Progranulin (PGRN) is an anti-inflammatory molecule involved in a variety of biological phenomena, but its expression in the cervix and anti-inflammatory effects remain unclear. We investigated the dynamics of PGRN during pregnancy and its anti-inflammatory effect on the cervix. This study was conducted under the approval of the institutional ethics committee. In 36 mothers, PGRN concentrations in serum at mid- and late-term pregnancy and postpartum and in cervical mucus before delivery were measured by ELISA. The effects of estradiol and progesterone administration on PGRN expression were examined in a cervical cell line by real-time PCR. The effect of TNF-α administration followed by PGRN on suppression of inflammatory cytokines was examined. We examined the anti-inflammatory effect in the cervix when PGRN was administered to the cervix using a preterm mouse model. Serum PGRN concentrations in late pregnancy were predominantly higher than those in midpregnancy and postpartum. A significant negative correlation was found between PGRN concentration in cervical mucus and Bishop score before labor onset (r2=0.47 p<0.01). In the cervical cell line, PGRN expression was enhanced by P4 stimulation. PGRN treatment in cervical cells showed a predominant suppression of inflammatory cytokines (IL1β, IL-6, and IL-8) induced by TNF-α. In the preterm mouse model, induction of IL1β in the cervix was predominantly suppressed by PGRN treatment. These results suggest that PGRN expression is upregulated during pregnancy under the influence of P4 and that PGRN in the cervix plays an important role in regulating cervical ripening through its anti-inflammatory effect.
Lipid metabolism is an essential process in cancer growth and progression. It is highly relevant in tumors with an adipocyte-rich microenvironment, such as ovarian carcinoma (OC). Carnitine palmitoyltransferase 2 (CPT2) is a key enzyme in fatty acid oxidation (FAO) that functions as a tumor suppressor in OC. Downregulation of CPT2 is reportedly associated with poor prognosis of OC patients. At the cellular level, low CPT2 translates into reduced NADPH level and unopposed reactive-oxygen species (ROS)/nuclear factor kappa B (NFκB) signaling which are paralleled by induction of mesenchymal mediators, invasion and metastasis. While strategies to propagate the tumor suppressive properties of CPT2 have yet to be developed, a comprehensive approach of co-assessment and co-targeting of CPT2 and its family member CPT1, or/and other key FAO players with FAO-specific inhibitors or/and less specific inhibitors (e.g. targeting NFκB, STAT3) is worth pursuing to improve understanding of the metabolic aspects of OC and develop a lipid metabolism-centered therapeutic strategy that can benefit OC patients.
This chapter addresses the physical security component of school security. It explores the individual elements of deterrence, detection, delay, and response. The chapter also introduced basic principles of Crime Prevention Through Environmental Design (CPTED).
Individuals with mixed dyslipidemia have elevated triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and increased risk for coronary disease. Fibrate therapy is commonly used to lower TG and increase HDL-C. Common genetic variants are known to affect the response to fibrate therapy. We sought to identify rare genetic variants (frequency ≤ 1%) in genes involved in TG and HDL-C metabolism that affect the response to fenofibric acid (FA) therapy.Four genes with a major role in HDL-C and TG metabolism APOA1, APOC2, APOC-III and LPL were sequenced in 2385 participants with mixed dyslipidemia in a randomized, double-blind, active-controlled study comparing therapy with FA alone, in combination with statins, or statin alone. Rare variants collapsing or SKAT methods were used for the analysis.Synonymous rare variants in the LPL gene were significantly associated with absolute HDL-C change (P = 9 × 10−4) and TG percent change (P = 6.76 × 10−4) in those treated with FA only. Participants with these rare variants had a 2 mg/dL increase in HDL-C and 39 mg/dL decrease in TG as compared to 6.2 mg/dL increase in HDL-C and 100 mg/dL decrease in TG in those without these variants. Rare variants in the APOC-III gene were associated with a modest 3 mg/dL less reduction in APOB (P = 8.72 × 10−4) in those receiving FA and statin.In individuals with mixed dyslipidemia rare synonymous variants within LPL gene were associated with attenuated response to FA therapy while APOCIII rare variants were associated with a modest effect on APOB response to FA-statin therapy. These results should be replicated in a similar clinical trial for further confirmation.
Background: Insufficient oxygen supply is closely associated with the pathophysiology of fetal growth restriction (FGR). Although the erythrocyte is the most abundant and only cell type to deliver oxygen in our body, its function and regulatory mechanism in FGR remains unknown. Recently, intracellular adenosine uptake by equilibrative nucleoside transporter 1 (ENT1), a key adenosine transporter predominantly expressed in erythrocytes, was reported to be crucial for erythrocytes to deliver oxygen. Current study was aimed to investigate the involvement of erythrocytes’ oxygen delivering capacity in maintaining fetal growth by focusing on erythrocyte ENT1. Methods and Results: Conditional knockout mice with erythrocyte-specific gene deletion of ENT1 were utilized in this study. These mice indeed showed reduction in oxygen delivering capacity during pregnancy compared to control mice. We found that genetic ablation of mouse erythrocyte ENT1 in dams results in FGR without showing any maternal features of preeclampsia. Unbiased highthroughput metabolic profiling led us to discover that these transgenic mice have lower amino acid concentration in the placenta and higher amino acid concentration in the serum compared to the control dams. Mechanistically and functionally, we revealed genetic ablation of maternal erythrocyte
: Preterm birth (PTB) is divided into spontaneous and artificial PTB, and spontaneous PTB (SPTB) occurs in about 70 %. And history of SPTB itself is a risk factor for SPTB in next pregnancy. The rate of repeated SPTB in Japan is 22.3% according to a recent report. Although there are a lot of causes for SPTB, intra-uterine inflammation (histological chorioamnionitis: hCAM) is the main reason. So, intra-uterine inflammation/infection in preterm labor (PTL) is the most important marker as same as clinical symptom such as genital bleeding and maturation of cervix. In particular, super-infection (bacteria and Ureaplasma/Mycoplasma) in amnion is strongly related with earlier According to the intra-amniotic environment of PTL, antibiotics and/or progesterone (17- α -hydroxyprogesterone caproate: 17OHP-C) are selected with maintenance tocolysis, the pregnant period prolong for about 4 weeks. However, in cases with severe intra-amniotic inflammation/infection, there is a limitation not
HPV infection is the primary cause of cervical cancer and its precancer. With popularization of HPV prophylactic vaccines, the incidence of cervical cancer is expected to decrease, however, it will take time to eradicate cervical cancer. In order to prevent and control cervical cancer, it is important to implement a step-by-step preventive strategy according to the level of prevention: the primary prevention by HPV prophylactic vaccines; the secondary prevention by screening and treatment; and the tertiary prevention by the treatment of invasive cervical cancer. In this review, we especially focus on the secondary prevention and discuss the management of HPV-related cervical precancer based on the HPV genotypes as well as human immune responses against HPV infection.
Recurrent pregnancy loss (RPL) is one of the major concerns in Japan. We performed a long-term multicenter prospective study to reveal the risk factors and pregnancy outcomes of RPL in Japan. Antiphospholipid antibodies (aPL), malformation of the uterus, thyroid dysfunction, parental karyotype abnormality, factor XII deficiency, and protein S deficiency were defined as the risk factors of RPL. The prevalence of each risk factor was similar to previous studies except aPL positive rate. No risk factors were detected in more than half of RPL patients (65.2%). In transiently aPL-positive patients, the live birth rates with LDA were comparable to that with heparin + LDA. Despite that factor XII deficiency and protein S deficiency are not recognized as risk factors for RPL in general, low-dose aspirin (LDA) or unfractionated heparin + LDA therapy improved live birth rates. However, the live birth rate treated with LDA and that with unfractionated heparin + LDA were comparable in factor XII deficiency and protein S deficiency. Factor XII deficiency and protein S deficiency might be considered to be the risk factors of RPL and LDA therapy might be recommended in Factor XII deficiency, protein S deficiency, and transiently aPL-positive patients. We have discussed the risk factors and the live birth rate after treatment between Japan and worldwide.
: the of rapidly in the ‘Two Step Theory’ been proposed and widely the soluble receptor crucial roles. HDP model and the HDP In the research of HDP, many Japanese researchers have occupied important parts in both in vitro and in vivo experiments, in addition to clinical discoveries. In this review, we explain about the relations between HDP and sFlt-1, and then introduce mainly two kinds of model mice of HDP by our groups.
Inflammation with macrophage infiltration is a key feature of atherosclerosis. Although the mechanisms had been unclear, emerging evidence unveiled that NLRP3 inflammasomes, which regulate caspase-1 activation and subsequent processing of pro-IL-1β, trigger vascular wall inflammatory responses and lead to progression of atherosclerosis. NLRP3 inflammasomes are activated by various danger signals, such as cholesterol crystals, calcium phosphate crystals, and oxidized low-density lipoprotein in macrophages, to initiate inflammatory responses in the atherosclerotic lesion. Recent studies have further clarified the regulatory mechanisms and the potential therapeutic agents that target NLRP3 inflammasomes. In this study, we reviewed the present state of knowledge on the role of NLRP3 inflammasomes in the pathogenesis of atherosclerosis and discussed the therapeutic approaches that target NLRP3 inflammasomes.
Unexpected fetal loss is one of the common complications of pregnancy; however, the pathogenesis of many miscarriages, particularly those not associated with infections, is unknown. We previously found that activated DEC‐205 + dendritic cells (DCs) and NK1.1 + invariant natural killer T (iNKT) cells are recruited into the myometrium of mice when miscarriage is induced by the intraperitoneal administration of α‐galactosylceramide (α‐GalCer). Here we demonstrate that the adoptive transfer of DEC‐205 + bone marrow‐derived DCs cocultured with α‐GalCer (DEC‐205 + BMDCs‐c/w‐α‐GalCer) directly induced marked fetal loss by syngeneic pregnant C57BL/6 (B6) mice and allogeneic mice (B6 (♀) × BALB/c (♂)), which was accompanied by the accumulation of activated iNKT cells in the myometrium. Further, the adoptive transfer of NK1.1 + iNKT cells obtained from B6 mice injected with α‐GalCer facilitated miscarriages in syngeneic Jα18 (−/−) (iNKT cell‐deficient) mice. These results suggest that DEC‐205 + DCs and NK1.1 + iNKT cells play crucial roles required for the initiation of fetal loss associated with stimulation by glycolipid antigens and sterile inflammation.
Venomous animals produce toxins that inhibit ion channels with high affinity. These small peptide inhibitors are used in the characterization of ion channels structurally as well as pharmacologically. So, identification of these toxins is an important task. In this study, based on the pseudo amino acid (PseAA) composition and feature selection method, the random forest algorithm was used for predicting three different groups of ion channel inhibitors. The prediction results indicated that our algorithm achieved the sensitivity of 60.00% for calcium channel inhibitor, 71.90% for potassium channel inhibitor and 86.80% for sodium channel inhibitor when evaluated by the jackknife test. In addition, for comparing with other algorithms, this algorithm was used to predict the dataset with 343 ion channel inhibitors, and the higher predictive success rates than the previous algorithms were obtained by our algorithm.
