9]). We performed a replication study to examine the associations between these three SNPs and adult height in the Japanese population based on autopsy cases. However, it was not possible to confirm that all these SNPs influenced adult height in the study population. We first conducted a wide-ranging survey of these three SNPs in the above genes using nine different populations including Asians, Africans and Caucasians, and demonstrated that the genotypes of rs12338076 and rs17032362 were distributed in an ethnicity-dependent manner; even within Asian populations, the genotype distributions of the SNPs differed widely. Although there are differences in height distribution between different populations, possibly due to genetic factors and/or gene-environmental interactions, the contradictory results of the association study and ethnic differences in genotype distribution allow us to assume that these height-related SNPs in the genes may contribute to adult height to a slight extent, at least in the Japanese population. It is anticipated that the present information will be useful for developing a reliable tool for personal identification through elucidation of the genetic basis of human height

Distribution and toxicity evaluation of ZnO dispersion nanoparticles in single intravenously exposed mice

ZnO nanoparticles (NPs) have been widely used in various commercial products. Application of ZnO NPs is expected to apply to cancer diagnosis and therapy, used as drug delivery carriers. In the present study, the lethal dose 50 (LD50) of intravenously administered ZnO NPs (0.3 mg/kg) was calculated in mice. Blood kinetics and tissue distribution of a toxic dose of ZnO NPs (0.2 mg/kg, 0.05 mg/kg) were investigated after intravenous exposure. In addition, 8-hydroxy-2’-deoxyguanosine (8-OHdG) was evaluated. Following the injection, ZnO NPs were rapidly removed from the blood and distributed to organs. Pulmonary emphysema was observed pathologically study in mice at 3 days after the 0.2 mg/kg dose and at 6 days after the 0.05 mg/kg dose. ZnO NPs were mainly accumulated in the lung and spleen within 60 min. From the long-term tissue distribution study, the liver showed peak concentration at 6 days, and spleen peaked at 1 day. The lungs kept high levels until 6 days. Tissue distribution and pathological study showed that the spleen, liver, and lungs are target organs for ZnO NPs. Accumulation in the liver and spleen may be due to the phagocytosis by macrophages. A dose-dependent increase in 8-OHdG was observed in mice treated with ZnO NPs. This study is the first to show information on kinetics and target organs following intravenous ZnO injection

Visualization of mandibular movement relative to the maxilla during mastication in mice: integration of kinematic analysis and reconstruction of a three-dimensional model of the maxillofacial structure

Background: Mastication is one of the most fundamental functions for the conservation of human life. To clarify the pathogenetic mechanism of various oral dysfunctions, the demand for devices for evaluating stomatognathic function has been increasing. The aim of the present study was to develop a system to reconstruct and visualize 3-dimensional (3D) mandibular movements relative to the maxilla, including dynamic transition of occlusal contacts between the upper and lower dentitions during mastication in mice.Methods: First, mandibular movements with six degrees of freedom were measured using a motion capture system comprising two high-speed cameras and four reflective markers. Second, 3D models of maxillofacial structure were reconstructed from micro-computed tomography images. Movement trajectories of anatomical landmark points on the mandible were then reproduced by integrating the kinematic data of mandibular movements with the anatomical data of maxillofacial structures. Lastly, 3D surface images of the upper dentition with the surrounding maxillofacial structures were transferred to each of the motion capture images to reproduce mandibular movements relative to the maxilla. We also performed electromyography (EMG) of masticatory muscles associated with mandibular movements.Results: The developed system could reproduce the 3D movement trajectories of arbitrary points on the mandible, such as incisor, molars and condylar points with high accuracy and could visualize dynamic transitions of occlusal contacts between upper and lower teeth associated with mandibular movements.Conclusions: The proposed system has potential to elucidate the mechanisms underlying motor coordination of masticatory muscles and to clarify their roles during mastication by taking advantage of the capability to record EMG data synchronously with mandibular movements. Such insights will enhance our understanding of the pathogenesis and diagnosis of oral motor disorders by allowing comparisons between normal mice and genetically modified mice with oral behavioral dysfunctions