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Article ; Online: Molecular and Epigenetic Control of Aldosterone Synthase, CYP11B2 and 11-Hydroxylase, CYP11B1

Yoshimichi Takeda / Masashi Demura / Mitsuhiro Kometani / Shigehiro Karashima / Takashi Yoneda / Yoshiyu Takeda

International Journal of Molecular Sciences, Vol 24, Iss 5782, p

2023 Volume 5782

Abstract: Aldosterone and cortisol serve important roles in the pathogenesis of cardiovascular diseases and metabolic disorders. Epigenetics is a mechanism to control enzyme expression by genes without changing the gene sequence. Steroid hormone synthase gene ... ...

Abstract	Aldosterone and cortisol serve important roles in the pathogenesis of cardiovascular diseases and metabolic disorders. Epigenetics is a mechanism to control enzyme expression by genes without changing the gene sequence. Steroid hormone synthase gene expression is regulated by transcription factors specific to each gene, and methylation has been reported to be involved in steroid hormone production and disease. Angiotensin II or potassium regulates the aldosterone synthase gene, CYP11B2 . The adrenocorticotropic hormone controls the 11b-hydroxylase, CYP11B1 . DNA methylation negatively controls the CYP11B2 and CYP11B1 expression and dynamically changes the expression responsive to continuous stimulation of the promoter gene. Hypomethylation status of the CYP11B2 promoter region is seen in aldosterone-producing adenomas. Methylation of recognition sites of transcription factors, including cyclic AMP responsive element binding protein 1 or nerve growth factor-induced clone B, diminish their DNA-binding activity. A methyl-CpG-binding protein 2 cooperates directly with the methylated CpG dinucleotides of CYP11B2 . A low-salt diet, treatment with angiotensin II, and potassium increase the CYP11B2 mRNA levels and induce DNA hypomethylation in the adrenal gland. A close association between a low DNA methylation ratio and an increased CYP11B1 expression is seen in Cushing’s adenoma and aldosterone-producing adenoma with autonomous cortisol secretion. Epigenetic control of CYP11B2 or CYP11B1 plays an important role in autonomic aldosterone or cortisol synthesis.
Keywords	aldosterone ; cortisol ; methylation ; adrenal gland ; hormone-producing adenoma ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: DNA Methylation of the Angiotensinogen Gene, AGT and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases

Yoshimichi Takeda / Masashi Demura / Takashi Yoneda / Yoshiyu Takeda

International Journal of Molecular Sciences, Vol 22, Iss 4587, p

2021 Volume 4587

Abstract: Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene ... ...

Abstract	Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene CYP11B2 is regulated by angiotensin II and potassium. DNA methylation negatively regulates AGT and CYP11B2 expression and dynamically changes in response to continuous promoter stimulation of each gene. High salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT-enhancer-binding-protein (CEBP) sites of the CYP11B2 promoter region, thereby converting the phenotype of AGT expression from an inactive to an active state in visceral adipose tissue and heart. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in salt-sensitive hypertensive rats. Salt-dependent hypertension may be partially affected by increased cardiac AGT expression. CpG dinucleotides in the CYP11B2 promoter are hypomethylated in aldosterone-producing adenomas. Methylation of recognition sequences of transcription factors, including CREB1, NGFIB (NR4A1), and NURR1 (NR4A2) diminish their DNA-binding activity. The methylated CpG-binding protein MECP2 interacts directly with the methylated CYP11B2 promoter. Low salt intake and angiotensin II infusion lead to upregulation of CYP11B2 expression and DNA hypomethylation in the adrenal gland. Treatment with the angiotensin II type 1 receptor antagonist decreases CYP11B2 expression and leads to DNA hypermethylation. A close association between low DNA methylation and increased CYP11B2 expression are seen in the hearts of patients with hypertrophic cardiomyopathy. These results indicate that epigenetic regulation of both AGT and CYP11B2 contribute to the pathogenesis of cardiovascular diseases.
Keywords	angiotensinogen ; aldosterone ; methylation ; cardiovascular disease ; salt ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Remitting Seronegative Symmetrical Synovitis with Pitting Edema Syndrome Worsen after the Administration of Dulaglutide

Toshitaka Sawamura / Shigehiro Karashima / Ai Ohmori / Kei Sawada / Mitsuhiro Kometani / Yoshiyu Takeda / Takashi Yoneda

Medicina, Vol 58, Iss 289, p

2022 Volume 289

Abstract: Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is characterized by symmetrical polyarthritis and limb pitting edema. Although the detailed mechanisms of this syndrome have not been clearly understood, some agents ... ...

Abstract	Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is characterized by symmetrical polyarthritis and limb pitting edema. Although the detailed mechanisms of this syndrome have not been clearly understood, some agents including dipeptidyl peptidase-4 inhibitors have been reported to induce RS3PE syndrome. However, glucagon-like peptide-1 (GLP-1) analogues have not been reported to be associated with this syndrome. A 91-year-old woman was admitted to our hospital with complaints of severe polyarthritis and limb edema. She was diagnosed with RS3PE syndrome. Oral prednisolone improved her symptoms. However, her symptoms worsened after the administration of dulaglutide, with elevated serum inflammatory markers. Discontinuation of dulaglutide without additional treatment improved her symptoms and laboratory findings. This case might indicate the possibility of development and worsening of RS3PE syndrome caused after GLP-1 analogue.
Keywords	RS3PE syndrome ; GLP-1 analogue ; dulaglutide ; Medicine (General) ; R5-920
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A clinical assessment of portable point-of-care testing for quick cortisol assay during adrenal vein sampling

Ko Aiga / Mitsuhiro Kometani / Shigehiro Karashima / Seigo Konishi / Takuya Higashitani / Daisuke Aono / Xurong Mai / Mikiya Usukura / Takahiro Asano / Ayako Wakayama / Yuko Noda / Wataru Koda / Tetsuya Minami / Satoshi Kobayashi / Toshinori Murayama / Takashi Yoneda

Scientific Reports, Vol 13, Iss 1, Pp 1-

2023 Volume 10

Abstract: Abstract This study assessed the clinical performance of point-of-care testing (POCT) for quick cortisol assay (QCA) during adrenal vein sampling (AVS) using a newly invented portable quantitative assay instrument. An observational study was conducted ... ...

Abstract	Abstract This study assessed the clinical performance of point-of-care testing (POCT) for quick cortisol assay (QCA) during adrenal vein sampling (AVS) using a newly invented portable quantitative assay instrument. An observational study was conducted prospectively at two centres in Japan. Forty-eight patients with primary aldosteronism considered for adrenalectomy were enrolled in this study and underwent AVS. Three basal adrenal vein samples from each adrenal vein and two from the inferior vena cava were collected sequentially. The cortisol concentration of adrenal vein samples was measured by routine method and QCA. A total of 338 adrenal vein samples were analysed from 250 sites to determine AVS success or failure. The distribution of turnaround time of the QCA for AVS success or failure followed a normal distribution with an average of 20.5 min. A positive correlation between the routine method and QCA was observed regarding cortisol concentration or selectivity index. No significant difference between the two methods was observed regarding the success rate of AVS. Using the routine method as a reference, the sensitivity and specificity of AVS success or failure were 99.1% (210/212) and 81.6% (31/38), respectively. Easy, quick, portable, and precise POCT-QCA demonstrated its compatibility with routine methods regarding clinical performance.
Keywords	Medicine ; R ; Science ; Q
Subject code	630
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The association of primary aldosteronism with glaucoma-related fundus abnormalities.

Yoshimi Ohshima / Tomomi Higashide / Kimikazu Sakaguchi / Makoto Sasaki / Sachiko Udagawa / Shinji Ohkubo / Takashi Yoneda / Kazuhisa Sugiyama

PLoS ONE, Vol 15, Iss 11, p e

2020 Volume 0242090

Abstract: Purpose To elucidate glaucoma-related fundus abnormalities in patients with primary aldosteronism (PA). Methods The study compared 272 eyes from 137 PA patients and 352 eyes from 177 control subjects selected randomly from 1173 participants of a public ... ...

Abstract	Purpose To elucidate glaucoma-related fundus abnormalities in patients with primary aldosteronism (PA). Methods The study compared 272 eyes from 137 PA patients and 352 eyes from 177 control subjects selected randomly from 1173 participants of a public glaucoma screening. The presence of glaucomatous optic disc appearance (rim thinning and cup enlargement) and retinal nerve fiber layer defects (RNFLDs) was determined independently from fundus photographs. The results were compared between the PA and control groups. Results There were 9 patients (6.6%) with glaucomatous optic disc abnormalities in the PA group and 10 cases (5.6%) identified in the control group (p = 0.92). RNFLDs were detected more frequently in the PA group (55 eyes, 20.2%) than in the control group (26 eyes, 7.4%; p<0.001). The two types of RNFLDs were classified as either having their central ends at the disc margin (D) or away from the disc margin and around the retinal vessels (V). Type D and V RNFLDs were detected in 35 (12.9%) and 26 (9.6%) eyes in the PA group and in 25 (7.1%) and 4 (1.1%) eyes in the control group, respectively. Both types of RNFLDs were more frequent in the PA group than in the control group (Type D and V, p = 0.03, <0.001, respectively). Conclusion Although the prevalence of glaucomatous optic disc appearance did not differ between the two groups, RNFLDs were more frequent in PA patients than in the control group. Moreover, RNFLDs with their central ends located around retinal vessels were characteristic of PA patients.
Keywords	Medicine ; R ; Science ; Q
Subject code	796
Language	English
Publishing date	2020-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Impact of Gut Microbiome on Hypertensive Patients With Low-Salt Intake

Satoshi Nagase / Shigehiro Karashima / Hiromasa Tsujiguchi / Hirohito Tsuboi / Sakae Miyagi / Mitsuhiro Kometani / Daisuke Aono / Takuya Higashitani / Masashi Demura / Hiroyuki Sakakibara / Akihiro Yoshida / Akinori Hara / Hiroyuki Nakamura / Yoshiyu Takeda / Hidetaka Nambo / Takashi Yoneda / Shigefumi Okamoto

Frontiers in Medicine, Vol

Shika Study Results

2020 Volume 7

Abstract: Salt intake is one of the most important environmental factors impacting hypertension onset. Meanwhile, the potential roles of the gut microbiome (GM) in altering the health status of hosts have drawn considerable attention. Here, we aimed to perform an ... ...

Abstract	Salt intake is one of the most important environmental factors impacting hypertension onset. Meanwhile, the potential roles of the gut microbiome (GM) in altering the health status of hosts have drawn considerable attention. Here, we aimed to perform an observational study to investigate the impact of intestinal bacterial flora in hypertensive patients with low-salt or high-salt intake. A total of 239 participants were enrolled, and their gut microbiomes, clinical and demographic details, as well as physiological parameters pertaining to the renin-angiotensin-aldosterone system and inflammatory cytokine profiles, were examined. The participants were classified into four groups based on the presence of different enterotype bacteria, as determined via cluster analysis, and salt intake: low salt/GM enterotype 1, low salt/GM enterotype 2, high salt/GM enterotype 1, and high salt/GM enterotype 2. Results show that the prevalence of hypertension was significantly lower in the low-salt/GM enterotype 2 group (27%) compared to the low salt/GM enterotype 1 group (47%; p = 0.04). Alternatively, no significant differences were observed in hypertension prevalence between the two high-salt intake groups (GM enterotype 1 = 50%, GM enterotype 2 = 47%; p = 0.83). Furthermore, The low-salt/GM enterotype 2 was higher in the relative abundances of Blautia, Bifidobacterium, Escherichia-Shigella, Lachnoclostridium, and Clostridium sensu stricto than the low-salt/GM enterotype 1. differed significantly between the GM enterotypes. These results suggested that consumption of a low-salt diet was ineffective in regulating hypertension in individuals with a specific gut bacteria composition. Our findings support the restoration of GM homeostasis as a new strategy for controlling blood pressure and preventing the development of hypertension.
Keywords	gut microbiome ; blood pressure ; salt-intake ; renin-angiotensin-aldosterone system ; hypertension ; Medicine (General) ; R5-920
Subject code	333
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	Frontiers Media S.A.
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: PEP-on-DEP: A competitive peptide-based disposable electrochemical aptasensor for renin diagnostics

Biyani, Manish / Eiichi Tamiya / Hiromi Ushijima / Keiko Kawai / Koichiro Kitamura / Madhu Biyani / Miyuki Chikae / Takashi Yoneda / Yuzuru Takamura

Biosensors & bioelectronics. 2016 Oct. 15, v. 84

2016

Abstract: Antibody-based immunosensors are relatively less accessible to a wide variety of unreachable targets, such as low-molecular-weight biomarkers that represent a rich untapped source of disease-specific diagnostic information. Here, we present a peptide ... ...

Abstract	Antibody-based immunosensors are relatively less accessible to a wide variety of unreachable targets, such as low-molecular-weight biomarkers that represent a rich untapped source of disease-specific diagnostic information. Here, we present a peptide aptamer-based electrochemical sensor technology called ‘PEP-on-DEP’ to detect less accessible target molecules, such as renin, and to improve the quality of life. Peptide-based aptamers represent a relatively smart class of affinity binders and show great promise in biosensor development. Renin is involved in the regulation of arterial blood pressure and is an emerging biomarker protein for predicting cardiovascular risk and prognosis. To our knowledge, no studies have described aptamer molecules that can be used as new potent probes for renin. Here, we describe a portable electrochemical biosensor platform based on the newly identified peptide aptamer molecules for renin. We constructed a randomized octapeptide library pool with diversified sequences and selected renin specific peptide aptamers using cDNA display technology. We identified a few peptide aptamer sequences with a KD in the μM binding affinity range for renin. Next, we grafted the selected peptide aptamers onto gold nanoparticles and detected renin in a one-step competitive assay using our originally developed DEP (Disposable Electrochemical Printed) chip and a USB powered portable potentiostat system. We successfully detected renin in as little as 300ngmL−1 using the PEP-on-DEP method. Thus, the generation and characterization of novel probes for unreachable target molecules by merging a newly identified peptide aptamer with electrochemical transduction allowed for the development of a more practical biosensor that, in principle, can be adapted to develop a portable, low-cost and mass-producible biosensor for point-of-care applications.
Keywords	binding capacity ; biomarkers ; blood pressure ; complementary DNA ; diagnostic techniques ; electrochemistry ; immunosensors ; nanogold ; oligonucleotides ; prediction ; prognosis ; quality of life ; renin ; risk
Language	English
Dates of publication	2016-1015
Size	p. 120-125.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	1011023-9
ISSN	1873-4235 ; 0956-5663
ISSN (online)	1873-4235
ISSN	0956-5663
DOI	10.1016/j.bios.2015.12.078
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Age-stratified comparison of clinical outcomes between medical and surgical treatments in patients with unilateral primary aldosteronism

Scientific Reports, Vol 11, Iss 1, Pp 1-

2021 Volume 10

Abstract: Abstract Although adrenalectomy (ADX) is an established treatment for unilateral primary aldosteronism (uPA), the influence of age on the surgical outcomes is poorly understood. Therefore, we aimed to elucidate how age affects the clinical outcomes after ...

Abstract	Abstract Although adrenalectomy (ADX) is an established treatment for unilateral primary aldosteronism (uPA), the influence of age on the surgical outcomes is poorly understood. Therefore, we aimed to elucidate how age affects the clinical outcomes after treatments. We analyzed 153 older (≥ 65 years) and 702 younger patients (< 65 years) with uPA, treated either with ADX or mineralocorticoid receptor antagonist (MRA) in the Japan PA Study, and compared the estimated glomerular filtration rate (eGFR) or blood pressure over a 36-month period after treatments. ADX-treated patients showed severer biochemical indicators than MRA-treated patients. During 6 and 36 months, the eGFR decreased more prominently in older but not in younger patients with ADX than in those with MRA, which remained significant after adjustment with the inverse probability of treatment weighting (IPTW). There was a significant interaction between the age-groups and the treatment choices in the change of the eGFR with IPTW-adjusted analysis. The post-treatment dose of antihypertensive medication was lower in younger and higher in older patients with ADX than those with MRA. The clinical benefit of ADX differed between younger and older patients with uPA. These findings indicate the need for further validation on whether ADX can benefit older patients with uPA.
Keywords	Medicine ; R ; Science ; Q
Subject code	616
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cortisol overproduction results from DNA methylation of CYP11B1 in hypercortisolemia

Mitsuhiro Kometani / Takashi Yoneda / Masashi Demura / Hiroshi Koide / Koshiro Nishimoto / Kuniaki Mukai / Celso E. Gomez-Sanchez / Tadayuki Akagi / Takashi Yokota / Shin-ichi Horike / Shigehiro Karashima / Isamu Miyamori / Masakazu Yamagishi / Yoshiyu Takeda

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 9

Abstract: Abstract Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. ... ...

Abstract	Abstract Adrenocortical hormone excess, due to primary aldosteronism (PA) or hypercortisolemia, causes hypertension and cardiovascular complications. In PA, hypomethylation of aldosterone synthase (CYP11B2) is associated with aldosterone overproduction. However, in hypercortisolemia, the role of DNA methylation of 11β-hydroxylase (CYP11B1), which catalyzes cortisol biosynthesis and is highly homologous to CYP11B2, is unclear. The aims of our study were to determine whether the CYP11B1 expression was regulated through DNA methylation in hypercortisolemia with cortisol-producing adenoma (CPA), and to investigate a possible relationship between DNA methylation and somatic mutations identified in CPA. Methylation analysis showed that the CYP11B1 promoter was significantly less methylated in CPA than in adjacent unaffected adrenal tissue and white blood cells. Furthermore, in CPA with somatic mutations in either the catalytic subunit of protein kinase A (PRKACA) or the guanine nucleotide-binding protein subunit alpha (GNAS) gene, the CYP11B1 promoter was significantly hypomethylated. In addition, DNA methylation reduced CYP11B1 promoter activity using a reporter assay. Our study results suggest that DNA methylation at the CYP11B1 promoter plays a role in the regulation of CYP11B1 expression and cortisol production in CPA, and that somatic mutations associated with CPA reduce DNA methylation at the CYP11B1 promoter.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2017-09-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Correlation Between Lateralization Index of Adrenal Venous Sampling and Standardized Outcome in Primary Aldosteronism.

Umakoshi, Hironobu / Tsuiki, Mika / Yokomoto-Umakoshi, Maki / Takeda, Yoshiyu / Takashi, Yoneda / Kurihara, Isao / Itoh, Hiroshi / Katabami, Takuyuki / Ichijo, Takamasa / Wada, Norio / Shibayama, Yui / Yoshimoto, Takanobu / Ashida, Kenji / Ogawa, Yoshihiro / Kawashima, Junji / Sone, Masakatsu / Inagaki, Nobuya / Takahashi, Katsutoshi / Watanabe, Minemori /

Journal of the Endocrine Society

2018 Volume 2, Issue 8, Page(s) 893–902

Abstract: Objectives: The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cutoffs on surgical outcomes.: Patients and methods: Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with ...

Abstract	Objectives: The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cutoffs on surgical outcomes. Patients and methods: Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with primary aldosteronism (PA) who were evaluated 6 months after surgery. Main outcome measures: The proportion of patients that achieved clinical benefit and complete biochemical success based on the AVS aldosterone lateralization index (LI) was determined. Results: Clinical benefit was achieved in 29 of 47 patients with an LI between 2 and 4, in 66 of 101 with an LI between 4 and 10, and in 158 of 203 with an LI > 10 ( Conclusions: Difference of clinical outcome was relatively small when strict LI diagnostic threshold was used; biochemical cure was sufficiently achieved when an LI > 4 was used. Our study by standardized outcome measures validated that an LI > 4 may be appropriate for determining unilateral disease in PA.
Language	English
Publishing date	2018-05-24
Publishing country	United States
Document type	Journal Article
ISSN	2472-1972
ISSN (online)	2472-1972
DOI	10.1210/js.2018-00055
Database	MEDical Literature Analysis and Retrieval System OnLINE

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