Faculty Profiles - TERASAKA Tomohiro

Papers - TERASAKA Tomohiro

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Mutual effects of melatonin and activin on induction of aldosterone production by human adrenocortical cells Reviewed

Takayuki Hara, Fumio Otsuka, Naoko Tsukamoto-Yamauchi, Kenichi Inagaki, Takeshi Hosoya, Eri Nakamura, Tomohiro Terasaka, Motoshi Komatsubara, Hirofumi Makino

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 152 8 - 15 2015.8

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

Melatonin has been reported to suppress adrenocorticotropin (ACTH) secretion in the anterior pituitary and cortisol production in the adrenal by different mechanisms. However, the effect of melatonin on aldosterone production has remained unknown. In this study, we investigated the role of melatonin in the regulation of aldosterone production using human adrenocortical H295R cells by focusing on the activin system expressed in the adrenal. Melatonin receptor MT1 mRNA and protein were expressed in H295R cells and the expression levels of MT1 were increased by activin treatment. Activin increased ACTH-induced, but not angiotensin II (Ang II)-induced, aldosterone production. Melatonin alone did not affect basal synthesis of either aldosterone or cortisol. However, melatonin effectively enhanced aldosterone production induced by co-treatment with ACTH and activin, although melatonin had no effect on aldosterone production induced by Ang II in combination with activin. These changes in steroidogenesis became apparent when the steroid production was evaluated by the ratio of aldosterone/cortisol. Melatonin also enhanced dibutyryl-AMP-induced aldosterone/cortisol levels in the presence of activin, suggesting a functional link to the cAMP-PICA pathway for induction of aldosterone production by melatonin and activin. In accordance with the data for steroids, ACTH-induced, but not Ang II-induced, CAMP synthesis was also amplified by co-treatment with melatonin and activin. Furthermore, the ratio of ACTH-induced mRNA level of CYP11B2 compared with that of CYP17 was amplified in the condition of treatment with both rnelatonin and activin. In addition, melatonin increased expression of the activin type-I receptor ALK-4 but suppressed expression of inhibitory Smads6/7, leading to the enhancement of Smad2 phosphorylation. Collectively, the results showed that melatonin facilitated aldosterone production induced by ACTH and activin via the cAMP-PICA pathway. The results also suggested that mutual enhancement of melatonin and activin receptor signaling is involved in the induction of aldosterone output by adrenocortical cells. (C) 2015 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jsbmb.2015.04.012

A Paraganglioma in a Hypertensive Patient with Unilateral Renal Hypoplasia Reviewed

Tomohiro Terasaka, Hideharu Hagiya, Kosuke Kimura, Takahiro Nada, Eri Nakamura, Yoshihisa Hanayama, Hitoshi Sugiyama, Yasuyuki Kobayashi, Hiroyuki Yanai, Fumio Otsuka

ACTA MEDICA OKAYAMA 69 ( 2 ) 119 - 122 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

We report the case of a 46-year-old hypertensive Japanese female with renal insufficiency related to unilateral renal hypoplasia. The patient was found to have developed paraganglioma in the retroperitoneal space over a 5-year period. Catecholamine-producing tumors are not usually recognized as conditions associated with renal hypoplasia. Our long-term observation of the patient eventually led us to the diagnosis of paraganglioma. In hypertensive patients with chronic kidney disease, not only the renin-angiotensin-aldosterone system but also catecholamine activity may be involved, particularly in the patients whose cases are complicated with unilateral renal hypoplasia.

DOI： 10.18926/AMO/53341

Complication of Chronic Eosinophilic Pneumonia in an Elderly Patient with Sjogren Syndrome Reviewed

Koichi Waseda, Hideharu Hagiya, Yoshihisa Hanayama, Tomohiro Terasaka, Kosuke Kimura, Takao Tsuzuki, Kou Hasegawa, Takahiro Nada, Eri Nakamura, Kazutoshi Murakami, Eisei Kondo, Fumio Otsuka

ACTA MEDICA OKAYAMA 69 ( 2 ) 123 - 127 2015.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

An 81-year-old Japanese male with primary Sjogren syndrome (pSS) developed a low-grade fever and productive cough which were refractory to antibiotic therapy. Based on the high level of eosinophils observed in his bronchial alveolar lavage, he was diagnosed with chronic eosinophilic pneumonia (CEP) and successfully treated by oral prednisolone. Interstitial lung diseases associated with pSS (pSS-ILDs) usually present as nonspecific interstitial pneumonia or usual interstitial pneumonia; therefore, the present case is extremely unique in that the patient's condition was complicated with CEP. A diagnosis of advanced gallbladder cancer was made in the patient's clinical course, suggesting the advisability of a whole-body workup in cases of pSS, especially in elderly patients.

DOI： 10.18926/AMO/53342

Regulatory role of BMP-9 in steroidogenesis by rat ovarian granulosa cells Reviewed

Takeshi Hosoya, Fumio Otsuka, Eri Nakamura, Tomohiro Terasaka, Kenichi Inagaki, Naoko Tsukamoto-Yamauchi, Takayuki Hara, Kishio Toma, Motoshi Komatsubara, Hirofumi Makino

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 147 85 - 91 2015.3

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

BMPs expressed in the ovary differentially regulate steroidogenesis by granulosa cells. BMP-9, a circulating BMP, is associated with cell proliferation, apoptosis and differentiation in various tissues. However, the effects of BMP-9 on ovarian function have yet to be elucidated. Here we investigated BMP-9 actions on steroidogenesis using rat primary granulosa cells. BMP-9 potently suppressed FSH-induced progesterone production, whereas it did not affect FSH-induced estradiol production by granulosa cells. The effects of BMP-9 on FSH-induced steroidogenesis were not influenced by the presence of oocytes. FSH-induced cAMP synthesis and FSH-induced mRNA expression of steroidogenic factors, including StAR, P450scc, 3 beta HSD2 and FSHR, were suppressed by treatment with BMP-9. BMP-9 mRNA expression was detected in granulosa cells but not in oocytes. BMP-9 readily activated Smad1/5/8 phosphorylation and Id-1 transcription in granulosa cells. Analysis using ALK inhibitors indicated that BMP-9 actions were mediated via type-I receptors other than ALK-2, -3 and -6. Furthermore, experiments using extracellular domains (ECDs) for BMP type-I and -II receptor constructs revealed that the effects of BMP-9 were reversed by ECDs for ALK-1 and BMPRII. Thus, the functional receptors for BMP-9 in granulosa cells were most likely to be the complex of ALK-1 and BMPRII. Collectively, the results of the present study showed that BMP-9 can affect luteinization and that there are two possible sources of BMP-9, serum and granulosa cells in the ovary. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jsbmb.2014.12.007

Interaction of pituitary hormones and expression of clock genes modulated by bone morphogenetic protein-4 and melatonin Reviewed

Naoko Tsukamoto-Yamauchi, Tomohiro Terasaka, Yasumasa Iwasaki, Fumio Otsuka

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 459 ( 1 ) 172 - 177 2015.3

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

Functional interaction of clock genes and pituitary hormones was investigated by focusing on bone morphogenetic protein (BMP)-4 and melatonin actions in anterior pituitary cells. A significant correlation between the mRNA expression of proopiomelanocortin (POMC) and Per2 was revealed in serial cultures of corticotrope AtT20 cells. Knockdown of Per2 expression by siRNA in AtT20 cells resulted in a significant reduction of POMC mRNA level with or without corticotropin-releasing hormone (CRH) stimulation. Treatments with BMP-4 and melatonin, both of which suppress POMC expression, reduced Per2 mRNA as well as protein levels in AtT20 cells. On the other hand, in lactosomatotrope GH3 cells, an expressional correlation was found between prolactin (PRL) and Clock mRNA levels, which was attenuated in the presence of forskolin treatment. The siRNA-mediated knockdown of Clock expression, but not that of Bmal1, significantly reduced PRL mRNA levels in GH3 cells. Interestingly, Clock mRNA and protein levels did not fluctuate with melatonin, BMP-4 or forskolin treatment, although Small expression was significantly increased by forskolin treatment. Collectively, a significant correlation between the expression of POMC and Per2 and that. between PRL and Clock were uncovered in corticotrope and lactosomatotrope cells, respectively. Per2 expression was inhibited by POMC modulators including melatonin and BMP-4, while Clock expression was steadily maintained. Thus, the effects of melatonin and BMP-4 on clock gene expression may imply differential stability of circadian rhythms of adrenocorticotropin (ACTH) and PRL secreted from the anterior pituitary. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2015.02.100

Myopathy and Eosinophilic Pneumonia Coincidentally Induced by Treatment with Daptomycin Reviewed

Hideharu Hagiya, Kou Hasegawa, Kikuko Asano, Tomohiro Terasaka, Kosuke Kimura, Takahiro Nada, Eri Nakamura, Koichi Waseda, Yoshihisa Hanayama, Fumio Otsuka

INTERNAL MEDICINE 54 ( 5 ) 525 - 529 2015

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

A 34-year-old man with 22q11.2 deletion syndrome (DiGeorge syndrome) concurrently suffered from myopathy and eosinophilic pneumonia shortly after receiving daptomycin (DAP) for right-sided infective endocarditis. The simultaneous occurrence of these phenomena in relation to DAP therapy has not been previously well described. An allergic reaction was suspected as a possible etiology of these DAP-related complications. This case highlights the need for close observation in order to detect both musculoskeletal and respiratory disorders from the start of DAP therapy. Physicians should pay more attention to this new drug, which is expected to be frequently used in various clinical settings.

DOI： 10.2169/internalmedicine.54.3397

An Insulinoma Discovered in a Patient with Diffusely Calcified Chronic Pancreatitis Reviewed

Tomohiro Terasaka, Keiko Tsukamoto, Kenichi Inagaki, Fumio Otsuka

INTERNAL MEDICINE 54 ( 21 ) 2785 - 2786 2015

Aortic vascular graft infection caused by Cardiobacterium valvarum: A case report Reviewed

Hideharu Hagiya, Susumu Kokeguchi, Hiroko Ogawa, Tomohiro Terasaka, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Kaori Oda, Hisatoshi Mori, Toru Miyoshi, Fumio Otsuka

JOURNAL OF INFECTION AND CHEMOTHERAPY 20 ( 12 ) 804 - 809 2014.12

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

A 53-year-old man with a past medical history of total arch replacement surgery and severe aortic regurgitation presented with a 1-month history of persistent general malaise, anorexia, body weight loss and night sweats. His recent history included gingival hyperplasia for 6 years, gingivitis after tooth extraction 3 years before, prolonged inflammatory status for 4 months, fundal hemorrhage and leg tenderness for 2 months. A pathogen was detected from blood culture, but conventional microbiological examination failed to identify the pathogen. The organism was eventually identified as Cardiobacterium valvarum by 16S rRNA analysis, and the patient was diagnosed with infective endocarditis and prosthetic vascular graft infection. The patient received intravenous antibiotic therapy using a combination of ceftriaxone and levofloxacin for 5 weeks and was discharged with a good clinical course.
C. valvarum is a rare human pathogen in clinical settings. Only 10 cases have been reported to date worldwide, and therefore, the clinical characteristics of C. valvarum infection are not fully known. This is a first well-described case of C. valvarum infection in Japan, and further, a first report of aortic prosthetic vascular graft infection worldwide. Identification of C. valvarum is usually difficult due to its phenotypic characteristics, and molecular approaches would be required for both clinicians and microbiologists to facilitate more reliable diagnosis and uncover its clinical picture more clearly. (C) 2014, Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jiac.2014.07.008

Melatonin counteracts BMP-6 regulation of steroidogenesis by rat granulosa cells Reviewed

Eri Nakamura, Fumio Otsuka, Tomohiro Terasaka, Kenichi Inagaki, Takeshi Hosoya, Naoko Tsukamoto-Yamauchi, Kishio Toma, Hirofumi Makino

JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY 143 233 - 239 2014.9

Language：English Publishing type：Research paper (scientific journal) Publisher：PERGAMON-ELSEVIER SCIENCE LTD

The ovarian bone morphogenetic protein (BMP) system is a physiological inhibitor of luteinization in growing ovarian follicles. BMP-6, which is expressed in oocytes and granulosa cells of healthy follicles, specifically inhibits FSH actions by suppressing adenylate cyclase activity. In the present study, we studied the role of melatonin in ovarian steroidogenesis using rat primary granulosa cells of immature female rat ovaries by focusing on the interaction with BMP-6 activity. Treatment with melatonin had no direct effect on FSH-induced progesterone or estradiol production by granulosa cells, and the results were not affected by the presence of co-cultured oocytes. In addition, synthesis of CAMP by granulosa cells was not significantly altered by melatonin treatment. To elucidate the interaction between activities of melatonin and BMPs, the effect of melatonin treatment on suppression of progesterone synthesis by BMP-6 was investigated. Interestingly, the inhibitory effect of BMP-6 on FSH-induced progesterone production was impaired by co-treatment with melatonin. Granulosa cells express higher levels of MT1 than MT2, and BMP-6 had no significant effect on MT1 expression in granulosa cells. However, BMP-6-induced Smad1/5/8 phosphorylation and Id-1 transcription were suppressed by melatonin, suggesting that melatonin has an inhibitory effect on BMP receptor signaling in granulosa cells. Although the expression levels of ALK-2, -6, ActRII and BMPRII were not affected by melatonin, inhibitory Smad6, but not Smad7, expression was upregulated by melatonin. Thus, melatonin plays a role in the regulation of BMP-6 signal intensity for controlling progesterone production in the ovary. These findings suggest that the effect of melatonin on maintenance of ovarian function is, at least in part, due to the regulation of endogenous BMP activity in granulosa cells. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.jsbmb.2014.04.003

Retroperitoneal bronchogenic cyst: a rare incidentaloma discovered in a juvenile hypertensive patient Reviewed

Tomohiro Terasaka, Fumio Otsuka, Kanako Ogura-Ochi, Tomoko Miyoshi, Kenichi Inagaki, Yasuyuki Kobayashi, Yasutomo Nasu, Hirofumi Makino

HYPERTENSION RESEARCH 37 ( 6 ) 595 - 597 2014.6

Long-term Observation of Osteomalacia Caused by Adefovir-Induced Fanconi's Syndrome Reviewed

Tomohiro Terasaka, Eijiro Ueta, Hirotaka Ebara, Koichi Waseda, Yoshihisa Hanayama, Akinobu Takaki, Tomoko Kawabata, Hitoshi Sugiyama, Ko Hidani, Fumio Otsuka

ACTA MEDICA OKAYAMA 68 ( 1 ) 53 - 56 2014.2

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

A 64-year-old man suffering polyarthralgia and bone pain was referred to our hospital. Renal dysfunction, hypophosphatemia and increased levels of bone alkaline phosphatase were found. The patient's serum creatinine level had gradually increased after the initiation of adefovir dipivoxil administration for hepatitis B. In agreement with multifocal uptakes of bone scintigraphy, iliac bone biopsy revealed an abnormal increase in osteoid tissues. Reducing the dose of adefovir and initiating the administration of eldecalcitol were effective for reducing proteinuria and glucosuria, and for ameliorating bone pain with an increase in serum phosphate level. This case first showed a clinical course of hypophosphatemic osteomalacia caused by secondary Fanconi's syndrome for 8 years after adefovir administration. Early diagnosis is important for the reversibility of bone damage and for a better renal prognosis.

DOI： 10.18926/AMO/52145

Fosfomycin for the Treatment of Prostate Infection Reviewed

Hideharu Hagiya, Megumi Ninagawa, Kou Hasegawa, Tomohiro Terasaka, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Toshiaki Sendo, Fumio Otsuka

INTERNAL MEDICINE 53 ( 22 ) 2643 - 2646 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

A 69-year-old man with diabetes mellitus was diagnosed with a prostate abscess. Although the pathogen was fluoroquinolone-resistant Escherichia coli and the oral administration of trimethoprim-sulfamethoxazole was initiated, the infection recurred after three months. The antibiotic therapy was subsequently changed to intravenous fosfomycin, and the patient's condition promptly improved. Four weeks of fosfomycin therapy was successfully continued without any adverse events. In the era of antibiotic resistance, revival of forgotten drugs is an important issue for clinicians. Fosfomycin can be applied as an alternative option for prostate infections, considering the remaining susceptibility of multidrug-resistant pathogens to fosfomycin and the good pharmacokinetics of this drug in prostatic tissue.

DOI： 10.2169/internalmedicine.53.3098

Filarial Chyluria as a Rare Cause of Urinary Retention Reviewed

Hideharu Hagiya, Tomohiro Terasaka, Kosuke Kimura, Asuka Satou, Kikuko Asano, Koichi Waseda, Yoshihisa Hanayama, Takahide Takahashi, Michinori Aoe, Koji Iio, Toshiyuki Watanabe, Eisei Kondo, Fumio Otsuka

INTERNAL MEDICINE 53 ( 17 ) 2001 - 2005 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

We herein describe a case of Wuchereria bancrofti infection in a previously healthy 37-year-old Nepalese man. The patient presented with a history of milky urine with subsequent acute urinary retention lasting for a few days. The presence of microfilariae was confirmed on both peripheral blood and urine smears obtained at midnight. He was conservatively treated with diethylcarbamazine combined with doxycycline. Filariasis was previously endemic in southern parts of Japan, although it has been eradicated. Clinicians should remember filariasis as a potential etiology of urinary retention, especially in cases that may be associated with imported infectious disease.

DOI： 10.2169/internalmedicine.53.2572

Recurrent Stenotrophomonas maltophilia Bacteremia after Iliac Crest Bone Graft Harvest Reviewed

Hideharu Hagiya, Hiroko Ogawa, Tomoharu Ishida, Tomohiro Terasaka, Kosuke Kimura, Koichi Waseda, Yoshihisa Hanayama, Masahiro Horita, Yasunori Shimamura, Eisei Kondo, Fumio Otsuka

INTERNAL MEDICINE 53 ( 15 ) 1693 - 1698 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

We describe a rare case of recurrent Stenotrophomonas maltophilia bacteremia in a previously healthy 45-year-old man. The infection was caused by osteomyelitis at the site of an iliac crest bone graft harvest. A genetic analysis using enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) revealed that the blood isolates and pathogens obtained from the surgical wound were identical. Initial treatment with levofloxacin and cefozopran was ineffective, but the patient's infection was successfully treated by long-term administration of latamoxef and trimethoprim-sulfamethoxazole. The present case suggests that attention should be given to the possibility of S. maltophilia infection in any situations.

DOI： 10.2169/internalmedicine.53.1995

Successful Treatment of Persistent MRSA Bacteremia using High-dose Daptomycin Combined with Rifampicin Reviewed

Hideharu Hagiya, Tomohiro Terasaka, Kosuke Kimura, Asuka Satou, Kikuko Asano, Koichi Waseda, Yoshihisa Hanayama, Fumio Otsuka

INTERNAL MEDICINE 53 ( 18 ) 2159 - 2163 2014

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPAN SOC INTERNAL MEDICINE

We herein report a case of persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia that was successfully treated with combination therapy consisting of high-dose daptomycin (DAP, 10 mg/kg) and rifampicin. The patient's condition was complicated with multiple infectious foci, including an iliopsoas abscess and epidural abscess, as well as discitis and spondylitis at the cervical, thoracic and lumbar levels. Monotherapy treatments with vancomycin, linezolid and usual-dose DAP were all ineffective. It has been shown that usual-dose DAP administration may result in the emergence of a resistant strain and treatment failure. We would like to emphasize the importance of high-dose DAP therapy for MRSA bacteremia, a condition with a potentially high mortality rate.

DOI： 10.2169/internalmedicine.53.2711

Mutual interaction of kisspeptin, estrogen and bone morphogenetic protein-4 activity in GnRH regulation by GT1-7 cells Reviewed

Tomohiro Terasaka, Fumio Otsuka, Naoko Tsukamoto, Eri Nakamura, Kenichi Inagaki, Kishio Toma, Kanako Ogura-Ochi, Christine Glidewell-Kenney, Mark A. Lawson, Hirofumi Makino

MOLECULAR AND CELLULAR ENDOCRINOLOGY 381 ( 1-2 ) 8 - 15 2013.12

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

Reproduction is integrated by interaction of neural and hormonal signals converging on hypothalamic neurons for controlling gonadotropin-releasing hormone (GnRH). Kisspeptin, the peptide product of the kiss1 gene and the endogenous agonist for the GRP54 receptor, plays a key role in the regulation of GnRH secretion. In the present study, we investigated the interaction between kisspeptin, estrogen and BMPs in the regulation of GnRH production by using mouse hypothalamic GT1-7 cells. Treatment with kisspeptin increased GnRH mRNA expression and GnRH protein production in a concentration-dependent manner. The expression levels of kiss1 and GPR54 were not changed by kisspeptin stimulation. Kisspeptin induction of GnRH was suppressed by co-treatment with BMPs, with BMP-4 action being the most potent for suppressing the kisspeptin effect. The expression of kisspeptin receptor, GPR54, was suppressed by BMPs, and this effect was reversed in the presence of kisspeptin. It was also revealed that BMP-induced Smad1/5/8 phosphorylation and Id-1 expression were suppressed and inhibitory Smad6/7 was induced by kisspeptin. In addition, estrogen induced GPR54 expression, while kisspeptin increased the expression levels of ER alpha. and ER beta, suggesting that the actions of estrogen and kisspeptin are mutually enhanced in GT1-7 cells. Moreover, kisspeptin stimulated MAPKs and AKT signaling, and ERK signaling was functionally involved in the kisspeptin-induced GnRH expression. BMP-4 was found to suppress kisspeptin-induced GnRH expression by reducing ERK signaling activity. Collectively, the results indicate that the axis of kisspeptin-induced GnRH production is bi-directionally controlled, being augmented by an interaction between ER alpha/beta and GPR54 signaling and suppressed by BMP-4 action in GT1-7 neuron cells. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mce.2013.07.009

Melatonin receptor activation suppresses adrenocorticotropin production via BMP-4 action by pituitary AtT20 cells Reviewed

Naoko Tsukamoto, Fumio Otsuka, Kanako Ogura-Ochi, Kenichi Inagaki, Eri Nakamura, Kishio Toma, Tomohiro Terasaka, Yasumasa Iwasaki, Hirofumi Makino

MOLECULAR AND CELLULAR ENDOCRINOLOGY 375 ( 1-2 ) 1 - 9 2013.8

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

The role of melatonin, a regulator of circadian rhythm, in adrenocorticotropin (ACTH) production by corticotrope cells has not been elucidated. In this study, we investigated the effect of melatonin on ACTH production in relation to the biological activity of bone morphogenetic protein (BMP)-4 using mouse corticotrope AtT20 cells that express melatonin type-1 (MT1R) but not type-2 (MT2R) receptors. We previously reported that BMP-4 inhibits corticotropin-releasing hormone (CRH)-induced ACTH production and proopiomelanocortin (POMC) transcription by inhibiting MAPK signaling. Both melatonin and an MT1R/MT2R agonist, ramelteon, suppressed CRH-induced ACTH production, POMC transcription and cAMP synthesis. The inhibitory effects of ramelteon on basal and CRH-induced POMC mRNA and ACTH levels were more potent than those of melatonin. Treatment with melatonin or ramelteon in combination with BMP-4 additively suppressed CRH-induced ACTH production. Of note, the level of MTIR expression was upregulated by BMP-4 stimulation. The suppressive effects of melatonin and ramelteon on POMC transcription and cAMP synthesis induced by CRH were not affected by an MT2R antagonist, luzindole. On the other hand, BMP-4-induced Smad1/5/8 phosphorylation and the expression of a BMP target gene, Id-1, were augmented in the presence of melatonin and ramelteon. Considering that the expression levels of BMP receptors, ALK-3/BMPRII, were increased by ramelteon, MTIR action may play an enhancing role in BMP-receptor signaling. Among the MTIR signaling pathways including AKT, ERK and JNK pathways, inhibition of AKT signaling functionally reversed the MT1R effects on both CRH-induced POMC transcription and BMP-4-induced Id-1 transcription. Collectively, MT1R signaling and BMP-4 actions were mutually augmented, leading to fine-tuning of ACTH production by corticotrope cells. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mce.2013.05.010

Functional interaction of bone morphogenetic protein and growth hormone releasing peptide in adrenocorticotropin regulation by corticotrope cells Reviewed

Naoko Tsukamoto, Fumio Otsuka, Tomoko Miyoshi, Kenichi Inagaki, Eri Nakamura, Tomohiro Terasaka, Masaya Takeda, Toshio Ogura, Yasumasa Iwasaki, Hirofumi Makino

MOLECULAR AND CELLULAR ENDOCRINOLOGY 344 ( 1-2 ) 41 - 50 2011.9

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

Mechanisms by which GHRP stimulates ACTH release in corticotrope cells were investigated using mouse corticotrope AtT20 cells by focusing on the biological activity of BMP-4. GHRP-2 increased ACTH and cAMP secretion by AtT20 cells; however, its effects were less potent than the effects of CRH. BMP-4 suppressed basal ACTH production and POMC transcription, and the inhibition of endogenous BMP receptor signaling led to an increase in ACTH production. Of note, BMP-4 suppressed ACTH production and POMC-promoter activity induced by CRH more efficaciously than that induced by GHRP-2. BMP-4 had no significant effect on cAMP synthesis induced by CRH or GHRP-2. Stimulation with CRH, but not GHRP-2, activated ERK1/2, p38, SAPK/JNK and Akt phosphorylation, in which CRH-induced phosphorylation of ERR and p38 was suppressed by BMP-4. GHRP-2-induced ACTH secretion was not affected by inhibitors of ERR, p38 and Akt pathways, which effectively suppressed CRH-induced ACTH release. Blockage of the cAMP-PKA pathway reversed CRH- as well as GHRP-2-induced ACTH secretion. Furthermore, the inhibition of ERR and p38 significantly reduced cAMP synthesis induced by CRH but not by GHRP-2. Thus, CRH activates ACTH production through ERR and p38 pathways in addition to the cAMP-PKA pathway, which is also activated downstream of MAPK. On the other hand, GHRP-2-induced ACTH production was predominantly linked to the cAMP-PKA pathway. Moreover, CRH and GHRP-2 upregulated BMP receptor signaling, while BMP-4, CRH and GHRP-2 had no significant effect on the expression level of GHSR. In addition, GHRP-2 suppressed the expression of Smad7, which is an inhibitor of the BMP-Smad1/5/8 pathway. Collectively, the results revealed a functional interaction between GHRP-2 and BMP signaling, in which endogenous BMP may act as an autoregulatory system in controlling ACTH production. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.mce.2011.06.016

Regulation of GNRH production by estrogen and bone morphogenetic proteins in GT1-7 hypothalamic cells Reviewed

Hiroyuki Otani, Fumio Otsuka, Masaya Takeda, Tomoyuki Mukai, Tomohiro Terasaka, Tomoko Miyoshi, Kenichi Inagaki, Jiro Suzuki, Toshio Ogura, Mark A. Lawson, Hirofumi Makino

JOURNAL OF ENDOCRINOLOGY 203 ( 1 ) 87 - 97 2009.10

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

Recent studies have shown that bone morphogenetic proteins (BMPs) are important regulators in the pituitary-gonadal endocrine axis. We here investigated the effects of BMPs on GNRH production controlled by estrogen using murine GT1-7 hypothalamic neuron cells. GT1-7 cells expressed estrogen receptor alpha (ER alpha; ESR1 as listed in MGI Database), ER beta (ESR2 as listed in MGI Database), BMP receptors, SMADs, and a binding protein follistatin. Treatment with BMP2 and BMP4 had no effect on Gnrh mRNA expression; however, BMP6 and BMP7 significantly increased Gnrh mRNA expression as well as GnRH production by GT1-7 cells. Notably, the reduction of Gnrh expression caused by estradiol (E(2)) was restored by cotreatment with BMP2 and BMP4, whereas it was not affected by BMP6 or BMP7. E(2) activated extracellular signal-regulated kinase (ERK) 1/2 and stress-activated protein kinase/c-Jun NH(2)-terminal kinase (SAPK/JNK) signaling but did not activate p38-mitogen-activated protein kinase (MAPK) signaling in GT1-7 cells. Inhibition of ERK1/ERK2 reversed the inhibitory effect of estrogen on Gnrh expression, whereas SAPK/JNK inhibition did not affect the E(2) actions. Expression levels of Era and Er beta were reduced by BMP2 and BMP4, but were increased by BMP6 and BMP7. Treatment with an ER antagonist inhibited the E, effects on Gnrh suppression including reduction of E(2)-induced ERK phosphorylation, suggesting the involvement of genomic ER actions in Gnrh suppression. BMP2 and BMP4 also suppressed estrogen-induced phosphorylation of ERK1/ERK2 and SAPK/JNK signaling, suggesting that BMP2 and BMP4 downregulate estrogen effects by attenuating ER-MAPK. signaling. Considering that BMP6 and BMP7 increased the expression of alpha 1E-subunit of R-type calcium channel (Cacna1e), which is critical for GNRH secretion, it is possible that BMP6 and BMP7 directly stimulate GNRH release by GT1-7 cells. Collectively, a newly uncovered interaction of BMPs and ER may be involved in controlling hypothalamic GNRH production and secretion via an autocrine/paracrine mechanism. Journal of Endocrinology (2009) 203, 87-97

DOI： 10.1677/JOE-09-0065

Primary aldosteronism caused by a unilateral adrenal adenoma accompanied by autonomous cortisol secretion Reviewed

Jiro Suzuki, Fumio Otsuka, Kenichi Inagaki, Hiroyuki Otani, Tomoko Miyoshi, Tomohiro Terasaka, Toshio Ogura, Masako Omori, Yasutomo Nasu, Hirofumi Makino

HYPERTENSION RESEARCH 30 ( 4 ) 367 - 373 2007.4

Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE SOC HYPERTENSION CENT ACADEMIC SOC, PUBL OFFICE

A 35-year-old Japanese woman was referred for further examination of persistent hypertension with hypokalemia. Her serum aldosterone levels were high and her plasma renin activity markedly suppressed. Radiological examinations revealed the presence of a 3-cm diameter left adrenal tumor. I-131-adosterol was specifically accumulated in the left adrenal tumor, whereas the accumulation in the right adrenal was completely suppressed. Low-dose dexamethasone failed to suppress cortisol secretion although the serum cortisol levels were within the normal range. Urinary excretion of 17-hydroxycorticosteroids but not 17-ketosteroids was increased. Levels of plasma adrenocorticotropin (ACTH) and serum dehydroepiandrosterone sulfate (DHEAS) were decreased. Upon diagnosis of left aldosteronoma with autonomous secretion of cortisol, left adrenalectomy was performed by laparoscopy. In the resected adenoma tissues, clear cells expressed P450c17 protein and the ratio of CYP17/CYP11B2 mRNA evaluated by quantitative real-time polymerase chain reaction (PCR) was apparently higher than that of typical aldosteronomas. Based on the corticotropin-releasing hormone (CRH) loading tests, the contra-lateral adrenal functions were restored 3 months after surgery. These results indicate that evaluation for autonomy of cortisol secretion and contralateral adrenal function is clinically important to avoid the risk of adrenal failure after surgery for primary aldosteronism.

DOI： 10.1291/hypres.30.367

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