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Article: Adrenomedullin Therapy in Moderate to Severe COVID-19.

Kita, Toshihiro / Kitamura, Kazuo

2022 Volume 10, Issue 3

Abstract: The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines, antiviral medicines, and antibody formulations can suppress COVID-19 symptoms and ... ...

Abstract	The 2019 coronavirus (COVID-19) pandemic is still in progress, and a significant number of patients have presented with severe illness. Recently introduced vaccines, antiviral medicines, and antibody formulations can suppress COVID-19 symptoms and decrease the number of patients exhibiting severe disease. However, complete avoidance of severe COVID-19 has not been achieved, and more importantly, there are insufficient methods to treat it. Adrenomedullin (AM) is an endogenous peptide that maintains vascular tone and endothelial barrier function. The AM plasma level is markedly increased during severe inflammatory disorders, such as sepsis, pneumonia, and COVID-19, and is associated with the severity of inflammation and its prognosis. In this study, exogenous AM administration reduced inflammation and related organ damage in rodent models. The results of this study strongly suggest that AM could be an alternative therapy in severe inflammation disorders, including COVID-19. We have previously developed an AM formulation to treat inflammatory bowel disease and are currently conducting an investigator-initiated phase 2a trial for moderate to severe COVID-19 using the same formulation. This review presents the basal AM information and the most recent translational AM/COVID-19 study.
Language	English
Publishing date	2022-02-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10030533
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Article ; Online: Translational studies of adrenomedullin and related peptides regarding cardiovascular diseases.

Kita, Toshihiro / Kitamura, Kazuo

Hypertension research : official journal of the Japanese Society of Hypertension

2022 Volume 45, Issue 3, Page(s) 389–400

Abstract: Adrenomedullin (AM) is a vasodilative peptide with various physiological functions, including the maintenance of vascular tone and endothelial barrier function. AM levels are markedly increased during severe inflammation, such as that associated with ... ...

Abstract	Adrenomedullin (AM) is a vasodilative peptide with various physiological functions, including the maintenance of vascular tone and endothelial barrier function. AM levels are markedly increased during severe inflammation, such as that associated with sepsis; thus, AM is expected to be a useful clinical marker and therapeutic agent for inflammation. However, as the increase in AM levels in cardiovascular diseases (CVDs) is relatively low compared to that in infectious diseases, the value of AM as a marker of CVDs seems to be less important. Limitations pertaining to the administrative route and short half-life of AM in the bloodstream (<30 min) restrict the therapeutic applications of AM for CVDs. In early human studies, various applications of AM for CVDs were attempted, including for heart failure, myocardial infarction, pulmonary hypertension, and peripheral artery disease; however, none achieved success. We have developed AM as a therapeutic agent for inflammatory bowel disease in which the vasodilatory effect of AM is minimized. A clinical trial evaluating this AM formulation for acute cerebral infarction is ongoing. We have also developed AM derivatives that exhibit a longer half-life and less vasodilative activity. These AM derivatives can be administered by subcutaneous injection at long-term intervals. Accordingly, these derivatives will reduce the inconvenience in use compared to that for native AM and expand the possible applications of AM for treating CVDs. In this review, we present the latest translational status of AM and its derivatives.
MeSH term(s)	Adrenomedullin/therapeutic use ; Cardiovascular Diseases/drug therapy ; Heart Failure/drug therapy ; Humans ; Hypertension, Pulmonary ; Myocardial Infarction/drug therapy
Chemical Substances	Adrenomedullin (148498-78-6)
Language	English
Publishing date	2022-01-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1175297-x
ISSN	1348-4214 ; 0916-9636
ISSN (online)	1348-4214
ISSN	0916-9636
DOI	10.1038/s41440-021-00806-y
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Article: Adrenomedullin: A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease.

Ashizuka, Shinya / Kita, Toshihiro / Inatsu, Haruhiko / Kitamura, Kazuo

Biomedicines

2021 Volume 9, Issue 8

Abstract: Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, ... ...

Abstract	Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn's disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment.
Language	English
Publishing date	2021-08-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines9081068
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Article ; Online: Adrenomedullin

Shinya Ashizuka / Toshihiro Kita / Haruhiko Inatsu / Kazuo Kitamura

Biomedicines, Vol 9, Iss 1068, p

A Novel Therapeutic for the Treatment of Inflammatory Bowel Disease

2021 Volume 1068

Abstract	Adrenomedullin (AM) is a bioactive peptide with various physiological functions, including vasodilation, angiogenesis, anti-inflammation, organ protection, and tissue repair. AM suppresses inflammatory cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function, mucosal epithelial repair, and immune function in the intestinal bacteria of animal models with intestinal inflammation. We have been promoting translational research to develop novel therapeutic agents for inflammatory bowel disease (IBD) using AM and have started clinical research for IBD patients since 2010. A multicenter clinical trial is currently underway in Japan for patients with refractory ulcerative colitis and Crohn’s disease. Moreover, since current AM administration is limited to continuous intravenous infusion, the development of a subcutaneous formulation using long-acting AM is underway for outpatient treatment.
Keywords	adrenomedullin ; inflammatory bowel disease ; ulcerative colitis ; Crohn’s disease ; translational research ; drug discovery research ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Seasonal variation of novel arterial stiffness indexes in Japanese hypertensive patients.

Kita, Toshihiro / Kitamura, Kazuo

Clinical and experimental hypertension (New York, N.Y. : 1993)

2018 Volume 41, Issue 7, Page(s) 670–674

Abstract: Background ... ...

Abstract	Background and
MeSH term(s)	Aged ; Arteries/physiopathology ; Blood Pressure ; Female ; Heart Rate ; Humans ; Hypertension/physiopathology ; Japan ; Male ; Middle Aged ; Pulse Wave Analysis ; Seasons ; Vascular Stiffness
Language	English
Publishing date	2018-11-08
Publishing country	England
Document type	Journal Article
ZDB-ID	604757-9
ISSN	1525-6006 ; 0730-0077
ISSN (online)	1525-6006
ISSN	0730-0077
DOI	10.1080/10641963.2018.1539092
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Zs.A 1429: Show issues

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Article ; Online: Identification and genetic mapping of novel resistance gene, Rvn4, for pear scab in Chinese pear

Terakami, Shingo / Ogata, Natsumi / Kita, Kōichi / Gonai, Takeru / Saito, Toshihiro / Yamamoto, Toshiya

Scientia Horticulturae. 2023 July, v. 317 p.112032-

2023

Abstract: Pear scab, caused by Venturia nashicola, is one of the most harmful diseases of pears, especially of Japanese and Chinese pears. The breeding of new cultivars resistant to pear scab has long been an aim of the Asian pear breeding programs. Although loci ... ...

Abstract	Pear scab, caused by Venturia nashicola, is one of the most harmful diseases of pears, especially of Japanese and Chinese pears. The breeding of new cultivars resistant to pear scab has long been an aim of the Asian pear breeding programs. Although loci for pear scab disease resistance have been identified in Japanese and European pears, information on the genes controlling scab resistance in Chinese pears is limited. Genetic control of scab resistance in Chinese pear is reported to involve a single dominant gene. Here, we reaffirmed the scab resistance in the Chinese pear ‘Hong Li’ controls a single dominant gene and identified the exact location of a scab resistance gene, Rvn4. We first mapped Rvn4 at the top of linkage group (LG) 7 and then used public genome sequences to develop novel simple sequence repeat (SSR) markers to enrich the target region. Using these novel SSRs and the previously published SSR markers, we constructed a LG 7 of ‘Hong Li’ with an average marker density of 1.4 cM per marker. The novel SSR marker Pbr.chr07.20 had a significant linkage to Rvn4, with a genetic distance of 1.3 cM. The identification of the precise locus of Rvn4 in Chinese pear, together with previous studies in Japanese and European pear, will enhance our understanding of the mechanisms of pear scab resistance. DNA markers linked to the novel gene may also allow efficient selection of scab-resistant seedlings in pear breeding programs and the pyramiding of multiple resistance genes.
Keywords	DNA ; Venturia nashicola ; cultivars ; disease resistance ; dominant genes ; genetic distance ; linkage groups ; loci ; microsatellite repeats ; pears ; resistance genes ; Scab ; Pyrus bretschneideri ; Genetic mapping
Language	English
Dates of publication	2023-07
Publishing place	Elsevier B.V.
Document type	Article ; Online
ZDB-ID	185557-8
ISSN	0304-4238
ISSN	0304-4238
DOI	10.1016/j.scienta.2023.112032
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Safety, Tolerability, and Pharmacokinetics of Adrenomedullin in Healthy Males: A Randomized, Double-Blind, Phase 1 Clinical Trial.

Kita, Toshihiro / Kaji, Yoshikazu / Kitamura, Kazuo

Drug design, development and therapy

2020 Volume 14, Page(s) 1–11

Abstract: Background: Adrenomedullin (AM), an endogenous vasodilative peptide, has immunomodulative effects and acts as an accelerator of mucosal regeneration in the digestive tract. AM has shown beneficial effects in rodent models of inflammatory bowel disease ... ...

Abstract	Background: Adrenomedullin (AM), an endogenous vasodilative peptide, has immunomodulative effects and acts as an accelerator of mucosal regeneration in the digestive tract. AM has shown beneficial effects in rodent models of inflammatory bowel disease and patients with ulcerative colitis. The present study aimed to evaluate the pharmacodynamic properties and safety of AM in healthy male adults in a phase 1 clinical trial. Methods: This phase 1, randomized, double-blind, single-center study was conducted on healthy males aged 20-65 years. Subjects received either a placebo, 3 ng/kg/min AM, 9 ng/kg/min AM, or 15 ng/kg/min AM via continuous 12-h intravenous infusion. Other subjects received either placebo or 15 ng/kg/min AM for 8 h per day for 7 days. Adverse events (AEs), vital signs, physical examinations, laboratory tests, electrocardiograms (ECG), and pharmacokinetics were assessed. Findings: All 24 subjects in the single-dose test completed the study. Of the 12 subjects in multiple dosing test, one from the AM group withdrew owing to a headache. No serious AEs were reported. Hemodynamic parameters were well maintained in all subjects. Slight ECG abnormalities were observed in the single-dose test. The plasma concentration of AM progressively increased in a dose-dependent manner and reached C Interpretation: This is the first phase 1 trial in healthy men evaluating the safety of AM. Our results demonstrate the safety and tolerability of AM for subsequent Phase 2 trials.
MeSH term(s)	Adrenomedullin/administration & dosage ; Adrenomedullin/adverse effects ; Adrenomedullin/pharmacokinetics ; Adult ; Aged ; Double-Blind Method ; Drug Administration Schedule ; Drug Compounding ; Drug Tolerance ; Healthy Volunteers ; Humans ; Injections, Intravenous ; Male ; Middle Aged ; Young Adult
Chemical Substances	Adrenomedullin (148498-78-6)
Language	English
Publishing date	2020-01-06
Publishing country	New Zealand
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial
ZDB-ID	2451346-5
ISSN	1177-8881 ; 1177-8881
ISSN (online)	1177-8881
ISSN	1177-8881
DOI	10.2147/DDDT.S225220
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Article ; Online: Relationship between microorganisms and volatile components in each fermentation process in the kusaya gravy that plays an important role in the manufacturing of kusaya, a traditional Japanese fermented fish product.

Kita, Kosuke / Unno, Ryosuke / Osada, Takahiro / Yoshiyama, Hiromori / Masaki, Sachiko / Nogimura, Sakura / Matsutani, Minenosuke / Ishikawa, Morio / Suzuki, Toshihiro

Bioscience, biotechnology, and biochemistry

2023 Volume 88, Issue 1, Page(s) 111–122

Abstract: The relationship between the microbiota and volatile components of kusaya gravy involved in the manufacturing of kusaya, a traditional Japanese fermented fish product, in the Izu Islands (Niijima and Hachijojima) and the fermentation processes are not ... ...

Abstract	The relationship between the microbiota and volatile components of kusaya gravy involved in the manufacturing of kusaya, a traditional Japanese fermented fish product, in the Izu Islands (Niijima and Hachijojima) and the fermentation processes are not clear. In this study, we aimed to investigate the relationship between the microbiota and volatile compounds involved in the manufacturing and management of kusaya gravy. 16S ribosomal RNA (rRNA) gene-based amplicon sequencing revealed that the microbiota in kusaya gravy was significantly different between the two islands, and the microbiota hardly changed during each fermentation process. Gas chromatography-mass spectrometry analysis also revealed that the volatile components were strongly related to the microbiota in kusaya gravy, with Hachijojima samples containing sulfur-containing compounds and Niijima samples containing short-chain fatty acids. Therefore, our findings suggest that kusaya gravy is a characteristic fermented gravy with a stable microbiota, and the fermented pickling gravy is fermented by microorganisms.
MeSH term(s)	Animals ; Fermentation ; Japan ; Microbiota ; Sulfur Compounds ; Fish Products
Chemical Substances	Sulfur Compounds
Language	English
Publishing date	2023-11-27
Publishing country	England
Document type	Journal Article
ZDB-ID	1106450-x
ISSN	1347-6947 ; 0916-8451
ISSN (online)	1347-6947
ISSN	0916-8451
DOI	10.1093/bbb/zbad144
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Zs.A 4647: Show issues

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Article ; Online: Nitrogen loading increases the ozone sensitivity of larch seedlings with higher sensitivity to nitrogen loading.

Sugai, Tetsuto / Watanabe, Toshihiro / Kita, Kazuhito / Koike, Takayoshi

The Science of the total environment

2019 Volume 663, Page(s) 587–595

Abstract: Larch (Larix sp.) tree is a critical species for the future afforestation in Northeast Asia. The impacts of elevated concentrations of ground-level ozone ( ... ...

Abstract	Larch (Larix sp.) tree is a critical species for the future afforestation in Northeast Asia. The impacts of elevated concentrations of ground-level ozone (O
MeSH term(s)	Air Pollutants/adverse effects ; Larix/drug effects ; Larix/growth & development ; Nitrogen/adverse effects ; Ozone/adverse effects ; Seedlings/drug effects ; Seedlings/growth & development
Chemical Substances	Air Pollutants ; Ozone (66H7ZZK23N) ; Nitrogen (N762921K75)
Language	English
Publishing date	2019-01-24
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	121506-1
ISSN	1879-1026 ; 0048-9697
ISSN (online)	1879-1026
ISSN	0048-9697
DOI	10.1016/j.scitotenv.2019.01.292
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Article ; Online: Efficient screening of patients with aldosterone-producing adenoma using the ACTH stimulation test.

Kita, Toshihiro / Furukoji, Eiji / Sakae, Tatefumi / Kitamura, Kazuo

Hypertension research : official journal of the Japanese Society of Hypertension

2019 Volume 42, Issue 6, Page(s) 801–806

Abstract: Adrenal venous sampling (AVS) is the gold standard test for distinguishing between unilateral and bilateral primary aldosteronism (PA); however, AVS requires advanced and time consuming technique. The needs for AVS have been increasing due to the ... ...

Abstract	Adrenal venous sampling (AVS) is the gold standard test for distinguishing between unilateral and bilateral primary aldosteronism (PA); however, AVS requires advanced and time consuming technique. The needs for AVS have been increasing due to the increased utilization of screening for PA. An efficient selection of unilateral PA, such as aldosterone-producing adenoma (APA), before AVS is useful to avoid undesirable AVS in bilateral PA, such as idiopathic hyperaldosteronism. In this study, 40 patients who received all three confirmatory tests, including the captopril challenge test, furosemide upright test and adrenocorticotropin (ACTH) stimulation test (AST), and who were diagnosed as having PA by AVS were recruited. Subjects were diagnosed as having unilateral aldosterone excess (n = 22) or bilateral aldosterone excess (n = 18) by AVS. All patients with unilateral PA underwent an operation and were finally diagnosed with APA. Major differences were detected in serum potassium level, basal plasma aldosterone concentration (PAC), presence of adrenal tumor, and AST results between the two groups. The PAC/cortisol ratio at 120 min in the AST showed the highest diagnostic capability for distinguishing the subtypes of PA according to a receiver operating characteristic (ROC) curve analysis (area under the ROC curve was 0.956). At a cutoff value of 1.20 for the PAC/cortisol ratio at 120 min on the AST, the sensitivity was 95.5%, and the specificity was 88.9%. This sufficiently high sensitivity suggests that the PAC/cortisol ratio at 120 min in the AST could be useful for the screening of patients with PA who are suitable for AVS.
MeSH term(s)	Adenoma/diagnosis ; Adenoma/metabolism ; Adrenal Gland Neoplasms/diagnosis ; Adrenal Gland Neoplasms/metabolism ; Adrenocorticotropic Hormone/pharmacology ; Adult ; Aged ; Aldosterone/metabolism ; Captopril/pharmacology ; Diuretics/pharmacology ; Female ; Furosemide/pharmacology ; Humans ; Hyperaldosteronism/diagnosis ; Hyperaldosteronism/metabolism ; Male ; Mass Screening/methods ; Middle Aged ; Predictive Value of Tests ; ROC Curve ; Retrospective Studies ; Sensitivity and Specificity ; Stimulation, Chemical
Chemical Substances	Diuretics ; Aldosterone (4964P6T9RB) ; Furosemide (7LXU5N7ZO5) ; Adrenocorticotropic Hormone (9002-60-2) ; Captopril (9G64RSX1XD)
Language	English
Publishing date	2019-01-08
Publishing country	England
Document type	Journal Article
ZDB-ID	1175297-x
ISSN	1348-4214 ; 0916-9636
ISSN (online)	1348-4214
ISSN	0916-9636
DOI	10.1038/s41440-018-0191-5
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