[Show abstract][Hide abstract] ABSTRACT: Pre-eclampsia affects approximately 5% of all pregnant women and remains a major cause of maternal and fetal morbidity and mortality. The hypertension associated with pre-eclampsia develops during pregnancy and remits after delivery, suggesting that the placenta is the most likely origin of this disease. The pathophysiology involves insufficient trophoblast invasion, resulting in incomplete narrow placental spiral artery remodeling. Placental insufficiency, which limits the maternal-fetal exchange of gas and nutrients, leads to fetal intrauterine growth restriction. In this study, in our attempt to develop a new therapy for pre-eclampsia, we directly rescued placental and fetal hypoxia with nano-scale size artificial oxygen carriers (hemoglobin vesicles). The present study is the first to demonstrate that artificial oxygen carriers successfully treat placental hypoxia, decrease maternal plasma levels of anti-angiogenic proteins and ameliorate fetal growth restriction in the pre-eclampsia rat model.
[Show abstract][Hide abstract] ABSTRACT: Fallopian tubal epithelium is a candidate for the origin of high-grade serous ovarian cancer. Transferrin-containing follicular fluid and/or retrograde menstrual blood are possible risk factors for carcinogenesis. Accumulation of DNA double-strand breaks (DNA-DSBs) in the fallopian tubal epithelium is considered to play an important role in the development of cancer. However, the mechanisms by which DNA-DSBs accumulate have not yet been fully elucidated. The hydroxyl radical, which is produced in a Fenton reaction catalyzed by an iron ion, serves as a potent DNA-DSB-inducing molecule, raising the potential of an iron ion transporter of transferrin in the formation of DNA-DSBs. We studied the potential involvement of transferrin in DNA damage and the development of ovarian cancer. Treatment with transferrin facilitated the formation of histone 2AX phosphorylated at Serine 139 (γH2AX), which is known as a DNA-DSB marker, in human fallopian tube secretory epithelial cells and A2780 ovarian cancer cells. Knockdown of transferrin receptor 1 (TfR1), but not transferrin receptor 2, suppressed the transferrin uptake and consequent formation of γH2AX. As hydroxyl radicals in reactive oxygen species (ROS) are involved in DNA-DSBs, the formation of ROS was determined. Treatment with TfR1-specific small interference RNAs significantly diminished transferrin-induced formation of ROS. Moreover, TfR1-dependent uptake of transferrin was revealed to augment the formation of DNA-DSBs in the presence of hydrogen peroxide, which served as a substrate for the Fenton reaction. An ex vivo study with murine fallopian tubes further demonstrated that transferrin treatment introduced DNA-DSBs in the fallopian tubal epithelium. Collectively, these data suggested that the transferrin-TfR1 axis accounts for the induction of DNA-DSBs that potentially lead to DNA damage/genome instability. These findings also suggested that exposure to transferrin initiates and promotes the development of ovarian cancer by aiding the accumulation of DNA-DSBs in the fallopian tubal epithelium.Oncogene advance online publication, 9 November 2015; doi:10.1038/onc.2015.425.
[Show abstract][Hide abstract] ABSTRACT: During pregnancy, both ischemic reperfusion and bacterial agent LPS are known risk factors for fetal brain damage. However, there is a lack of evidence to explain whether vaginal LPS affects the fetus response to ischemic reperfusion. Here we reported that there was more than 2 folds higher vulnerability of fetal brain hemorrhage response to ischemic reperfusion when mother mouse was treated with vaginal LPS. As our previously reported, ischemic reperfusion induces P53-dependent fetal brain damage was based on a molecular mechanism: the transcriptional pattern was changed from HIF-1alpha-dependent to P53-dependent immediately. In the present work, only with vaginal LPS precondition, phosphorylation of activated transcriptional factor (ATF) 2 at Thr71 appeared in response to ischemic reperfusion. Moreover, this phosphorylation was completely blocked by pre-treatment with a P53 inhibitor, pifithrin-α. We concluded that vaginal LPS precondition trigged the p53-dependent phosphorylation of ATF2 in response to ischemic reperfusion, which played an important role of increasing vulnerability to hemorrhage in fetus.
Biochemical and Biophysical Research Communications 11/2015; DOI:10.1016/j.bbrc.2015.10.125 · 2.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This prospective cohort study compared measurements of maternal home blood pressure (HBP) with clinic blood pressure (CBP) before 20 weeks' gestation to determine associations with the risk of delivering a lower birth weight infant. A total of 605 Japanese women were included. Exposures were initial CBP, made between 10 weeks 0 days and 19 weeks 0 days, and HBP for comparison made within 1 week of CBP. Outcome was infant's birth weight, categorized and ranked as follows: ⩾3500 g, 3000-3499 g, 2500-2999 g and <2500 g. The proportional odds model with possible confounding factors was applied to compare the associations between CBP and HBP on infant birth weight. When both CBP and HBP were included simultaneously, the adjusted odds ratios (ORs) per 1 standard deviation (1s.d.) increase in clinic and home diastolic BP (DBP) were 1.06 (95% confidence interval (CI): 0.87-1.30) and 1.28 (95% CI: 1.04-1.58), respectively. The adjusted ORs per 1s.d. increase in clinic and home mean arterial pressure (MAP) were 1.02 (95% CI: 0.83-1.24) and 1.29 (95% CI: 1.04-1.59), respectively. Systolic BP measurement was not associated with infant birth weight. In conclusion, high maternal home DBP and MAP before 20 weeks' gestation was associated with a higher risk of lower infant birth weight than clinic DBP and MAP. Therefore, in addition to CBP, it may be worth having pregnant women measure HBP to determine the risk of lower infant birth weight.Hypertension Research advance online publication, 29 October 2015; doi:10.1038/hr.2015.108.
Hypertension Research 10/2015; DOI:10.1038/hr.2015.108 · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
To examine psychological distress among pregnant women in Miyagi prefecture which was directly affected by the Great East Japan Earthquake and tsunami and compare other areas of Japan that were less damaged.
This study was conducted in conjunction with the Japan Environment and Children's Study (JECS). We examined 10,129 Japanese women using the primary fixed data of the JECS. The Kessler 6-item psychological distress scale (K6) was administered to 7473 eligible women including 998 in Miyagi unit center ('Miyagi UC') and 6475 in the other unit centers ('13UCs'). We compared the prevalence and the risk of distress (K6 ≥13) during pregnancy in 'Miyagi UC' and '13UCs'.
More women in 'Miyagi UC' (4.9%) suffered psychological distress, compared with '13UCs' (3.1%) (p<0.001). A significantly higher prevalence of women in 'Miyagi UC' (55.5%) had experienced negative life events, whereas '13UCs' showed 42.7% (p<0.0001). In multivariable logistic analyses adjusted for baseline characteristics, there was a significant regional difference of psychological distress (adjusted odds ratio; aOR in Miyagi UC=1.488; 95%CI, 1.059-2.090). After further adjusting for negative life events, the association was diminished (aOR=1.338; 95%CI, 0.949-1.884).
The JECS had no data before the earthquake and the extent of damage was not investigated. Possible regional representativeness is also a limitation.
After the Great East Japan Earthquake, the prevalence of pregnant women with psychological distress (K6≥13) were high in Miyagi prefecture. Especially in the coastal area directly affected by tsunami, it is high with or without negative life events experienced.
[Show abstract][Hide abstract] ABSTRACT: Targeting cell motility, which is required for dissemination and metastasis, has therapeutic potential for ovarian cancer metastasis, and regulatory mechanisms of cell motility need to be uncovered for developing novel therapeutics. Invasive ovarian cancer cells spontaneously formed protrusions, such as lamellipodia, which are required for generating locomotive force in cell motility. Short interfering RNA screening identified class II phosphatidylinositol 3-kinase C2β (PI3KC2β) as the predominant isoform of PI3K involved in lamellipodia formation of ovarian cancer cells. The bioactive sphingolipid ceramide has emerged as an antitumorigenic lipid, and treatment with short-chain C6-ceramide decreased the number of ovarian cancer cells with PI3KC2β-driven lamellipodia. Pharmacological analysis demonstrated that long-chain ceramide regenerated from C6-ceramide through the salvage/recycling pathway, at least in part, mediated the action of C6-ceramide. Mechanistically, ceramide was revealed to interact with the PIK-catalytic domain of PI3KC2β and affect its compartmentalization, thereby suppressing PI3KC2β activation and its driven cell motility. Ceramide treatment also suppressed cell motility promoted by epithelial growth factor, which is a prometastatic factor. To examine the role of ceramide in ovarian cancer metastasis, ceramide liposomes were employed and confirmed to suppress cell motility in vitro. Ceramide liposomes had an inhibitory effect on peritoneal metastasis in a murine xenograft model of human ovarian cancer. Metastasis of PI3KC2β knocked-down cells was insensitive to treatment with ceramide liposomes, suggesting specific involvement of ceramide interaction with PI3KC2β in metastasis suppression. Our study identified ceramide as a bioactive lipid that limits PI3KC2β-governed cell motility, and ceramide is proposed to serve as a metastasis-suppressor lipid in ovarian cancer. These findings could be translated into developing ceramide-based therapy for metastatic diseases.Oncogene advance online publication, 14 September 2015; doi:10.1038/onc.2015.330.
[Show abstract][Hide abstract] ABSTRACT: Gaucher's disease is caused by defects in acid β-glucosidase 1 (GBA1) and has been also proposed as an inflammatory disease. GBA1 cleaves glucosylceramide to form ceramide, an established bioactive lipid, and defects in GBA1 lead to aberrant accumulation in glucosylceramide and insufficient formation of ceramide. We investigated if the pro-inflammatory kinase p38 is activated in Gaucher's disease, since ceramide has been proposed to suppress p38 activation. Three Gaucher's disease mouse models were employed, and p38 was found to be activated in lung and liver tissues of all Gaucher's disease mice. Most interestingly, neuronopathic Gaucher's disease type mice, but not non-neuronopathic ones, displayed significant activation of p38 and up-regulation of p38-inducible proinflammatory cytokines in brain tissues. In addition, all type of Gaucher's disease mice also showed increases in serum IL-6. As cellular signalling is believed to represent an in vivo inflammatory phenotype in Gaucher's disease, activation of p38 and possibly its-associated formation of proinflammatory cytokines were assessed in fibroblasts established from neuronopathic Gaucher's disease mice. In mouse Gaucher's disease cells, p38 activation and IL-6 formation by TNF-α treatment were enhanced as compared to those of wild type. Furthermore, human fibroblasts from Gaucher's disease patients also displayed increases in p38 activation and IL-6 formation as comparison to healthy counterpart. These results raise the potential that proinflammatory responses such as p38 activation and IL-6 formation are augmented in Gaucher's disease.
PLoS ONE 08/2015; 10(8):e0136633. DOI:10.1371/journal.pone.0136633 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Parity has previously been reported to affect the difference in blood pressure (BP) measured in the office and at home, also known as the white-coat effect, during pregnancy. The objective of this study was to identify possible factors that cause the white-coat effect during pregnancy, focusing on parity. In total, 530 pregnant women (31.3±4.7 years old) who delivered at a maternal clinic were eligible for the study. The association between parity and the white-coat effect (clinic BP compared with home BP) was investigated for each trimester of pregnancy by multivariate analysis of covariance adjusted for age, body mass index, family history of hypertension and smoking habits. The magnitudes of the white-coat effect for systolic BP in the first, second and third trimesters were 4.1±9.8, 3.4±7.1 and 1.8±6.0 mm Hg, respectively and those for diastolic BP were 3.8±7.4, 1.6±5.8 and 2.4±4.9 mm Hg, respectively. Parity was significantly and negatively associated with the white-coat effect for systolic BP in the first trimester of pregnancy (nulliparous women: 5.07±0.61 mm Hg and multiparous women: 2.78±0.74 mm Hg, P=0.02) as well as for diastolic BP in the second and third trimesters of pregnancy. Age, body mass index, family history of hypertension and smoking were not significantly associated with the white-coat effect in any trimester of pregnancy. Parity may have an influence on the white-coat effect in pregnancy; however, the observed effect, on average 1-2 mm Hg, was small.Hypertension Research advance online publication, 27 August 2015; doi:10.1038/hr.2015.97.
Hypertension Research 08/2015; DOI:10.1038/hr.2015.97 · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The Tohoku Medical Megabank Organization reports the whole-genome sequences of 1,070 healthy Japanese individuals and construction of a Japanese population reference panel (1KJPN). Here we identify through this high-coverage sequencing (32.4 × on average), 21.2 million, including 12 million novel, single-nucleotide variants (SNVs) at an estimated false discovery rate of <1.0%. This detailed analysis detected signatures for purifying selection on regulatory elements as well as coding regions. We also catalogue structural variants, including 3.4 million insertions and deletions, and 25,923 genic copy-number variants. The 1KJPN was effective for imputing genotypes of the Japanese population genome wide. These data demonstrate the value of high-coverage sequencing for constructing population-specific variant panels, which covers 99.0% SNVs of minor allele frequency ≥0.1%, and its value for identifying causal rare variants of complex human disease phenotypes in genetic association studies.
[Show abstract][Hide abstract] ABSTRACT: We investigated the role of human leukocyte antigen (HLA) class II alleles in multistage cervical carcinogenesis. Cross-sectional analysis for HLA association with cervical cancer included 1253 Japanese women: normal cytology (NL, n=341), cervical intraepithelial neoplasia grade 1 (CIN1, n=505), CIN grade 2 or 3 (CIN2/3, n=96) or invasive cervical cancer (ICC, n=311). HLA class II allele frequencies were compared by Fisher's exact test or the χ2 test. The Bonferroni adjustment corrected for multiple comparisons. Among the study subjects, 454 women with low-grade squamous intraepithelial lesion (LSIL) cytology were prospectively monitored by cytology and colposcopy every 3-4 months to analyze cumulative risk of CIN3 within the next 10 years in relation to HLA Class II alleles. HLA class II DRB1*1302 allele frequency was similar between women with NL (11.7%) and CIN1 (11.9%), but significantly decreased to 5.2% for CIN2/3 and 5.8% for ICC (P=0.0003). Correction for multiple testing did not change this finding. In women with LSIL cytology, the cumulative risk of CIN3 diagnosed within 10 years was significantly reduced among DRB1*1302-positive women (3.2% vs. 23.7%, P=0.03). In conclusion, the two different types of analysis in this single study demonstrated the protective effect of the DRB1*1302 allele against progression from CIN1 to CIN2/3. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Cancer Science 08/2015; DOI:10.1111/cas.12760 · 3.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Residents of areas affected by the Great East Japan Earthquake may suffer from diseases or health problems. We are conducting a cross-sectional study from 2012 to 2015 to investigate and address the health needs of schoolchildren affected by this disaster. In this paper, we describe the protocol and research perspectives of our long-term child health study, and present the results obtained immediately after the disaster. The parent-administered questionnaire includes the International Study of Asthma and Allergies in Childhood questionnaire for asthma and eczema symptoms, the Strengths and Difficulties Questionnaire (SDQ), and a questionnaire on influenza infection and vaccination status. In 2012, we distributed the questionnaire to 3,505 (2(nd), 4(th), 6(th), and 8(th) graders) in three municipalities located in southern coastal area among the 28 municipalities, and 1,277 (36.4%) returned the completed questionnaire. Mean age was 11.1 ± 2.2 years old. The number of children with symptoms of wheeze and eczema in the past 12 months was 146 (11.4%) and 199 (15.6%), respectively. The SDQ total difficulties score revealed 174 (13.6%) children with some form of difficulty in their daily lives. From May 2011 to April 2012, 195 (15.3%) and 649 (50.8%) children received the influenza vaccination once and twice, respectively, and 532 (41.7%) had suffered from influenza. The prevalence of eczema symptoms or some form of difficulty was higher than the Japanese average. However, careful interpretation was required because of potential self-selection bias from the low response rate. We will continue this study of schoolchildren to provide aggregate findings.
The Tohoku Journal of Experimental Medicine 07/2015; 236(2):123-30. DOI:10.1620/tjem.236.123 · 1.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Analysis of the placenta can be a useful way to determine the fatty acid (FA) status of pregnant women and neonates since this large organ can be obtained easily and non-invasively. Although several studies have been conducted on using placental tissue for FA analysis, the sampling methods have not been thoroughly examined. The aim of the present study was to determine a suitable method of sampling human placentae by focusing on their heterogeneity. Twenty-four placentae were collected from healthy pregnant Japanese women in the Miyagi Prefecture of Japan. Five of them were used to compare the FA composition between the peripheral area and the central area of the placentae. The other 19 were examined to determine differences in the FA composition between the fetal and maternal side. Placental tissue crude lipid was saponified, and methyl was esterified with 14% sodium boron trifluoride methanol for gas chromatography with flame ionization detector analysis. Fifty-six peaks were detected from the methyl esters of the placental total lipid, and 33 of those were identified as FA methyl esters. There were considerable variations in the FA composition, as the variation was low in the central parts and high in the peripheral parts of the placentae. The 18:1n-9 and 18:2n-6 levels were higher in the fetal side, whereas the 20:3n-6, 20:4n-6, and 22:6n-3 levels were higher in the maternal side. These findings indicate the presence of heterogeneity in the FA composition of human placenta, and they suggest the necessity for standardizing the sampling method so that the placental tissue can be used to determine the FA status.
[Show abstract][Hide abstract] ABSTRACT: Hachimijiogan (HJG), Ba-Wei-Di-Huang-Wan in Chinese, is one of the most popular herbal medicines in Japanese Kampo. HJG is often prescribed for the prevention and treatment of age-related diseases. Muscle atrophy plays an important role in aging-related disabilities such as sarcopenia. The purpose of this study was to investigate the possible beneficial effect of HJG on skeletal muscle.
Cells of murine skeletal muscle myoblast cell line C2C12 were used as an in vitro model of muscle cell proliferation and differentiation. The effect of HJG on C2C12 cell proliferation and differentiation was assessed. We counted the number of myotubes morphologically to assess the degree of differentiation.
HJG treatment (200 μg/mL) for 3 days significantly increased C2C12 cell number by 1.23-fold compared with that of the control. HJG promoted the proliferation of C2C12 cells through activation of the ERK1/2 signaling pathway without affecting the Akt signaling pathway. HJG did not affect the differentiation of C2C12 cells.
HJG had beneficial effects on skeletal muscle myoblast proliferation. These findings may provide a useful intervention for the prevention and treatment of sarcopenia.