Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Smoking during pregnancy is one of the causes of low birthweight. Ingestion of nicotine during pregnancy has various metabolic impacts on the fetus and offspring. According to the developmental origins of health and disease theory, low birthweight is a risk factor for developing various non-communicable diseases, including diabetes. We hypothesized that when nicotine-induced low-birthweight rats, when exposed to a high-fat diet (HFD) after growth, are predisposed to glucose intolerance as a result of a mismatch between the eutrophic environment and small body size. Therefore, we investigated whether hyperinsulinemia was caused by exposure of nicotine-induced low-birthweight rats to HFD, including whether this phenomenon exhibited possible sex differences. The average birthweight and body weight at weaning day of offspring from nicotine-administered dams was lower than those of controls. The offspring from nicotine-administered dams did not show rapid fat accumulation after exposure to HFD, and weight and body fat ratio of these animals did not differ from those of the controls. Blood glucose levels did not differ between the groups, but insulin levels increased only in male HFD-exposed offspring from nicotine-administered dams. Similarly, only in HFD-exposed male from nicotine-administered dams showed decreases in the insulin receptor expression in the liver. We conclude that male rats subjected to prenatal nicotine exposure develop hyperinsulinemia when exposed to HFD after growth. Our results suggest that decreased expression of insulin receptors in the liver may be involved in the mechanism underlying hyperinsulinemia in low-birthweight offspring, a phenomenon that appeared to exhibit a sex-specific bias.

DOI： 10.3389/fendo.2021.694336

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Porcine steroid hormone profiles have some unique characteristics. We previously studied human and murine steroidogenesis using steroidogenic cells-derived from mesenchymal stem cells (MSCs). To investigate porcine steroidogenesis, we induced steroidogenic cells from porcine subcutaneous preadipocytes (PSPA cells), which originate from MSCs. Using cAMP, adenovirus-mediated introduction of steroidogenic factor-1 (SF-1)/adrenal 4-binding protein (Ad4BP) induced the differentiation of PSPA cells into sex steroid-producing cells. Introducing SF-1/Ad4BP also induced the aldo-keto reductase 1C1 (AKR1C1) gene. Porcine AKR1C1 had 17β-hydroxysteroid dehydrogenase activity, which converts androstenedione and 11-ketoandrostenedione into testosterone (T) and 11-ketotestosteorne (11KT). Furthermore, differentiated cells expressed hydroxysteroid 11β-dehydrogenase 2 (HSD11B2) and produced 11KT. HSD11B2 was expressed in testicular Leydig cells and the adrenal cortex. 11KT was present in the plasma of both immature male and female pigs, with slightly higher levels in the male pigs. T levels were much higher in the male pigs. It is noteworthy that in the female pigs, the 11KT levels were >10-fold higher than the T levels. However, castration altered the 11KT and T plasma profiles in the male pigs to near those of the females. 11KT induced endothelial nitric oxide synthase (eNOS) in porcine vascular endothelial cells. These results indicate that 11KT is produced in porcine adrenal glands and testes, and may regulate cardiovascular functions through eNOS expression.

DOI： 10.1016/j.jsbmb.2021.105847

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Being delivered as a low birthweight (LBW) infant is a risk factor for elevated blood pressure and future problems with cardiovascular and cerebellar diseases. Although premature babies are reported to have low numbers of nephrons, some unclear questions remain about the mechanisms underlying elevated blood pressure in full-term LBW infants. We previously reported that glucocorticoids increased miR-449a expression, and increased miR-449a expression suppressed Crhr1 expression and caused negative glucocorticoid feedback. Therefore, we conducted this study to clarify the involvement of pituitary miR-449a in the increase in blood pressure caused by higher glucocorticoids in LBW rats. We generated a fetal low-carbohydrate and calorie-restricted model rat (60% of standard chow), and some individuals showed postnatal growth failure caused by growth hormone receptor expression. Using this model, we examined how a high-fat diet (lard-based 45kcal% fat)-induced mismatch between prenatal and postnatal environments could elevate blood pressure after growth. Although LBW rats fed standard chow had slightly higher blood pressure than control rats, their blood pressure was significantly higher than controls when exposed to a high-fat diet. Observation of glomeruli subjected to periodic acid methenamine silver (PAM) staining showed no difference in number or size. Aortic and cardiac angiotensin II receptor expression was altered with compensatory responses. Blood aldosterone levels were not different between control and LBW rats, but blood corticosterone levels were significantly higher in the latter with high-fat diet exposure. Administration of metyrapone, a steroid synthesis inhibitor, reduced blood pressure to levels comparable to controls. We showed that high-fat diet exposure causes impairment of the pituitary glucocorticoid negative feedback via miR-449a. These results clarify that LBW rats have increased blood pressure due to high glucocorticoid levels when they are exposed to a high-fat diet. These findings suggest a new therapeutic target for hypertension of LBW individuals.

DOI： 10.1371/journal.pone.0238223

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17β-Hydroxysteroid dehydrogenases (17β-HSDs) catalyze the reduction of 17-ketosteroids and the oxidation of 17β-hydroxysteroids to regulate the production of androgens and estrogens. Among them, 17β-HSD type 3 (HSD17B3) is expressed almost exclusively in testicular Leydig cells and contributes to development of male sexual characteristics by converting androstenedione (A4) to testosterone (T). Mutations of HSD17B3 genes cause a 46,XY disorder of sexual development (46,XY DSD) as a result of low T production. Therefore, the evaluation of 17β-HSD3 enzymatic activity is important for understanding and diagnosing this disorder. We adapted a method that easily evaluates enzymatic activity of 17β-HSD3 by quantifying the conversion from A4 to T using androgen receptor (AR)-mediated transactivation. HEK293 cells were transduced to express human HSD17B3, and incubated medium containing A4. Depending on the incubation time with HSD17B3-expressing cells, the culture media progressively increased luciferase activities in CV-1 cells, transfected with the AR expression vector and androgen-responsive reporter. Culture medium from HSD17B1 and HSD17B5-expressing cells also increased the luciferase activities. This system is also applicable to detect the conversion of 11-ketoandrostenedione to 11-ketotestosterone by HSD17B3. Establishment of HEK293 cells expressing various missense mutations in the HSD17B3 gene associated with 46,XY DSD revealed that this system is effective to evaluate the enzymatic activities of mutant proteins.

DOI： 10.1016/j.jsbmb.2019.105493

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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DOI： 10.1007/978-981-10-5526-3_6

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Diethylstilbestrol (DES), a strong estrogenic compound, is well-known to affect the reproductive system. In this study, we investigated the effects of DES administration on gonadotropin levels and ovarian steroidogenesis in prepubertal rats. DES treatment acutely reduced serum LH levels, followed by a reduction in the expression of various steroidogenesis-related genes in theca cells. Serum FSH levels were almost unaffected by DES-treatment, even though Cyp19a1 expression was markedly reduced. Serum progesterone, testosterone and estradiol levels were also declined at this time. LH levels recovered from 12 h after DES-treatment and gradually increased until 96 h with a reduction of ER alpha expression observed in the pituitary. Steroidogenesis-related genes were also up-regulated during this time, except for Cyp17a1 and Cyp19a1. Consistent with observed gene expression pattern, serum testosterone and estradiol concentrations were maintained at lower levels, even though progesterone levels recovered. DES-treatment induced the inducible nitric oxide synthase (iNOS) in granulosa cells, and a nitric oxide generator markedly repressed Cyp19a1 expression in cultured granulosa cells. These results indicate that DES inhibits thecal androgen production via suppression of pituitary LH secretion and ovarian Cyp17a1 expression. In addition, DES represses Cyp19a1 expression by inducing iNOS gene expression for continuous inhibition of estrogen production in granulosa cells.

DOI： 10.1038/s41598-017-08780-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Cardiomyocytes possess a non-neuronal cardiac cholinergic system (NNCCS) regulated by a positive feedback system; however, its other regulatory mechanisms remain to be elucidated, which include the epigenetic control or regulation by the female sex steroid, estrogen. Here, the NNCCS was shown to possess a circadian rhythm; its activity was upregulated in the light-off phase via histone acetyltransferase (HAT) activity and downregulated in the light-on phase. Disrupting the circadian rhythm altered the physiological choline acetyltransferase (ChAT) expression pattern. The NNCCS circadian rhythm may be regulated by miR-345, independently of HAT, causing decreased cardiac ChAT expression. Murine cardiac ChAT expression and ACh contents were increased more in female hearts than in male hearts. This upregulation was downregulated by treatment with the estrogen receptor antagonist tamoxifen, and in contrast, estrogen reciprocally regulated cardiac miR-345 expression. These results suggest that the NNCCS is regulated by the circadian rhythm and is affected by sexual dimorphism.

DOI： 10.1007/s12265-017-9750-4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PORTLAND PRESS LTD  

We previously developed cardiac ventricle-specific choline acetyltransferase (ChAT) gene-overexpressing transgenic mice (ChAT tgm), i.e. an in vivo model of the cardiac non-neuronal acetylcholine (NNA) system or non-neuronal cardiac cholinergic system (NNCCS). By using this murine model, we determined that this system was responsible for characteristics of resistance to ischaemia, or hypoxia, via the modulation of cellular energy metabolism and angiogenesis. In line with our previous study, neuronal ChAT-immunoreactivity in the ChAT tgm brains was not altered from that in the wild-type (WT) mice brains; in contrast, the ChAT tgm hearts were the organs with the highest expression of the ChAT transgene. ChAT tgm showed specific traits in a central nervous system (CNS) phenotype, including decreased response to restraint stress, less depressive-like and anxiety-like behaviours and anti-convulsive effects, all of which may benefit the heart. These phenotypes, induced by the activation of cardiac NNCCS, were dependent on the vagus nerve, because vagus nerve stimulation (VS) in WT mice also evoked phenotypes similar to those of ChAT tgm, which display higher vagus nerve discharge frequency; in contrast, lateral vagotomy attenuated these traits in ChAT tgm to levels observed in WT mice. Furthermore, ChAT tgm induced several biomarkers of VS responsible for anti-convulsive and anti-depressive-like effects. These results suggest that the augmentation of the NNCCS transduces an effective and beneficial signal to the afferent pathway, which mimics VS. Therefore, the present study supports our hypothesis that activation of the NNCCS modifies CNS to a more stress-resistant state through vagus nerve activity.

DOI： 10.1042/CS20160277

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Microtubules play an important role in the intracellular transport of secretory granules in endocrine cells and in mitosis and the maintenance of cell morphology and are composed of heterodimers of alpha- and beta-tubulin. alpha-Tubulin N-acetyltransferase 1 (ATAT1), which acetylates the lysine residue at position 40 of alpha-tubulin, functions not only in stabilizing microtubule structures and forming the primary cilium assembly but also in vesicular trafficking in neurons. However, the localization of ATAT1 and the role of alpha-tubulin acetylation in endocrine cells in the pituitary are still poorly understood. Corticotrophs in the anterior lobe of the pituitary produce and secrete adrenocorticotropin (ACTH). Although removal of the adrenal gland, a target organ of ACTH, is reported to promote the synthesis and secretion of ACTH in corticotrophs and to induce structural alterations in their organelles, uncertainty remains as to whether the acetylation of alpha-tubulin is involved in such intracellular events of corticotrophs. We investigate the expression and localization of ATAT1 and the acetylation of alpha-tubulin in the pituitary of normal and adrenalectomized rats. We find that ATAT1 is localized to the Golgi apparatus of endocrine cells in the anterior lobe of normal pituitary and that the expression levels of ATAT1 and acetylation levels of alpha-tubulin increase following adrenalectomy. These results agree with the hypothesis that the acetylation of alpha-tubulin by ATAT1 regulates the intracellular transport of secretory granules in corticotrophs.

DOI： 10.1007/s00441-016-2441-7

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Cilia are microtubule-based hair-like organelles on basal bodies located beneath the cell membrane in various tissues of multicellular animals, and are usually classified into motile cilia and primary cilia. Microtubules are assembled from the heterodimers of alpha- and beta-tubulin. The lysine residue at position 40 (K40) of alpha-tubulin is an important site for acetylation, and this site is acetylated in the cilium. alpha-Tubulin N-acetyltransferase 1 (ATAT1) is an acetyltransferase specific to the K40 residue of alpha-tubulin; however, its intracellular distribution in mammalian tissues remains unclear. In this study, we analyzed ATAT1 localization in rat trachea, oviduct, kidney, retina, testis and the third ventricle of the brain by immunohistochemical techniques using a specific antibody against ATAT1. ATAT1 was distributed to the motile cilia of multiciliated cells of the trachea, third ventricle of the brain and oviduct, and in the primary cilia of the renal medullary collecting duct. ATAT1 also localized to the primary cilia, inner and outer segments of retinal photoreceptor cells, and at the Golgi apparatus of spermatocytes and spermatids of testis. These results indicated that alpha-tubulin acetylation by ATAT1 at distinct subcellular positions may influence the functional regulation of microtubules and cilia in a variety of ciliated cells.

DOI： 10.1007/s00795-015-0132-1

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Authorship：Lead author,　Last author,　Corresponding author   Language：English  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BIOSCIENTIFICA LTD  

Low birth weight (LBW) is related to increased incidence of common cardiovascular and metabolic disorders, and psychopathologies later in life. Recent studies have suggested that maternal malnutrition affects fetal hypothalamic-pituitary-adrenal (HPA) axis programing although the mechanism is unknown. We demonstrated that LBW offspring delivered from malnourished dams showed prolonged elevated plasma corticosterone concentrations when compared with those of normal-birth-weight (NBW) offspring and impaired downregulation of corticotropin-releasing factor receptor type 1 (CRF-R1, Crhr1) in the anterior pituitary in restraint. Restraint increased expression of miR449a, which we had previously demonstrated to be involved in Crhr1 downregulation, in the anterior pituitary and serum exosomal miR449a contents through glucocorticoids in NBW offspring, but not in LBW offspring. Although plasma corticosterone concentrations were higher at 2000 h than at 0800 h in both LBW and NBW offspring, they were significantly higher in LBW offspring than in NBW offspring at 2000 and 0200 h. There were no significant diurnal changes in miR449a expression levels in the anterior pituitary of either NBW or LBW offspring, but the expression was significantly lower in LBW offspring than in NBW offspring at 1400, 2000, and 0200 h. The expression levels of GAS5, which inhibits glucocorticoid receptor (GR) binding to glucocorticoid-responsive element, in the anterior pituitary of LBW offspring were elevated when compared with those of NBW offspring. The downregulation of GR found in NBW offspring did not occur in restrained LBW offspring. These results indicate that impaired miR449a expression, probably induced by increased GAS5 expression, causes dysregulation of Crhr1 expression in the anterior pituitary, resulting in prolonged HPA axis activation in restrained LBW offspring.

DOI： 10.1530/JOE-14-0537

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Language：English   Publishing type：Research paper (bulletin of university, research institution)  

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Urocortin 2 (Ucn2) is a member of the corticotropin-releasing factor peptide family and is expressed by various tissues, including reproductive tissues such as the uterus, ovary, and placenta. However, the regulatory mechanisms of Ucn2 expression and the physiological significance of Ucn2 in these tissues remain unclear. We previously showed that passive immunization of immature female rats by i.p. injection of anti-Ucn2 IgG induces earlier onset of puberty. Therefore, this study was designed to clarify the site and regulatory mechanisms of Ucn2 expression in the uterus. Expression levels of Ucn2 mRNA in the uterus were higher in immature (2- and 4-week-old) and aged (17-month-old) rats than in mature (9-week-old) rats in the proestrus phase. In 9-week-old rats, mRNA expression levels and contents in the uterus were lower in the proestrus phase than in the diestrus phase, while plasma Ucn2 concentrations did not differ between the two phases. Ucn2-like immunoreactivitiy was detected in the endometrial gland epithelial cells of the uterus. S. c. injection of estradiol benzoate or an estrogen receptor alpha (ER alpha) agonist significantly reduced mRNA expression levels and contents of Ucn2 in the uterus when compared with vehicle-injected ovariectomized rats. By contrast, estradiol benzoate increased Ucn2 mRNA expression levels in the lung. Thus, estrogens downregulate Ucn2 expression in the uterus in a tissue-specific manner, and Ucn2 may play a role in the regulatory mechanisms of maturation of the uterus through ERa and estrous cycle.

DOI： 10.1530/JOE-13-0228

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：OXFORD UNIV PRESS INC  

The hypothalamic-pituitary-adrenal axis is controlled by the feedback of glucocorticoids on the hypothalamus and pituitary. Stress increases CRF, ACTH, and glucocorticoid secretion. The expression of not only CRF mRNA in the hypothalamus and proopiomelanocortin mRNA in corticotrophs, but also CRF type 1 receptor (CRF-R1) mRNA and protein on corticotrophs are downregulated through glucocorticoids. However, the mechanisms underlying the glucocorticoid-induced CRF-R1 downregulation are not fully understood. Short RNA molecules, called microRNAs (miRNAs), are posttranscriptional regulators that usually induce translational repression or gene silencing via binding to complementary sequences within target mRNAs. We hypothesized that glucocorticoids may induce the expression of miRNAs in the pituitary, which are involved in glucocorticoid-induced downregulation of CRF-R1. We found 3 miRNAs with sequences predicted to bind to the CRF-R1 3' untranslated region (3'-UTR) by database search. Expression of 1 of these miRNAs (miR-449a) was significantly higher in the anterior pituitary of restrained rats than in that of unrestrained control rats. Expression of miR-449a was evident in many anterior pituitary cells, including corticotrophs. Although overexpression of miR-449a decreased CRF-R1 mRNA and CRF-R1 protein expression, knockdown of miR-449a attenuated dexamethasone-induced suppression of CRF-R1 mRNA and CRF-R1 protein expression in the monolayer-cultured pituitary cells. Notably, luciferase activity was significantly lower in cells cotransfected with a luciferase vector containing the CRF-R1 3'-UTR and a miR-449a vector. miR-449a expression was significantly increased by dexamethasone. Adrenalectomy attenuated restraint-induced increase in miR-449a expression in the pituitary. These results indicated that miR-449a plays an important role in stress-induced, glucocorticoid-mediated downregulation of CRF-R1 expression.

DOI： 10.1210/me.2012-1357

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Intracerebroventricular (icy) injection of ghrelin increases food intake via activation of neuropeptide Y (NPY)/agouti-related protein (AgRP) neurons, which express growth hormone secretagogue receptor type la (GHS-R1a), in the arcuate nucleus of the hypothalamus (Arc) in male rats. Conversely, elevation in endogenous estrogens or exogenous estrogens decreases food intake, but the precise mechanism mediating this estrogenic effect is unknown. We studied whether the effects of icy ghrelin on food intake and on the expression of Fos, a marker of neuron activation, vary with estrous cycle phase in female rats. Icy ghrelin (100 pmol) significantly increased food intake after injection in diestrus, but it did not affect food intake in proestrus during light phase. Icy ghrelin increased the number of Fos-positive neurons in the Arc both in proestrus and diestrus; however, a significantly larger number of Fos-positive neurons appeared in diestrus than in proestrus. Real-time RT-PCR analysis showed no significant difference in GIIS-R1a mRNA expression levels in the mediobasal hypothalamus between diestrus and proestrus. These results indicated that not only the orexigenic effect but also the Fos-inducing effect of icy ghrelin were influenced by the estrous cycle phase; and both effects were reduced in proestrus but not in diestrus. Most NPY/AgRP neurons seemed to be influenced indirectly by estrogens during proestrus because only a few of the NPY/AgRP neurons present in the Arc express ER alpha. The change in GHS-R1a expression levels in the hypothalamus during estrous cycle is not probably involved in the estrous cycle-induced changes in ghrelin action because there was no difference in GHS-R1a mRNA expression between diestrus and proestrus. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2013.02.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER PHYSIOLOGICAL SOC  

Nemoto T, Mano A, Shibasaki T. Increased expression of miR-325-3p by urocortin 2 and its involvement in stress-induced suppression of LH secretion in rat pituitary. Am J Physiol Endocrinol Metab 302: E781-E787, 2012. First published January 17, 2012; doi: 10.1152/ajpendo.00616.2011.-Urocortin 2 (Ucn2) is a member of the corticotropin releasing factor (CRF) peptide family, which binds to CRF type 2 receptor. We previously reported on expression of Ucn2 in proopiomelanocortin cells of rat pituitary and its inhibitory action on LH secretion. We also demonstrated that Ucn2 is involved in the mechanism underlying immobilization-induced suppression of LH secretion; the details remain unclear. Here, we found that Ucn2 increased the expression of miR-325-3p, one of three microRNAs with predicted sequence for binding to LH beta-subunit 3'-untranslated region (3'-UTR) in monolayer cultured rat anterior pituitary cells, and that miR-325-3p was expressed in LH cells of the anterior pituitary. Immobilization also increased miR-325-3p expression in the anterior pituitary, and its increase was blocked by pretreatment with anti-Ucn2 IgG. Overexpression of miR-325-3p in cultured pituitary cells significantly suppressed intracellular contents and secretion of LH, while miR-325-3p knockdown blocked Ucn2-induced suppression of intracellular contents and secretion of LH. Coexpression of miR-325-3p with LH beta-subunit 3'-UTR-fused luciferase vector significantly suppressed luciferase activity compared with that of mock transfectants. These results suggest that miR-325-3p is involved in immobilization-induced suppression of LH translation and secretion and that Ucn2 plays a role in the increase in miR-325-3p expression.

DOI： 10.1152/ajpendo.00616.2011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：VERSITA  

Angiogenesis is involved in tumor growth and metastasis. Endostatin inhibits angiogenesis, but its precise mechanism is not fully understood. To clarify signal transduction involved in endostatin-induced angiogenesis inhibition (endothelial cell growth inhibition), it is important to identify an endostatin receptor, which is the aim of the present study. We hypothesized that vascular endothelial cadherin (VE-cadherin) is an endostatin receptor and found that endostatin induced apoptosis in cultured calf pulmonary artery endothelium (CPAE) cells. Immunoprecipitation and western blots revealed that endostatin specifically bound to VE-cadherin in a Ca(2+)-dependent manner. Binding of endostatin to VE-cadherin induced tyrosine phosphorylation of VE-cadherin, beta-catenin recruitment, and endothelial cell death. Antisense oligonucleotides against VE-cadherin rescued endostatin-induced endothelial cell death. Inhibition of tyrosine phosphorylation of VE-cadherin inhibited endostatin-induced beta-catenin recruitment and CPAE cell death. Taken together, we conclude that VE-cadherin is an endostatin receptor.

DOI： 10.2478/s11756-011-0070-x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Ghrelin, the endogenous ligand for growth hormone secretagogues (GHSs) receptor (GHS-R), increases adrenocorticotropin (ACTH) and cortisol (corticosterone) as well as GH secretion in humans and animals. However, the site of GHSs action to induce ACTH secretion is not fully understood. To clarify the mechanisms of the action of ghrelin/GHSs on ACTH secretion, we analyzed the effects of KP-102 and ghrelin on the mRNA expression and release of corticotropin releasing factor (CRF) and arginine vasopressin (AVP), ACTH secretagogues, in monolayer-cultured hypothalamic cells of rats. Incubation of cells with KP-102 for 4 h and 8 h and with ghrelin for 4 h significantly increased AVP mRNA expression and release without changing CRF mRNA expression. CRF levels in culture media were undetectable. Suppression of GHS-R expression by siRNA blocked ghrelin- and KP-102-induced AVP mRNA expression and release. NPY-significantly increased AVP mRNA expression and release. Furthermore, treatment of cells with anti-NPY IgG blocked KP-102-induced AVP mRNA expression and release. We previously reported that KP-102 significantly increases NPY mRNA expression in cultured hypothalamic cells. Taken together, these results suggest that ACTH secretion by ghrelin/GHSs is induced mainly through hypothalamic AVP, and that NPY mediates the action of ghrelin/GHSs. (C) 2011 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.peptides.2011.04.007

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Nemoto T, Iwasaki-Sekino A, Yamauchi N, Shibasaki T. Role of urocortin 2 secreted by the pituitary in the stress-induced suppression of luteinizing hormone secretion in rats. Am J Physiol Endocrinol Metab 299: E567-E575, 2010. First published July 27, 2010; doi: 10.1152/ajpendo.00163.2010.-We have previously shown that urocortin 2 (Ucn 2), a member of the corticotropin-releasing factor (CRF) peptide family that binds to CRF type 2 receptor, is expressed in proopiomelanocortin (POMC) cells of rat pituitary and that its secretion and expression are increased by CRF in both the anterior and intermediate lobes and suppressed by glucocorticoids in the anterior lobe. We have also shown that Ucn 2 secreted by POMC cells acts on gonadotrophs expressing CRF type 2 receptors and inhibits the expression and secretion of gonadotropins. In the present study, we examined whether pituitary Ucn 2 is involved in stress-induced inhibition of gonadotropin secretion. A 90-min period of immobilization stress increased POMC mRNA expression without influencing Ucn 2 mRNA expression and suppressed luteinizing hormone (LH) beta-subunit mRNA expression in the anterior lobe and plasma LH levels, while it increased both POMC and Ucn 2 mRNA expression in the intermediate lobe of the pituitary. Pretreatment with anti-CRF IgG blocked immobilization-induced increases in plasma ACTH and corticosterone and in POMC mRNA expression in both pituitary lobes and Ucn 2 mRNA expression in the intermediate pituitary. It also blocked immobilization-induced suppression of plasma LH and LH beta-subunit mRNA expression. Pretreatment with anti-Ucn 2 IgG blocked immobilization-induced suppression of plasma LH and LH beta-subunit expression without affecting immobilization-induced ACTH and corticosterone release and POMC or Ucn 2 mRNA expression. These results suggest that CRF suppresses the secretion and expression of LH probably through pituitary Ucn 2 in stress.

DOI： 10.1152/ajpendo.00163.2010

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To clarify the role of ghrelin and its receptor (GHS-R) in the regulatory mechanism of energy metabolism, we analyzed transgenic (Tg) rats expressing an antisense GHS-R mRNA under the control of the tyrosine hydroxylase (TH) promoter. Tg rats showed lower visceral fat weight and higher O(2) consumption, CO(2) production, rectal temperature, dark-period locomotor activity, brown adipose tissue (BAT) weight and uncoupling protein I expression compared with wild-type (WT) rats on a standard diet. A high-fat diet for 14 days significantly increased body weight, visceral fat weight, and the sizes of white and brown adipocytes in WT rats but not in Tg rats compared with the corresponding standard-diet groups. Antisense GHS-R mRNA was expressed and GHS-R expression was reduced in TH-expressing cells of the vagal nodose ganglion in Tg rats. Ghrelin administered intravenously suppressed noradrenaline release in the BAT of WT rats, but not in Tg rats. These results suggest that ghrelin/GHS-R plays an important role in energy storage by modifying BAT function and locomotor activity. As our previous study showed that peripheral ghrelin-induced noradrenaline release suppression in BAT is blocked by vagotomy, the present findings also suggest that vagal afferents transmit the peripheral ghrelin signal to the sympathetic nervous system innervating BAT. (C) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.regpep.2009.11.010

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To clarify the role of ghrelin in the regulatory mechanism of energy metabolism, we analyzed the effects of centrally and peripherally administered ghrelin on noradrenaline release in the brown adipose tissue (BAT) of rats using a microdialysis system. I.c.v. administration of ghrelin at a dose of 500 pmol suppressed noradrenaline release in BAT, and microinjection of ghrelin (50 pmol) into the paraventricular nucleus (PVN) or arcuate nucleus (ARC) of the hypothalamus also suppressed noradrenaline release in BAT. In addition, i.v. administered ghrelin (30 nmol) suppressed noradrenaline release in BAT, and this suppression was blocked by a vagotomy. Neither i.c.v. nor i.v. administration of des-acyl ghrelin, which does not bind to GH secretagogue receptor type la (GHS-R1a), affected noradrenaline release in BAT. These results indicate that ghrelin increases energy storage by suppressing the activity of the sympathetic nerve innervating BAT. It seems that the PVN and ARC, which express GHS-R1a, are the sites of action of ghrelin in the brain and that the action of peripheral ghrelin on the sympathetic nerve activity innervating BAT is mediated by the vagal nerve, which also expresses GHS-R1a. Journal of Endocrinology (2009) 201, 341-349

DOI： 10.1677/JOE-08-0374

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Urocortins 2 (Ucn 2), one of the corticotropin releasing factor (CRF) peptide family, is thought to be an endogenous ligand for CRF type 2 receptor (CRF-R2). We previously demonstrated that Ucn 2 is expressed in the corticotrophs of rat pituitary, and the mRNA expression and secretion of Ucn 2 in corticotrophs of rat,interior pituitary are regulated by CRF and glucocorticoids. Since CRF-R2 has been reported to be expressed on gonadotrophs of the rat pituitary, we hypothesized that pituitary Ucn 2 may control the expression and secretion of gonadotropins. Monolayer Culture of rat anterior pituitary cells showed that the secretion of gonadotropins was suppressed by Ucn 2. A CRF-R2 selective antagonist, adenoviral-mediated expression of short interfering RNA against CRF-R2, and anti-Ucn 2 rabbit IgG increased the secretion and mRNA expression of gonadotropins. intraperitoneal injection of anti-Ucn 2 IgG into immature male rats significantly increased the secretion and mRNA expression of gonadotropins compared with those in normal rabbit IgG-injected rats. Daily i.p. injection of anti-Ucn 2 IgG into immature female rats induced a tendency toward earlier Occurrence of menarche compared with normal rabbit IgG-injected rats. These findings suggest that pituitary Ucn 2 is involved in the regulatory mechanism of the expression and secretion of gonadotropins through its tonic and inhibitory action on gonadotrophs in a paracrine manner. Journal of Endocrinology (2009) 201, 105-114

DOI： 10.1677/JOE-08-0467

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：JOHN WILEY & SONS INC  

BACKGROUND. Substantial evidence supports a direct role of ornithine decarboxylase (ODC) in the development and maintenance of human tumors. Although antisense oligonucleotide therapy targeting various genes are useful for cancer treatment, 1 of the major limitations is the problem of delivery. A novel antisense oligonucleotide delivery method is described that allows prolonged sustainment and release of ODC antisense oligonucleotides in vivo using atelocollagen.
METHODS. The effect of ODC antisense oligonucleotides in the atelocollagen on cell growth of gastrointestinal cancer (MKN 45 and COLO201) and rhabdomyosarcoma (RD) was studied in vitro using a cell-counting method with a hemocytometer. In vivo, the effect of intratumoral, intramuscular, and intraperitoneal single administration of ODC antisense oligonucleotides in the atelocollagen on tumor growth of MKN45, COLO201, and RD cells was studied. ODC activity and polyamine contents were measured.
RESULTS. In vitro, ODC antisense oligonucleotides in the atelocollagen remarkably suppressed MKN45, COLO201, and RD cell growth. A single administration of antisense oligonucleotides in the atelocollagen via 3 routes remarkably suppressed the growth of MKN45, COLO201, and RD tumor over a period of 3542 days.
CONCLUSIONS. As various human cancers significantly express ODC, the results strongly suggest that this new antisense method may be of considerable value for treatment of human cancers.

DOI： 10.1002/cncr.22483

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SOC ENDOCRINOLOGY  

We previously demonstrated that urocortin 2 (Ucn 2) is expressed in the proopiomelanocortin (POMC) cells of rat pituitary. However, the regulatory mechanism of pituitary synthesis and secretion of Ucn 2 remained to be clarified. We hypothesized that hypothalamic hormones and glucocorticoids may control the expression and secretion of pituitary Ucn 2, as Ucn 2 is expressed in POMC-expressing cells in the pituitary. Thus, in the present study, we tested this hypothesis using primary culture of rat pituitary cells. The secretion of Ucn 2 from the anterior and intermediate pituitary cells was significantly increased by 50 mM KCl. In the anterior pituitary cells, corticotropin-releasing factor (CRF) increased mRNA expression levels and secretion of Ucn 2, although arginine vasopressin (AVP) did not induce any significant change in Ucn 2 expression or secretion. Under these conditions, both CRF and AVP increased ACTH secretion, but only CRF increased the level of POMC mRNA expression. Dexamethasone inhibited Ucn 2 and POMC mRNA expression levels, while it inhibited the secretion of only Ucn 2. In the intermediate pituitary, CRF increased both the mRNA expression levels and secretion of Ucn 2. Furthermore, dopamine did not affect either the mRNA expression level or secretion of Ucn 2 although it inhibited P-endorphin secretion in the intermediate pituitary cells. These results suggest that the mRNA expression and secretion of Ucn 2 in POW cells of the pituitary are positively regulated by CRF and negatively regulated by glucocorticoids.

DOI： 10.1677/joe.1.07023

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD  

In the present study, we investigated the relationship between ornithine decarboxylase, MAP kinase, and MMP-2 expression in vitro. Overexpression of ornithine decarboxylase cDNA induced MMP-2 expression both at mRNA and protein levels, Promoter analysis and gel shift assay showed that p53 and Ets-1 were involved in MMP-2 expression in ornithine decarboxylase overexpressing transfectants. Erk and p38 MAP kinase were significantly activated. Using specific inhibitors of MEK and p38, we clarified that MMP-2 expression was induced via both Erk and p38 MAP kinase signaling pathways. This is the first report showing the existence of a causal relationship between ornithine decarboxylase expression, Erk and p38 MAP kinase activation, and MMP-2 expression. (c) 2006 International Federation for Cell Biology. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.cellbi.2006.09.019

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

GH secretagogue (GHS)/ghrelin stimulates GH secretion by binding mainly to its receptor (GHS-R) on GHRH neurons in the arcuate nucleus (Arc) of the hypothalamus. GHRH, somatostatin, and neuropeptide Y (NPY) in the hypothalamus are involved in the regulatory mechanism of GH secretion. We previously created transgenic (Tg) rats whose GHS-R expression is reduced in the Arc, showing lower body weight and shorter nose-tail length. GH secretion is decreased in female Tg rats. To clarify how GHS-R affects GHRH expression in the Arc, we compared the numbers of GHS-R-positive, GHRH, and NPY neurons between Tg and wild-type rats. Immunohistochemical analysis showed that the numbers of GHS-R-positive neurons, GHRH neurons, and GHS-R-positive GHRH neurons were reduced in Tg rats, whereas the numbers of NPY neurons and GHS-R-positive NPY neurons did not differ between the two groups. The numbers of Fos-positive neurons and Fos-positive GHRH neurons in response to KP-102 were decreased in Tg rats. Competitive RT-PCR analysis of GHRH mRNA expression in the cultured hypothalamic neurons showed that KP-102 increased NPY mRNA expression level and that NPY decreased GHRH mRNA expression level. KP-102 increased GHRH mRNA expression level in the presence of anti-NPY IgG. GH increased somatostatin mRNA expression. Furthermore, GH and somatostatin decreased GHRH mRNA expression, whereas KP-102 showed no significant effect on somatostatin mRNA expression. These results suggest that GHS-R is involved in the up-regulation of GHRH and NPY expression and that NPY, somatostatin, and GH suppress GHRH expression. It is also suggested that the reduction of GHRH neurons of Tg rats is induced by a decrease in GHS-R expression.

DOI： 10.1210/en.2005-1619

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Academic Press Inc.  

Urocotins (Ucns) are newly discovered members of the corticotropin- releasing factor (CRF) neuropeptide family. Ucn 2 is expressed in the adrenal medulla, and its receptor, CRF2 receptor, is also expressed in the adrenal gland. To predict the physiological significance of Ucn 2 expression in the adrenal medulla, we examined the effects of Ucn 2 on catecholamine secretion and intracellular signaling using PC12 cells, a rat pheochromocytoma cell line. PC12 cells were found to express CRF2 receptor, but not CRF 1 receptor. Treatment with Ucn 2 increased noradrenaline secretion and induced phosphorylation of PKA and Erk1/2. Tyrosine hydroxylase (TH), a rate-limiting enzyme for catecholamine synthesis, was also phosphorylated by Ucn 2. Pretreatment with a PKA inhibitor blocked Ucn 2-induced NA secretion, and Erk1/2 and TH phosphorylation. Pretreatment with a MEK inhibitor did not block Ucn 2-induced noradrenaline secretion or PKA phosphorylation, although TH phosphorylation was blocked. Thus, Ucn 2 induces noradrenaline secretion and TH phosphorylation through the PKA pathway and the PKA-Erk1/2 pathway, respectively. These results suggest Ucn 2 in the adrenal gland may be involved in the regulation of catecholamine release and synthesis. © 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2005.03.031

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BAISHIDENG PUBL GRP CO LTD  

AIM: To investigate the expressions of ornithine decarboxylase (ODC), MMP-2, and Erk, and their relationship in human colon tumors.
METHODS: ODC activity, MMP-2 expression, and mitogen-activated protein (MAP) kinase activity (Erk phosphorylation) were determined in 58 surgically removed human colon tumors and their adjacent normal tissues, using [1-(14)C]-ornithine as a substrate, ELISA assay, and Western blotting, respectively.
RESULTS: ODC activity, MMP-2 expression, and Erk phosphorylation were significantly elevated in colon tumors, compared to those in adjacent normal tissues. A significant correlation was observed between ODC activities and MMP-2 levels.
CONCLUSION: This is the first report showing a significant correlation between ODC activities and MMP-2 levels in human colon tumors. As MMP-2 is involved in cancer invasion and metastasis, and colon cancer overexpresses ODC, suppression of ODC expression may be a rational approach to treat colon cancer which overexpresses ODC. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Autophagy is a process for the bulk degradation of cytosolic compartments by lysosomes/vacuoles. The formation of autophagosomes involves a dynamic rearrangement of the membrane for which two ubiquitinlike modifications ( the conjugation of Apg12p and the modification of a soluble form of MAP-LC3 to a membrane-bound form) are essential. In yeast, Apg10p is an E2-like enzyme essential for Apg12p conjugation. The isolated mouse APG10 gene product interacts with mammalian Apg12p dependent on mammalian Apg7p ( E1-like enzyme), and facilitates Apg12p conjugation. The interaction of Apg10p with Apg12p is dependent on the carboxyl-terminal glycine of Apg12p. Mutational analysis of the predicted active site cysteine (Cys(161)) within mouse Apg10p shows that mutant Apg10pC161S, which can form a stable intermediate with Apg12p, inhibits Apg12p conjugation even in the presence of Apg7p, while overexpression of Apg7p facilitates formation of an Apg12p-Apg5p conjugate. Furthermore, the coexpression of Apg10p with Apg7p facilitates the modification of a soluble form of MAP-LC3 to a membrane-bound form, a second modification essential for autophagy. Mouse Apg10p interacts with MAP-LC3 in HEK293 cells, while no mutant Apg10pC161S forms any intermediate with MAP-LC3. Direct interaction between Apg10p and MAP-LC3 is also demonstrated by yeast two-hybrid analysis. The inability of mutant Apg10pC161S to form any intermediate with MAP-LC3 has ruled out the possibility that MAP-LC3 interacts with Apg10p as a substrate.

DOI： 10.1074/jbc.M300550200

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

A dynamic membrane rearrangement occurs in cells during autophagy to form autophagosomes. In this dynamic process, two ubiquitin-like modifications, Apg12p-conjugation and LC3-modification, are essential for the formation of autophagosomes. Apg7p and Apg10p catalyze the conjugation of Apg12p to Apg5p. The same Apg7p and Apg3p catalyze the processing of LC3 to a membrane-bound form, LC3-II. In this paper, we investigated whether Apg12p has an influence on the second LC3-modification system. A cross-linking experiment revealed that Apg3p interacts with the endogenous Apg12p-Apg5p conjugate. However, Apg3p itself interacts with free Apg12p more preferentially than the Apg12p-Apg5p conjugate, when free Apg12p exists. When Apg12p was overexpressed, LC3 processing was significantly enhanced in the presence of Apg7p. In contrast, when the Apg12p-Apg5p conjugate itself was accumulated by the overexpression of Apg12p and Apg5p, LC3 processing was dominantly inhibited, even in the presence of Apg7p. These results indicate that both Apg12p and the Apg12p. Apg5p conjugate are regulatory factors for LC3 processing. (C) 2002 Elsevier Science (USA). All rights reserved.

DOI： 10.1016/S0006-291X(02)02057-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Angiogenesis, an essential process for tumor growth, is regulated by endothelial proliferation factors and their inhibitors such as endostatin. Endostatin, a carboxyl-terminal fragment of type XVIII collagen, inhibits endothelial proliferation, angiogenesis, and tumor growth. Ornithine decarboxylase (ODC), a molecule that is overexpressed in various cancers, is associated with promoting tumor growth and angiogenesis. We found that ODC-overexpressing human cancer cells and breast cancer specimens showed suppressed expression of type XVIII collagen and endostatin. We hypothesized that ODC overexpression may facilitate angiogenesis in tumors by suppressing endostatin expression. ODC-overexpressing COS cells, which showed suppressed type XVIII collagen and endostatin expression, were established. Conditioned media derived from these cells, containing decreased levels of endostatin, induced significant endothelial proliferation. ODC-overexpressing cells, when transplanted Into nude mice, suppressed type XVIII collagen expression and promoted neovascularization In vivo. Thus, overexpression of ODC facilitates endothelial proliferation by suppressing endostatin expression. (C) 2002 by The American Society of Hematology.

DOI： 10.1182/blood.V99.4.1478

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Authorship：Lead author,　Corresponding author   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publisher：(公社)日本産科婦人科学会  

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Language：Japanese   Publisher：日本産科婦人科学会  

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Other Link： https://projects.repo.nii.ac.jp/?action=repository_uri&item_id=456503

Authorship：Lead author,　Corresponding author   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：HUMANA PRESS INC  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JAPAN ENDOCRINE SOC  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(一社)日本内分泌学会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese  

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Event date： 2021.6

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