Thioredoxin binding protein (TBP)-2/Txnip and α-arrestin proteins in cancer and diabetes mellitus

Thioredoxin binding protein −2/ thioredoxin interacting protein is an α-arrestin protein that has attracted much attention as a multifunctional regulator. Thioredoxin binding protein −2 expression is downregulated in tumor cells and the level of thioredoxin binding protein is correlated with clinical stage of cancer. Mice with mutations or knockout of the thioredoxin binding protein −2 gene are much more susceptible to carcinogenesis than wild-type mice, indicating a role for thioredoxin binding protein −2 in cancer suppression. Studies have also revealed roles for thioredoxin binding protein −2 in metabolic control. Enhancement of thioredoxin binding protein −2 expression causes impairment of insulin sensitivity and glucose-induced insulin secretion, and β-cell apoptosis. These changes are important characteristics of type 2 diabetes mellitus. Thioredoxin binding protein −2 regulates transcription of metabolic regulating genes. Thioredoxin binding protein −2-like inducible membrane protein/ arrestin domain containing 3 regulates endocytosis of receptors such as the β2-adrenergic receptor. The α-arrestin family possesses PPXY motifs and may function as an adaptor/scaffold for NEDD family ubiquitin ligases. Elucidation of the molecular mechanisms of α-arrestin proteins would provide a new pharmacological basis for developing approaches against cancer and type 2 diabetes mellitus

Thioredoxin/Txnip: Redoxisome, as a Redox Switch for the Pathogenesis of Diseases

During the past few decades, it has been widely recognized that Reduction-Oxidation (redox) responses occurring at the intra- and extra-cellular levels are one of most important biological phenomena and dysregulated redox responses are involved in the initiation and progression of multiple diseases. Thioredoxin1 (Trx1) and Thioredoxin2 (Trx2), mainly located in the cytoplasm and mitochondria, respectively, are ubiquitously expressed in variety of cells and control cellular reactive oxygen species by reducing the disulfides into thiol groups. Thioredoxin interacting protein (Txnip/thioredoxin binding protein-2/vitamin D3 upregulated protein) directly binds to Trx1 and Trx2 (Trx) and inhibit the reducing activity of Trx through their disulfide exchange. Recent studies have revealed that Trx1 and Txnip are involved in some critical redox-dependent signal pathways including NLRP-3 inflammasome activation in a redox-dependent manner. Therefore, Trx/Txnip, a redox-sensitive signaling complex is a regulator of cellular redox status and has emerged as a key component in the link between redox regulation and the pathogenesis of diseases. Here, we review the novel functional concept of the redox-related protein complex, named “Redoxisome,” consisting of Trx/Txnip, as a critical regulator for intra- and extra-cellular redox signaling, involved in the pathogenesis of various diseases such as cancer, autoimmune disease, and diabetes

A Study of Regional Resource Utilization in Vocational Education of Special Needs Education High School Division: Based on efforts utilizing employment assistance conference and subsequent advice

本報告では、平成28年度に広島県内初の肢体不自由教育と知的障害教育に対応した併置校として新たにスタートした本校の地域資源を活用した職業教育の実践について述べる。この取組は、進路指導部を中核とした「就労支援プロジェクト」として展開している。このプロジェクトでは、地域資源とのネットワークを促進させ就労支援の充実を図ることを目的に、「就労支援会議」と「企業参観日」を開催している。初年度この会議に参加された方々から頂いた助言を基に、主に３つの取組を展開した。広島県特別支援学校技能検定で身に付けた力を日常生活の中でどのように般化し、主体的に応用できるかを目指した「技能検定に係る下学部への指導」、現場で得た課題を授業の中で整理、理解、改善して、再度現場で実践し、課題を克服することを目指した「グループ実習」、就労支援会議構成員との面談を通して、自己への気付きを深めていく「グループ面談」について、その具体的な実践内容について報告する。In this report, the authors describe the practices of vocational education utilizing regional resources at our school, re-established in 2017 as the first co-location school in Hiroshima Prefecture, that corresponds to both education for orthopedically impaired students and education for mentally retarded students. This approach is organized as an “employment assistance project” led by the career guidance department at its central core. In this project, the authors hold an“ employment assistance conference” and a“ company visit day” in order to further promote networking with regional resources and to enhance productive employment support. Based on advice from the conference participants in the first year, the authors developed three further approaches. The authors hereby describe the specific practices as such: “guidance to the lower division students associating with skill test” that focuses on how to generalize and proactively apply in daily life, the skills absorbed through the Hiroshima Prefectural Special Needs Education School Skill Test;“ group training” that aims towards overcoming challenges found in the training through the process of organizing, understanding, improving and practicing again onsite, and “group interview” that encourages deeper awareness of oneself through interview exchanges with employment assistance conference members

向精神薬のターゲット部位の遺伝子解析 : セロトニントランスポーター遺伝子多型とパーソナリティおよび痛覚との関連研究

我々はセロトニントランスポーター (5-HTT) 3\u27非翻訳領域 (3\u27UTR) 遺伝子多型の影響, 疼痛感受性個人差の原因, 性格の遺伝要因を解明する一助として5-HTT 3\u27UTR遺伝子多型と痛覚閾値およびパーソナリティとの3つの要因の関連性について調査検討を行った。　181人の健常者を対象に, 5-HTT 3\u27UTR遺伝子多型の判定には制限酵素切断長多型解析法を用い, 痛覚閾値に関しては冷水刺激試験および圧刺激試験を, パーソナリティの測定にはTCI (Temperament and Character Inventory) を行った。　遺伝子多型と痛覚閾値には関連がなかった。遺伝子多型とTCIの相関について, 男性ではST3｛超個人的同一化 (vs. 自己弁別)｝が遺伝子型G/G群で有意に高く, 女性ではST (自己超越性総合点) およびST2｛自己忘却 (vs. 自己意識経験)｝が遺伝子型G/T + T/T群で有意に高かった。痛覚閾値とTCIとの関係について, 男性群で冷水刺激閾値とNS4｛無秩序 (vs. 組織化)｝およびNS (新奇性追求) で負の相関, 女性群で冷水刺激閾値とSD4 (自己受容), C5｛純粋な良心 (vs. 利己主義)｝および圧刺激閾値とSD4 (自己受容) で正の相関が認められた。本研究から5-HTT 3\u27UTR遺伝子多型はCloningerの理論における性格次元に影響を与える可能性がある一方で, 痛覚は5-HTT 3\u27UTR遺伝子多型と関与せず, 一方でパーソナリティの一部と相関関係にある可能性が示唆された。To estimate the genetic factors influencing individual differences in sensitivity to pain, we have examined the associations among serotonin reuptake transporter (5-HTT) 3\u27 UTR gene polymorphism, sensitivity to pain and personality. After the procedures were fully explained and written informed consent was obtained, 5-HTT 3\u27 UTR gene polymorphism was investigated by PCR-RFLP, and personality assessment was performed by means of Temperament and Character Inventory (TCI), and pain threshold by means of cold water and pressure stimulation tests in 181 healthy Japanese volunteers. Males with the T allele (T/T and T/G) showed a significantly lower Self-Transcendence (ST) 3 subdimension score than those without the T allele (G/G). Females with the T allele (T/T and T/G) showed significantly higher ST2 subdimension and ST dimension scores than those without the T allele (G/G). There was no significant relationship between 5-HTT 3\u27 UTR gene polymorphism and pain sensitivity. As for pain sensitivity and TCI, there was low negative correlation between cold water stimulation in males and Novelty Seeking (NS) 4 subdimension and NS, and low positive correlation between cold water stimulation in females and Self-Directedness (SD) 4 subdimension and Cooperativeness (C) 5 subdimension, and between pressure stimulation in females and SD4. It is possible that 5-HTT 3\u27 UTR gene polymorphism may affect the character dimension in the theory of Cloninger, however, 5-HTT 3\u27 UTR gene polymorphism may not be related to the sense of pain, and that there is low correlation between pain and a part of the personality

The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells

Cancer-associated fibroblasts (CAFs) are pivotal in tumor progression. TP53-deficiency in cancer cells is associated with robust stromal activation. The apelin-apelin receptor (APJ) system has been implicated in suppressing fibroblast-to-myofibroblast transition in non-neoplastic organ fibrosis. The present study aimed to elucidate the oncogenic role of the apelin-APJ system in tumor fibroblasts. APJ expression and the effect of APJ suppression in fibroblasts were investigated for p53 status in cancer cells using human cell lines (TP53-wild colon cancer, HCT116, and Caco-2; TP53-mutant colon cancer, SW480, and DLD-1; and colon fibroblasts, CCD-18Co), resected human tissue samples of colorectal cancers, and immune-deficient nude mouse xenograft models. The role of exosomes collected by ultracentrifugation were also analyzed as mediators of p53 expression in cancer cells and APJ expression in fibroblasts. APJ expression in fibroblasts co-cultured with p53-suppressed colon cancer cells (HCT116sh p53 cells) was significantly lower than in control colon cancer cells (HCT116sh control cells). APJ-suppressed fibroblasts treated with an antagonist or small interfering RNA showed myofibroblast-like properties, including increased proliferation and migratory abilities, via accelerated phosphorylation of Sma- and Mad-related protein 2/3 (Smad2/3). In addition, xenografts of HCT116 cells with APJ-suppressed fibroblasts showed accelerated tumor growth. By contrast, apelin suppressed the upregulation of phosphorylated Smad2/3 in fibroblasts. MicroRNA 5703 enriched in exosomes derived from HCT116sh p53 cells inhibited APJ expression, and inhibition of miR-5703 diminished APJ suppression in fibroblasts caused by cancer cells. APJ suppression from a specific microRNA in cancer cell-derived exosomes induced CAF-like properties in fibroblasts. Thus, the APJ system in fibroblasts in the tumor microenvironment may be a promising therapeutic target.Saiki H., Hayashi Y., Yoshii S., et al. The apelin‑apelin receptor signaling pathway in fibroblasts is involved in tumor growth via p53 expression of cancer cells. International Journal of Oncology 63, 139 (2023); https://doi.org/10.3892/ijo.2023.5587

Differentiations and Ambivalence of Feminity in the Women\u27s Student

Many gender studies are based on the concept of patriarchy which stresses the dichotomous distinction between women and men and which focuses on men\u27s domination over women. But, in reality, women cannot be understood by the single category of "women" which is implicitly presupposed in the theory of patriarchy. They consist of multiple and differentiated layers. And the mechanisms through which femininity and domesticity are produced and reproduced should be reconsidered from the point of both feminine culture and the pratique or strategic actions of women. In this paper, the data from the survey of the women undergraduate students (for details, see Section I) are analyzed both quantitatively and qualitatively. In Section II, quantitative data are analyzed from the viewpoints of feminine socialization and housework practices (chapter A), feminine culture of consumption, domesticity and object-favoritism (chapter B), relationships between marital and professional perspectives (chapter C) and "conservatization" by two types of feminine strategic actions (chapter D). In Section III, the qualitative data (free description) are analyzed concerning the future expectation (chapter A), advantageous and disadvantageous experiences of being women (chapter B), and transformation of notions about males and marriage (chapter C). The perspective of "differentiation and ambivalence of femininity" is effective to analyze the (post-) modern gender relations

Deficiency of Thioredoxin Binding Protein-2 (TBP-2) Enhances TGF-β Signaling and Promotes Epithelial to Mesenchymal Transition

Transforming growth factor beta (TGF-β) has critical roles in regulating cell growth, differentiation, apoptosis, invasion and epithelial-mesenchymal transition (EMT) of various cancer cells. TGF-β-induced EMT is an important step during carcinoma progression to invasion state. Thioredoxin binding protein-2 (TBP-2, also called Txnip or VDUP1) is downregulated in various types of human cancer, and its deficiency results in the earlier onset of cancer. However, it remains unclear how TBP-2 suppresses the invasion and metastasis of cancer.In this study, we demonstrated that TBP-2 deficiency increases the transcriptional activity in response to TGF-β and also enhances TGF-β-induced Smad2 phosphorylation levels. Knockdown of TBP-2 augmented the TGF-β-responsive expression of Snail and Slug, transcriptional factors related to TGF-β-mediated induction of EMT, and promoted TGF-β-induced spindle-like morphology consistent with the depletion of E-Cadherin in A549 cells.Our results indicate that TBP-2 deficiency enhances TGF-β signaling and promotes TGF-β-induced EMT. The control of TGF-β-induced EMT is critical for the inhibition of the invasion and metastasis. Thus TBP-2, as a novel regulatory molecule of TGF-β signaling, is likely to be a prognostic indicator or a potential therapeutic target for preventing tumor progression

Contributions of mean and shape of blood pressure distribution to worldwide trends and variations in raised blood pressure: A pooled analysis of 1018 population-based measurement studies with 88.6 million participants

© The Author(s) 2018. Background: Change in the prevalence of raised blood pressure could be due to both shifts in the entire distribution of blood pressure (representing the combined effects of public health interventions and secular trends) and changes in its high-blood-pressure tail (representing successful clinical interventions to control blood pressure in the hypertensive population). Our aim was to quantify the contributions of these two phenomena to the worldwide trends in the prevalence of raised blood pressure. Methods: We pooled 1018 population-based studies with blood pressure measurements on 88.6 million participants from 1985 to 2016. We first calculated mean systolic blood pressure (SBP), mean diastolic blood pressure (DBP) and prevalence of raised blood pressure by sex and 10-year age group from 20-29 years to 70-79 years in each study, taking into account complex survey design and survey sample weights, where relevant. We used a linear mixed effect model to quantify the association between (probittransformed) prevalence of raised blood pressure and age-group- and sex-specific mean blood pressure. We calculated the contributions of change in mean SBP and DBP, and of change in the prevalence-mean association, to the change in prevalence of raised blood pressure. Results: In 2005-16, at the same level of population mean SBP and DBP, men and women in South Asia and in Central Asia, the Middle East and North Africa would have the highest prevalence of raised blood pressure, and men and women in the highincome Asia Pacific and high-income Western regions would have the lowest. In most region-sex-age groups where the prevalence of raised blood pressure declined, one half or more of the decline was due to the decline in mean blood pressure. Where prevalence of raised blood pressure has increased, the change was entirely driven by increasing mean blood pressure, offset partly by the change in the prevalence-mean association. Conclusions: Change in mean blood pressure is the main driver of the worldwide change in the prevalence of raised blood pressure, but change in the high-blood-pressure tail of the distribution has also contributed to the change in prevalence, especially in older age groups

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe