Publications by authors named "Masayoshi Shichiri"

94 Publications

GIP_HUMAN[22-51] is a new proatherogenic peptide identified by native plasma peptidomics.

Sci Rep 2021 Jul 14;11(1):14470. Epub 2021 Jul 14.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.

We recently established a new plasma peptidomic technique and comprehensively identified a large number of low-molecular weight and low-abundance native peptides using a single drop of human plasma. To discover a novel polypeptide that potently modulates the cardiovascular system, we performed a bioinformatics analysis of the large-scale identification results, sequentially synthesized the selected peptide sequences, tested their biological activities, and identified a 30-amino-acid proatherogenic peptide, GIP_HUMAN[22-51], as a potent proatherosclerotic peptide hormone. GIP_HUMAN[22-51] has a common precursor with the glucose-dependent insulinotropic polypeptide (GIP) and is located immediately N-terminal to GIP. Chronic infusion of GIP_HUMAN[22-51] into ApoE mice accelerated the development of aortic atherosclerotic lesions, which were inhibited by co-infusions with an anti-GIP_HUMAN[22-51] antibody. GIP_HUMAN[22-51] increased the serum concentrations of many inflammatory and proatherogenic proteins, whereas neutralising antibodies reduced their levels. GIP_HUMAN[22-51] induced IκB-α degradation and nuclear translocation of NF-κB in human vascular endothelial cells and macrophages. Immunoreactive GIP_HUMAN[22-51] was detected in human tissues but there was no colocalization with the GIP. The plasma GIP_HUMAN[22-51] concentration in healthy humans determined using a stable-isotope tagged peptide was approximately 0.6 nM. This study discovered a novel endogenous proatherogenic peptide by using a human plasma native peptidomic resource.
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http://dx.doi.org/10.1038/s41598-021-93862-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280211PMC
July 2021

Hemodialysis-Related Glycemic Disarray Proven by Continuous Glucose Monitoring: Glycemic Markers and Hypoglycemia.

Diabetes Care 2021 May 27. Epub 2021 May 27.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa, Japan.

Objective: There is a high risk of asymptomatic hypoglycemia associated with hemodialysis (HD) using glucose-free dialysate; therefore, the inclusion of glucose in the dialysate is believed to prevent intradialytic hypoglycemia. However, the exact glycemic fluctuation profiles and frequency of asymptomatic hypoglycemia using dialysates containing >100 mg/dL glucose have not been determined.

Research Design And Methods: We evaluated the glycemic profiles of 98 patients, 68 of whom were men, with type 2 diabetes undergoing HD (HbA 6.4 ± 1.2%; glycated albumin 20.8 ± 6.8%) with a dialysate containing 100, 125, or 150 mg/dL glucose using continuous glucose monitoring.

Results: Sensor glucose level (SGL) showed a sustained decrease during HD, irrespective of the dialysate glucose concentration, and reached a nadir that was lower than the dialysate glucose concentration in 49 participants (50%). Twenty-one participants (21%) presented with HD-related hypoglycemia, defined by an SGL <70 mg/dL during HD and/or between the end of HD and their next meal. All these hypoglycemic episodes were asymptomatic. Measures of glycemic variability calculated using the SGL data (SD, coefficient of variation, and range of SGL) were higher and time below range (<70 mg/dL) was lower in participants who experienced HD-related hypoglycemia than in those who did not, whereas time in range between 70 and 180 mg/dL, time above range (>180 mg/dL), HbA, and glycated albumin of the two groups were similar.

Conclusions: Despite the use of dialysate containing 100-150 mg/dL glucose, patients with diabetes undergoing HD experienced HD-related hypoglycemia unawareness frequently. SGL may fall well below the dialysate glucose concentration toward the end of HD.
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http://dx.doi.org/10.2337/dc21-0269DOI Listing
May 2021

A case of adrenocortical adenoma harboring venous thrombus mimicking adrenal malignancy.

Endocr J 2021 Jul 4;68(7):857-863. Epub 2021 Mar 4.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.

Advances in imaging technology and its widespread use have increased the number of identified patients with bilateral adrenal incidentalomas. The pathology of bilateral adrenal incidentalomas is gradually elucidated by its increased frequency. Although there is no consensus regarding the optimal management of bilateral adrenal lesions, adrenal lesions that are a suspected adrenocortical carcinoma on the basis of radiological imaging require surgical resection. We report a clinically interesting case of a 59-year-old female with adrenocortical adenoma harboring venous thrombus that mimicked adrenal malignancy. She was referred for evaluation of asymptomatic asymmetric lesions on both adrenal glands. Abdominal computed tomography and magnetic resonance imaging showed a 4.7-cm-diameter heterogenous lesion with peripheral enhancement in the right adrenal gland and a 2.0-cm-diameter homogenous lesion in the left adrenal gland. Adrenal scintigraphy with I-adosterol exhibited marked accumulation in the left lesion and slight accumulation in the middle inferior portion of the right lesion. Endocrine data revealed subclinical Cushing syndrome, and the patient underwent right laparoscopic adrenalectomy. The serum cortisol level was not suppressed on an overnight dexamethasone suppression test after the adrenalectomy. The resected tumor revealed a cortisol-producing adrenocortical adenoma harboring an organized and re-canalized venous thrombus, which was associated with focal papillary endothelial hyperplasia. This case illustrates the difficulty with preoperatively diagnosing this heterogeneously enhanced large benign adrenal lesion and differentiating it from adrenocortical carcinoma or angiosarcoma.
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http://dx.doi.org/10.1507/endocrj.EJ20-0667DOI Listing
July 2021

Circulating prorenin: its molecular forms and plasma concentrations.

Hypertens Res 2021 Jun 10;44(6):674-684. Epub 2021 Feb 10.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.

The renin-angiotensin-aldosterone system plays pivotal roles in the maintenance of fluid homeostasis and in the pathophysiology of major human diseases. However, the molecular forms of plasma renin/prorenin have not been fully elucidated, and measurements of plasma prorenin levels are still unavailable for clinical practice. We attempted to evaluate the molecular forms of human plasma prorenin and to directly measure its concentration without converting it to renin to determine its activity. Polyacrylamide gel electrophoresis and subsequent immunoblotting using antibodies that specifically recognise prosegment sequences were used to analyse its molecular forms in plasma. We also created a sandwich enzyme-linked immunosorbent assay suitable for directly quantifying the plasma concentration. The plasma level in healthy people was 3.0-13.4 μg/mL, which is from 3 to 4 orders of magnitude higher than the levels reported thus far. Plasma immunoreactive prorenin consists of three major distinct components: a posttranslationally modified full-length protein, an albumin-bound form and a smaller protein truncated at the common C-terminal renin/prorenin portion. In contrast to plasma renin activity, plasma prorenin concentrations were not affected by the postural changes of the donor. Hence, plasma prorenin molecules may be posttranslationally modified/processed or bound to albumin and are present in far higher concentrations than previously thought.
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http://dx.doi.org/10.1038/s41440-020-00610-0DOI Listing
June 2021

Suprabasin-derived bioactive peptides identified by plasma peptidomics.

Sci Rep 2021 01 13;11(1):1047. Epub 2021 Jan 13.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.

Identification of low-abundance, low-molecular-weight native peptides using non-tryptic plasma has long remained an unmet challenge, leaving potential bioactive/biomarker peptides undiscovered. We have succeeded in efficiently removing high-abundance plasma proteins to enrich and comprehensively identify low-molecular-weight native peptides using mass spectrometry. Native peptide sequences were chemically synthesized and subsequent functional analyses resulted in the discovery of three novel bioactive polypeptides derived from an epidermal differentiation marker protein, suprabasin. SBSN_HUMAN[279-295] potently suppressed food/water intake and induced locomotor activity when injected intraperitoneally, while SBSN_HUMAN[225-237] and SBSN_HUMAN[243-259] stimulated the expression of proinflammatory cytokines via activation of NF-κB signaling in vascular cells. SBSN_HUMAN[225-237] and SBSN_HUMAN[279-295] immunoreactivities were present in almost all human organs analyzed, while immunoreactive SBSN_HUMAN[243-259] was abundant in the liver and pancreas. Human macrophages expressed the three suprabasin-derived peptides. This study illustrates a new approach for discovering unknown bioactive peptides in plasma via the generation of peptide libraries using a novel peptidomic strategy.
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http://dx.doi.org/10.1038/s41598-020-79353-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806982PMC
January 2021

The effectiveness of growth hormone replacement on energy expenditure and body composition in patients with adult growth hormone deficiency.

Endocr J 2021 Apr 22;68(4):469-475. Epub 2020 Dec 22.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.

Numerous studies have shown that growth hormone (GH) replacement in adult GH deficiency (AGHD) improves the body composition and metabolic rate; however, data about the relationship between body composition and energy expenditure in these patients is scarce. Our study aimed to investigate the changes in resting energy expenditure (REE) and body composition after GH replacement in patients with AGHD. We enrolled 15 patients diagnosed with AGHD and evaluated the effect of GH replacement administered once daily for 12 months on REE, body composition measured by bioelectrical impedance analysis, and serological markers. GH replacement therapy significantly increased the serum insulin growth factor-1 levels after 4, 8, and 12 months. The REE and REE/basal energy expenditure (REE/BEE) ratio significantly increased from 1278.0 ± 490.0 kcal/day and 0.87 ± 0.23 at baseline to 1505.5 ± 449.2 kcal/day and 1.11 ± 0.21 at 4 months, 1,918.7 ± 631.2 kcal/day and 1.29 ± 0.27 at 8 months, and 1,511.1 ± 271.2 kcal/day, 1.14 ± 0.29 at 12 months (p < 0.005, p < 0.005; p < 0.01, p < 0.01; p < 0.01, p < 0.005, respectively). There was no change in the body weight, while the lean body mass increased significantly from 45.8 ± 9.5 kg at baseline to 46.9 ± 9.4 kg at 4 months and 47.5 ± 10.1 kg at 8 months (p < 0.005, p < 0.01, respectively). The fat mass also decreased at 12 months. Lipid metabolism improved after 4 and 8 months. GH replacement therapy in patients with AGHD significantly improved the REE and body composition.
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http://dx.doi.org/10.1507/endocrj.EJ20-0644DOI Listing
April 2021

Randomized study of prevention of gastrointestinal toxicities by nutritional support using an amino acid-rich elemental diet during chemotherapy in patients with esophageal cancer (KDOG 1101).

Esophagus 2021 Apr 3;18(2):296-305. Epub 2020 Oct 3.

Department of Gastroenterology, Kitasato University School of Medicine, 1-15-1 Kitasato Minami, Sagamihara, 252-0374, Japan.

Background: This randomized study was designed to evaluate the clinical effect of an elemental diet during chemotherapy in patients with esophageal cancer.

Methods: The inclusion criteria were as follows: (1) esophageal squamous cell carcinoma, (2) stage IB-IV, (3) schedule to receive docetaxel, cisplatin, and 5-fluorouracil (DCF chemotherapy), (4) 20-80 years old, (5) performance status of 0-2, (6) oral intake ability, and (7) written informed consent. Patients were divided into two groups: the elemental supplementary group and the non-supplementary group. Patients received ELENTAL (160 g/day) orally 9 weeks after the start of chemotherapy. Primary endpoint was the incidence of grade 2 or higher gastrointestinal toxicity according to the Common Terminology Criteria for Adverse Events, version 4.0. Secondary endpoints were the incidence of all adverse events and the evaluation of nutritional status.

Results: Thirty-six patients in the elemental supplementary group and 35 patients in the non-supplementary group were included in the analysis. The incidence of grade 2 or higher gastrointestinal toxicity and all grade 3 or 4 adverse events did not differ significantly between the groups. In the elemental supplementary group, the body weight (p = 0.057), muscle mass (p = 0.056), and blood levels of transferrin (p = 0.009), total amino acids (p = 0.019), and essential amino acids (p = 0.006) tended to be maintained after chemotherapy.

Conclusion: Nutritional support provided by an amino acid-rich elemental diet was ineffective for reducing the incidence of adverse events caused by DCF chemotherapy in patients with esophageal cancer.
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http://dx.doi.org/10.1007/s10388-020-00787-wDOI Listing
April 2021

Short-term Change in Resting Energy Expenditure and Body Compositions in Therapeutic Process for Graves' Disease.

Intern Med 2020 1;59(15):1827-1833. Epub 2020 Aug 1.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Japan.

Objective In the medical treatment of Graves' disease, we sometimes encounter patients who gain weight after the onset of the disease. To estimate the energy required during the course of treatment when hyperthyroidism ameliorates, we measured the resting energy expenditure (REE) and body composition in patients with Graves' disease before and during treatment in the short-term. Methods Twenty patients with newly diagnosed Graves' disease were enrolled, and our REE data of 19 healthy volunteers were used. The REE was measured by a metabolic analyzer, and the basal energy expenditure (BEE) was estimated by the Harris-Benedict formula. The body composition, including body weight, fat mass (FM), muscle mass (MM) and lean body mass (LBM), were measured by a multi-frequency body composition analyzer. We tailored the nutritional guidance based on the measured REE. Results Serum thyrotropin levels were significantly increased at three and six months. Serum free thyroxine, free triiodothyronine and REE values were significantly decreased at one, three and six months. The REE/BEE ratio was 1.58±0.28 at the onset and significantly declined to 1.34±0.34, 1.06±0.19 and 1.01±0.16 at 1, 3 and 6 months, respectively. Body weight, MM and LBM significantly increased at three and six months. Conclusion The REE significantly decreased during treatment of Graves' disease. The decline was evident as early as one month after treatment. The REE after treatment was lower than in healthy volunteers, which may lead to weight gain. These data suggest that appropriate nutritional guidance is necessary with short-term treatment before the body weight normalizes in order to prevent an overweight condition and the emergence of metabolic disorders.
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http://dx.doi.org/10.2169/internalmedicine.4462-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474983PMC
October 2020

Comparison of accuracy between flash glucose monitoring and continuous glucose monitoring in patients with type 2 diabetes mellitus undergoing hemodialysis.

J Diabetes Complications 2020 11 18;34(11):107680. Epub 2020 Jul 18.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa, Japan.

Introduction: We evaluated the accuracy and clinical utility of flash glucose monitoring (FGM) in comparison with continuous glucose monitoring (CGM) and self-monitoring blood glucose (SMBG) in patients with type 2 diabetes (T2D) undergoing hemodialysis (HD).

Methods: Simultaneous FGM (FreeStyle LibrePro), CGM (iPro2) and SMBG were performed on 13 T2D research subjects.

Results: There were good overall correlations between SMBG and FGM (64.7% and 30.8% within the A and B of Parkes Error Grid, respectively) and between SMBG and CGM (87.9% and 11.0% within the A and B, respectively). However, during HD, correlations between SMBG and FGM were only 49.7% and 37.2% within the A and B, respectively, while correlations of SMBG and CGM were 72.8% and 22.2% within the A and B, respectively. The percentage of FGM not in Zone A + B was more than 4 times higher than for CGM. The overall mean absolute relative difference (MARD) for FGM was 18.2%, this significantly higher than 11.2% for CGM. During HD, MARD for FGM was 22.8%, significantly higher than 15.0% for CGM.

Conclusion: FGM has good clinical agreement in T2D patients undergoing HD. However, the accuracy of FGM relative to SMBG was worse than that of CGM.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107680DOI Listing
November 2020

Use of Noncontact Infrared Skin Thermometer for Peripheral Arterial Disease Screening in Patients With and Without Diabetes.

Angiology 2020 08 22;71(7):650-657. Epub 2020 Apr 22.

The Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan.

Peripheral arterial disease (PAD) poses a threat of limb amputation and cardiovascular events. However, PAD diagnostic procedure requiring time, cost, and technical skills preclude its application as a screening test in the general population. Although PAD tends to be associated with lower foot skin temperature, none has yet to appreciate its usefulness for diagnosis/screening. We measured foot skin temperatures at the first and fifth metatarsal head and heel areas using noncontact infrared thermometer at the time of ankle brachial pressure index (ABI) measurement and limb arterial ultrasonography in 176 patients (345 legs) in participants. Foot skin temperatures correlated with ABI and showed distinctly lower levels in legs with ultrasound-confirmed arterial stenosis/occlusion and in those with ABI ≤0.90. Receiver operating characteristics analyses revealed that the lowest temperature value of the 3-foot locations had a higher sensitivity than every single location in detecting lower extremity PAD. Diagnostic efficiency for the ABI cutoff of 0.90 showed sensitivity/specificity of 41%/94%, while that for the lowest skin temperature cutoff of 30.8°C showed sensitivity/specificity of 60%/64%. In conclusion, an accurate skin temperature measurement using noncontact handheld infrared skin thermometer could serve as a new, cost-effective screening strategy for earlier diagnosis of PAD.
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http://dx.doi.org/10.1177/0003319720920162DOI Listing
August 2020

Oxidised Met of human serum albumin is a biomarker of oxidative stress, reflecting glycaemic fluctuations and hypoglycaemia in diabetes.

Sci Rep 2020 01 14;10(1):268. Epub 2020 Jan 14.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.

Oxidative stress has been linked to a number of chronic diseases, and this has aroused interest in the identification of clinical biomarkers that can accurately assess its severity. We used liquid chromatography-high resolution mass spectrometry (LC-MS) to show that oxidised and non-oxidised Met residues at position 147 of human serum albumin (Met) can be accurately and reproducibly quantified with stable isotope-labelled peptides. Met oxidation was significantly higher in patients with diabetes than in controls. Least square multivariate analysis revealed that glycated haemoglobin (HbA) and glycated albumin (GA) did not significantly influence Met oxidation, but the GA/HbA ratio, which reflects glycaemic excursions, independently affected Met oxidation status. Continuous glucose monitoring revealed that Met oxidation strongly correlates with the standard deviation of sensor glucose concentrations and the time spent with hypoglycaemia or hyperglycaemia each day. Thus, glycaemic variability and hypoglycaemia in diabetes may be associated with greater oxidation of Met. Renal function, high-density lipoprotein-cholesterol and serum bilirubin were also associated with the oxidation status of Met. In conclusion, the quantification of oxidised and non-oxidised Met in serum albumin using our LC-MS methodology could be used to assess the degree of intravascular oxidative stress induced by hypoglycaemia and glycaemic fluctuations in diabetes.
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http://dx.doi.org/10.1038/s41598-019-57095-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959251PMC
January 2020

Molecular form and concentration of serum α-macroglobulin in diabetes.

Sci Rep 2019 09 10;9(1):12927. Epub 2019 Sep 10.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.

α-Macroglobulin is a highly abundant serum protein involved in the development of atherosclerosis and cardiac hypertrophy. However, its circulating molecular form and exact concentrations in human health/diseases are not known. Blue native-polyacrylamide gel electrophoresis of human serum was used to confirm the native conformation of α-macroglobulin. We created an enzyme-linked immunosorbent assay suitable for quantifying its circulating molecular form and undertook a cross-sectional study to measure its serum levels in 248 patients with diabetes mellitus and 59 healthy volunteers. The predominant circulating molecular form of α-macroglobulin was the tetramer, whereas its dimer was detectable in patients with high serum levels of α-macroglobulin. The serum α-macroglobulin concentration was not associated with glycated hemoglobin or any other glycemic variable as evaluated from 48-h continuous glucose monitoring, but showed close correlation with left ventricular posterior wall thickness, carotid artery intima-media thickness, urinary albumin:creatinine ratio (ACR) and brachial-ankle pulse wave velocity (baPWV). Multivariate analysis revealed only the ACR and baPWV to be independent variables influencing serum levels of α-macroglobulin. Thus, an increased ACR and baPWV are associated with higher serum concentrations of α-macroglobulin, and the latter may contribute to the mechanism by which albuminuria increases the risk of developing cardiovascular diseases.
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http://dx.doi.org/10.1038/s41598-019-49144-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736885PMC
September 2019

Basal glucagon hypersecretion and response to oral glucose load in prediabetes and mild type 2 diabetes.

Endocr J 2019 Aug 28;66(8):663-675. Epub 2019 May 28.

Department of Diabetes, Endocrinology & Metabolism, Kitasato University, School of Medicine, Kanagawa 252-0374, Japan.

Dysregulation of glucagon secretion plays an important role in the pathogenesis of type 2 diabetes (T2DM). However it hasn't been elucidated involvement of glucagon dysregulation in pathophysiology of T2DM. Recently a new glucagon sandwich enzyme-linked immunosorbent assay (ELISA) became available that can measure plasma glucagon level with higher accuracy and simpler procedure than the conventional RIA method. We performed OGTT for adult subjects aged 20-69 years to define normal glucose tolerance (NGT, n = 25), borderline glucose intolerance (defined as pre-diabetes mellitus: preDM, n = 15), or diabetes mellitus (DM, n = 13), and we measured glucagon levels with this new ELISA method at fasting and during OGTT. Plasma glucose, insulin, glucagon and active GLP-1 were also measured. This study took place in diabetes outpatient clinic in Kitasato University Hospital and an affiliated outpatient clinic. PreDM and DM exhibited higher fasting plasma glucagon levels than NGT (34.4 ± 4.6 and 44.1 ± 5.0 vs. 20.6 ± 3.6 pg/mL), and statistical significance was observed between NGT and DM (p < 0.05). There was significant correlation between fasting glucagon level and indexes of insulin sensitivity. During OGTT, glucagon levels were less suppressed in DM and preDM than in NGT, whereas no apparent relationship was observed between glucagon and GLP-1 secretion. Significant positive correlation was observed between glucagon levels during OGTT and fasting TG. In conclusion, subjects with mild T2DM exhibited fasting hyperglucagonemia and insufficient suppression to oral glucose load compared to NGT subjects.
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http://dx.doi.org/10.1507/endocrj.EJ18-0372DOI Listing
August 2019

Identification of plasma binding proteins for glucose-dependent insulinotropic polypeptide.

Endocr J 2019 Jul 26;66(7):621-628. Epub 2019 Apr 26.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa, Japan.

Glucose-dependent insulinotropic polypeptide (GIP), secreted from enteroendocrine K cells, has potent insulin-releasing and extrapancreatic glucoregulatory activities. However, exogenous GIP has less potent biological effects compared with another incretin hormone, GLP-1, which limits its use for the treatment of type 2 diabetes. The fate and secretion of administered native GIP remain unclear. The aim of this study was to identify plasma binding proteins for human GIP. Fluorescent-labelled GIP was added to fresh human plasma and subjected to clear native polyacrylamide gel electrophoresis (CN-PAGE). Then fluorescent protein bands were in-gel trypsin-digested and subjected to liquid chromatography tandem-mass spectrometry (LC-MS/MS) analysis, revealing the presence of albumin, immunoglobulin G (IgG) and transferrin. In contrast to GIP, the binding of fluorescent GLP-1 and glucagon to plasma protein fractions were minimal. CN-PAGE analysis of synthetic GIP incubated with human serum albumin, purified IgG or transferrin, and subsequent western blot analysis revealed that GIP binds to each of these proteins. Taken together, these results indicate that GIP readily binds to albumin, IgG and transferrin, three plasma proteins highly abundant in the human peripheral circulation. Separation of protein complexes using CN-PAGE and the identification of in-gel digested proteins by LC-MS/MS analysis provide a promising strategy to identify plasma binding proteins for bioactive peptides.
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http://dx.doi.org/10.1507/endocrj.EJ18-0472DOI Listing
July 2019

Identification of the salusin-β receptor using proteoliposomes embedded with endogenous membrane proteins.

Sci Rep 2018 12 14;8(1):17865. Epub 2018 Dec 14.

Protosera Inc., 4-3-22 Nishinakajima, Yodogawa-ku, Osaka, 532-0011, Japan.

Although orphan G protein-coupled receptors (GPCRs) have been used as targets to discover unidentified natural ligands, increasing numbers of non-GPCRs have been found to mediate important biological functions. Bioinformatics of genome and cDNA resources predict putative bioactive peptides, demanding an alternative approach to efficiently unravel cell surface targets. In silico analysis of a full-length cDNA library previously allowed us to identify salusin-β, a parasympathomimetic/pro-atherosclerotic peptide with unique physicochemical properties. Here, we show that the β-chain of ATP synthase is a cell surface receptor for salusin-β by utilizing artificial liposomes embedded with endogenous membrane proteins directly transferred from animal tissues while retaining the ligand-binding capability. Conventional techniques using detergents identified a β-actin-profilin complex as membrane-associated salusin-β-binding proteins, but failed to identify the cell surface receptor. Since the α-chain of ATP synthase is a principal cell surface target for angiostatin, a potent endogenous angiogenesis inhibitor, we investigated whether salusin-β modulates angiogenesis. Salusin-β inhibited cell surface ATP synthase activity and prevented sarcoma cell-induced angiogenesis in an in vivo mouse air sac model. Therefore, salusin-β binds to membrane-bound ATP synthase and acts as an angiogenesis inhibitor. The current methodology allows the identification of novel cell surface targets, irrespective of the receptor structure.
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http://dx.doi.org/10.1038/s41598-018-35740-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294790PMC
December 2018

Effects of canagliflozin on body composition and hepatic fat content in type 2 diabetes patients with non-alcoholic fatty liver disease.

J Diabetes Investig 2019 Jul 4;10(4):1004-1011. Epub 2019 Jan 4.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa, Japan.

Aims/introduction: Non-alcoholic fatty liver disease is frequently associated with type 2 diabetes, and constitutes an important risk factor for the development of hepatic fibrosis and hepatocellular carcinoma. Because there remains no effective drug therapy for non-alcoholic fatty liver disease associated with type 2 diabetes, we evaluated the efficacy of sodium-glucose cotransporter 2 inhibitor.

Methods And Materials: In the present pilot, prospective, non-randomized, open-label, single-arm study, we evaluated the effect of 100 mg canagliflozin administered once daily for 12 months on serological markers, body composition measured by bioelectrical impedance analysis method and hepatic fat fraction measured by magnetic resonance imaging in type 2 diabetes patients with non-alcoholic fatty liver disease.

Results: Canagliflozin significantly reduced body and fat mass, and induced a slight decrease in lean body or muscle mass that did not reach significance at 6 and 12 months. Reductions in fat mass in each body segment (trunk, arms and legs) were evident, whereas those in lean body mass were not. The hepatic fat fraction was reduced from a baseline of 17.6 ± 7.5% to 12.0 ± 4.6% after 6 months and 12.1 ± 6.1% after 12 months (P < 0.0005 and P < 0.005), whereas serum liver enzymes and type IV collagen concentrations improved. From a mean baseline hemoglobin A1c of 8.7 ± 1.4%, canagliflozin significantly reduced hemoglobin A1c after 6 and 12 months to 7.3 ± 0.6% and 7.7 ± 0.7% (P < 0.0005 and P < 0.01).

Conclusions: Canagliflozin reduced body mass, fat mass and hepatic fat content without significantly reducing muscle mass.
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http://dx.doi.org/10.1111/jdi.12980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626966PMC
July 2019

Tolvaptan alleviates excessive fluid retention of nephrotic diabetic renal failure unresponsive to furosemide.

Nephrology (Carlton) 2018 Sep;23(9):883-886

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Sagamihara, Japan.

Patients with diabetic nephropathy develop nephrotic syndrome and may show limited response to conventional therapy. They often require earlier initiation of renal replacement therapy because they become refractory to diuretics, and experience excessive fluid retention. We aimed to investigate the efficacy of tolvaptan, an oral arginine vasopressin type 2 receptor antagonist, in a case series of 14 severe diabetic renal failure patients who were severely refractory to maximal doses of furosemide and had excessive fluid retention despite preserved cardiac function and residual renal function. All 14 patients experienced immediate and sustained water diuretic effects, resulting in alleviation of congestive heart failure. None required initiation of renal replacement therapy. Tolvaptan promptly increased urine volume and free water clearance, reversed progressive fluid retention, and alleviated congestive heart failure. Thus, tolvaptan could serve as a potential adjunct therapy for severe diabetic renal failure patients with excessive fluid retention and congestive heart failure.
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http://dx.doi.org/10.1111/nep.13390DOI Listing
September 2018

Identification and quantification of plasma free salusin-β, an endogenous parasympathomimetic peptide.

Sci Rep 2017 08 15;7(1):8275. Epub 2017 Aug 15.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.

Salusin-β is an endogenous parasympathomimetic proatherosclerotic peptide. Salusin-β was initially predicted from bioinformatic analyses and later immunologically detected in human biofluids. However, elucidation of salusin-β bioactivity has faced enormous challenges because of its unique physicochemical characteristics that cause it to strongly adhere to laboratory apparatus materials. In the strictest sense, the discovery of bioactive peptides is not complete until their exact native sequences have been confirmed in the peripheral circulation. In this study, we determined the plasma molecular form and levels of free salusin-β to determine its pathophysiological significance. Ultra-high-yield enrichment and preseparation of non-tryptic human plasma was followed by LC-MS/MS, and full-length salusin-β and seven different endogenous fragment sequences were identified. We established a new ELISA that specifically detects plasma free salusin-β without cross-reacting with any of its identified endogenous fragments. Free salusin-β levels exhibited a profound early morning nadir and rapidly decreased in response to parasympathetic nervous augmentation. Our technical advance in plasma native peptide analysis successfully identified a hard-to-detect bioactive peptide, salusin-β, together with its formerly unrecognized fragments, and further suggests that conventional immunological measurements of target peptides may not be fully representative.
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http://dx.doi.org/10.1038/s41598-017-08288-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557946PMC
August 2017

Methionine sulfoxides in serum proteins as potential clinical biomarkers of oxidative stress.

Sci Rep 2016 12 8;6:38299. Epub 2016 Dec 8.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan.

Oxidative stress contributes to the pathophysiology of a variety of diseases, and circulating biomarkers of its severity remains a topic of great interest for researchers. Our peptidomic strategy enables accurate and reproducible analysis of circulating proteins/peptides with or without post-translational modifications. Conventional wisdom holds that hydrophobic methionines exposed to an aqueous environment or experimental handling procedures are vulnerable to oxidation. However, we show that the mass spectra intensity ratio of oxidized to non-oxidized methionine residues in serum tryptic proteins can be accurately quantified using a single drop of human serum and give stable and reproducible results. Our data demonstrate that two methionine residues in serum albumin (Met-111 and Met-147) are highly oxidized to methionine sulfoxide in patients with diabetes and renal failure and in healthy smokers versus non-smoker controls. This label-free mass spectrometry approach to quantify redox changes in methionine residues should facilitate the identification of additional circulating biomarkers suitable for predicting the development or progression of human diseases.
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http://dx.doi.org/10.1038/srep38299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144094PMC
December 2016

Distinct biomarker roles for HbA and glycated albumin in patients with type 2 diabetes on hemodialysis.

J Diabetes Complications 2016 Nov - Dec;30(8):1494-1499. Epub 2016 Aug 24.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa, Japan.

Aims: HbA and glycated albumin (GA) are used to monitor glycemia, but their accuracy to represent glycemic profiles in hemodialysis remains controversial.

Methods: Continuous glucose monitoring in 97 patients with type 2 diabetes (41 on hemodialysis [HD] and 56 without nephropathy) was analyzed to evaluate whether HbA and/or GA serve as appropriate glycemic profile markers.

Results: The average glucose significantly correlated with HbA in both HD group and group without nephropathy (r=0.59, P<0.0001; r=0.40, P<0.005). The slopes of linear regression lines were statistically indistinguishable (F=0.30, P=0.744), while the y-intercepts were significantly different (F=57.86, P<0.0001). GA showed strong correlation with the glycemic standard deviation (r=0.68, P<0.0001), and with the average glucose (r=0.42, P<0.001). Least square analysis revealed that only HbA, but not GA, was significantly associated with the average glucose (F=10.20, P<0.0005; F=0.38, P=0.5427), while only GA was significantly associated with the glycemic variability in HD group.

Conclusions: In HD participants, HbA correlates with the average glucose more than GA, but underestimates it, and a correction formula of HbA1c can be developed as an appreciable marker. GA value itself reflects the average glucose, but less accurately than HbA, while it could serve as an indicator for hyperglycemia/hypoglycemia excursion.
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http://dx.doi.org/10.1016/j.jdiacomp.2016.08.015DOI Listing
March 2018

Distinct clinical characteristics and therapeutic modalities for diabetic ketoacidosis in type 1 and type 2 diabetes mellitus.

J Diabetes Complications 2017 Feb 29;31(2):468-472. Epub 2016 Jun 29.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Sagamihara, Kanagawa, 252-0374, Japan.

Aims: Patients with type 1 diabetes often develop diabetic ketoacidosis (DKA). Reportedly, DKA in type 2 diabetes has higher mortality despite its limited occurrence. The exact clinical characteristics and therapeutic modalities yielding successful outcomes in DKA type 2 diabetes remain unknown.

Methods: This retrospective study compared the clinical features and detailed treatment of consecutive type 1 and type 2 diabetes patients hospitalized with DKA between January 2001 and December 2014.

Results: We report on 127 patients with type 1 and 74 patients with type 2 diabetes whose DKA was successfully treated. The most frequent precipitating cause for DKA was infectious disease for patients with type 1 diabetes and consumption of sugar-containing beverages for those with type 2 diabetes. Type 2 diabetes patients showed higher mean plasma glucose levels than those with type 1 diabetes (48.4±21.6, vs. 37.1±16.4mmol/l, P<0.01) and higher serum creatinine, blood urea nitrogen, and hemoglobin levels, which normalized after DKA resolution. Compared with type 1 diabetes patients, those with type 2 diabetes required distinctly higher daily total insulin dosage (35.9±37.0U, vs. 20.2±23.3U, P<0.01), larger replacement fluid volumes (4.17±2.69L, vs. 2.29±1.57L, P<0.01) and greater potassium supplementation (23.9±36.5mEq, vs. 11.2±17.9mEq, P<0.01) to resolve DKA and reduce plasma glucose level to ≤16.7mmol/l.

Conclusions: DKA patients with type 2 diabetes required management with a modified treatment protocol to resolve their profound hyperglycemia and dehydration compared with those with type 1 diabetes.
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http://dx.doi.org/10.1016/j.jdiacomp.2016.06.023DOI Listing
February 2017

Contrasting effects of stanniocalcin-related polypeptides on macrophage foam cell formation and vascular smooth muscle cell migration.

Peptides 2016 08 21;82:120-127. Epub 2016 Jun 21.

Laboratory of Cardiovascular Medicine, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan. Electronic address:

Stanniocalcin (STC) is a calcium- and phosphate-regulating hormone secreted by the corpuscles of Stannius, an endocrine gland of bony fish. Its human homologues, STC1 and STC2 showing 34% amino acid identity each other, are expressed in a variety of human tissues. To clarify their roles in atherosclerosis, we investigated the effects of their full-length proteins, STC1(18-247) and STC2(25-302), and STC2-derived fragment peptides, STC2(80-100) and STC2(85-99), on inflammatory responses in human umbilical vein endothelial cells (HUVECs), human macrophage foam cell formation, the migration and proliferation of human aortic smooth muscle cells (HASMCs) and the extracellular matrix expression. All these polypeptides suppressed lipopolysaccharide-induced expressions of interleukin-6, monocyte chemotactic protein-1, and intercellular adhesion molecule-1 in HUVECs. Oxidized low-density lipoprotein-induced foam cell formation was significantly decreased by STC1(18-247) and increased by STC2(80-100) and STC2(85-99), but not STC2(25-302), in human macrophages. Expression of acyl-CoA:cholesterol acyltransferase-1 (ACAT1) was significantly suppressed by STC1(18-247) but stimulated by STC2(80-100) and STC2(85-99). Expression of ATP-binding cassette transporter A1 was significantly stimulated by STC1(18-247). Neither STC1(18-247) nor STC2-derived peptides significantly affected CD36 expression in human macrophages or HASMC proliferation. STC2(80-100) and STC2(85-99) significantly increased HASMC migration, whereas STC1(18-247) significantly suppressed the angiotensin II-induced HASMC migration. Expressions of collagen-1, fibronectin, matrix metalloproteinase-2, and elastin were mostly unchanged with the exception of fibronectin up-regulation by STC2(80-100). Our results demonstrated the contrasting effects of STC1 and STC2-derived peptides on human macrophage foam cell formation associated with ACAT1 expression and on HASMC migration. Thus, STC-related polypeptides could serve as a novel therapeutic target for atherosclerosis.
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http://dx.doi.org/10.1016/j.peptides.2016.06.009DOI Listing
August 2016

Levels of albuminuria and risk of developing macroalbuminuria in type 2 diabetes: historical cohort study.

Sci Rep 2016 05 23;6:26380. Epub 2016 May 23.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.

Although increased urinary albumin excretion may increase the risk of adverse renal outcomes in patients with diabetes, it remains unclear whether microalbuminuria is associated with a higher incidence of macroalbuminuria in the absence of non-diabetic kidney events that frequently develop during the long-term course of type 2 diabetes. This historical cohort study included patients with type 2 diabetes, spot urine albumin:creatinine ratio (ACR) <300 mg/gCr and normal serum creatinine concentrations treated between August 1988 and April 2015. Patients with any evidence suggesting non-diabetic kidney diseases at baseline were excluded. Over a median follow-up of 50 months, 70 of the 1760 included patients developed macroalbuminuria. Twenty-one of these patients were diagnosed with non-diabetic renal events. The five-year cumulative incidence of macroalbuminuria in patients with ACRs of 0-7.5 mg/gCr, 7.5-30 mg/gCr, 30-150 mg/gCr, and 150-300 mg/gCr were 0%, 0.53%, 3.5%, and 36.0%, respectively, with significant differences between each pair of ACR categories. In type 2 diabetes, higher urinary ACR, even within a level of normoalbuminuria, was associated with a greater incidence of macroalbuminuria when non-diabetic renal events were excluded. These results conflict with findings suggesting that microalbuminuria is a poor indicator for the progression of diabetic nephropathy.
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http://dx.doi.org/10.1038/srep26380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876475PMC
May 2016

Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages.

Am J Pathol 2016 06 13;186(6):1481-98. Epub 2016 Apr 13.

Department of Pharmacology, Kitasato University School of Medicine, Kanagawa, Japan. Electronic address:

The persistence of proinflammatory macrophages, which are recruited to the granulation tissue, impairs the healing of diabetic wounds. Herein, we examined the role of vascular endothelial growth factor receptor type 1 (VEGFR1) signaling in streptozotocin (STZ)-induced diabetic wound healing. Angiogenesis, lymphangiogenesis, and the healing of full-thickness skin wounds were impaired in STZ-treated wild-type (WT) mice compared with vehicle-treated WT mice, with attenuated recruitment of VEGFR1-positive macrophages expressing vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D to the wound granulation tissue. These phenomena were even more prevalent in STZ-treated VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK(-/-) mice). STZ-treated WT mice, but not STZ-treated VEGFR1 TK(-/-) mice, showed accelerated wound healing when treated with placenta growth factor. Compared with that of STZ-treated WT mice, the wound granulation tissue of STZ-treated VEGFR1 TK(-/-) mice contained more VEGFR1-positive cells expressing IL-1β [a classic (M1) activated macrophage marker] and fewer VEGFR1-positive cells expressing the mannose receptor [CD206; an alternatively activated (M2) macrophage marker]. Treatment of STZ-treated VEGFR1 TK(-/-) mice with an IL-1β-neutralizing antibody restored impaired wound healing and angiogenesis/lymphangiogenesis and induced macrophages in the wound granulation tissue to switch to an M2 phenotype. Taken together, these results suggest that VEGFR1 signaling plays a role in regulating the balance between macrophage phenotypes in STZ-induced diabetic wounds, prevents impaired diabetic wound healing, and promotes angiogenesis/lymphangiogenesis.
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http://dx.doi.org/10.1016/j.ajpath.2016.02.014DOI Listing
June 2016

Salusin-β as a powerful endogenous antidipsogenic neuropeptide.

Sci Rep 2016 Feb 12;6:20988. Epub 2016 Feb 12.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.

Salusin-β is an endogenous parasympathomimetic peptide, predominantly localized to the hypothalamus and posterior pituitary. Subcutaneously administered salusin-β (50 nmol/mouse) significantly increased water intake but did not affect locomotor activity or food intake. The salusin-β-induced increase in water intake was completely abrogated by pretreatment with muscarinic antagonist, atropine sulphate. In contrast, intracerebroventricular injection of salusin-β, at lower doses (10-100 fmol/mouse) caused a long-lasting decrease in water intake and locomotor activity throughout the entire dark phase of the diurnal cycle. Pre-injection of intracerebroventricular anti-salusin-β IgG completely abrogated the central salusin-β mediated suppression of water intake and locomotor activity. These results demonstrate contrasting actions of salusin-β in the control of water intake via the central and peripheral systems and highlight it as a potent endogenous antidipsogenic neuropeptide.
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http://dx.doi.org/10.1038/srep20988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4751483PMC
February 2016

SGLT2 inhibitors provide an effective therapeutic option for diabetes complicated with insulin antibodies.

Endocr J 2016 7;63(2):187-91. Epub 2015 Nov 7.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa 252-0374, Japan.

Diabetes mellitus complicated with insulin antibodies is rare in clinical practice but usually difficult to control. A high amount of insulin antibodies, especially with low affinity and high binding capacity, leads to unstable glycemic control characterized by hyperglycemia unresponsive to large volume of insulin and unanticipated hypoglycemia. There are several treatment options, such as changing insulin preparation, immunosupression with glucocorticoids, and plasmapheresis, most of which are of limited efficacy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of drug which decrease renal glucose reabsorption and lowers plasma glucose level independent of insulin action. We report here a case with diabetes complicated with insulin antibodies who was effectively controlled by an SGLT2 inhibitor. A 47-year-old man with type 2 diabetes treated with insulin had very poor glycemic control characterized by postprandial hyperglycemia unresponsive to insulin therapy and repetitive hypoglycemia due to insulin antibodies. Treatment with ipragliflozin, an SGLT2 inhibitor, improved HbA1c from 8.4% to 6.0% and glycated albumin from 29.4% to 17.9%. Continuous glucose monitoring revealed improvement of glycemic profile (average glucose level from 212 mg/dL to 99 mg/dL and glycemic standard deviation from 92 mg/dL to 14 mg/dL) with disappearance of hypoglycemic events. This treatment further ameliorated the characteristics of insulin antibodies and resulted in reduced insulin requirement. SGLT2 inhibitors may offer an effective treatment option for managing the poor glycemic control in diabetes complicated with insulin antibodies.
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http://dx.doi.org/10.1507/endocrj.EJ15-0523DOI Listing
December 2016

Regulation of growth hormone secretion by (pro)renin receptor.

Sci Rep 2015 Jun 3;5:10878. Epub 2015 Jun 3.

Department of Endocrinology, Diabetes and Metabolism, Kitasato University School of Medicine, Kanagawa, Japan.

(Pro)renin receptor (PRR) has a single transmembrane domain that co-purifies with the vacuolar H(+)-ATPase (V-ATPase). In addition to its role in cellular acidification, V-ATPase has been implicated in membrane fusion and exocytosis via its Vo domain. Results from the present study show that PRR is expressed in pituitary adenoma cells and regulates growth hormone (GH) release via V-ATPase-induced cellular acidification. Positive PRR immunoreactivity was detected more often in surgically resected, growth hormone-producing adenomas (GHomas) than in nonfunctional pituitary adenomas. GHomas strongly expressing PRR showed excess GH secretion, as evidenced by distinctly high plasma GH and insulin-like growth factor-1 levels, as well as an elevated nadir GH in response to the oral glucose tolerance test. Suppression of PRR expression in rat GHoma-derived GH3 cells using PRR siRNA resulted in reduced GH secretion and significantly enhanced intracellular GH accumulation. GH3 treatment with bafilomycin A1, a V-ATPase inhibitor, also blocked GH release, indicating mediation via impaired cellular acidification of V-ATPase. PRR knockdown decreased Atp6l, a subunit of the Vo domain that destabilizes V-ATPase assembly, increased intracellular GH, and decreased GH release. To our knowledge, this is the first report demonstrating a pivotal role for PRR in a pituitary hormone release mechanism.
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http://dx.doi.org/10.1038/srep10878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454151PMC
June 2015

A very rare case of primary meningococcal arthritis in an adult male.

Clin Case Rep 2015 Feb 6;3(2):76-80. Epub 2014 Oct 6.

Kitasato Institute for Life Sciences and Laboratory for Antimicrobial Agents, Kitasato University 1-15-1 Kitasato, Sagamihara, Kanagawa, 252-0373, Japan.

We report here a very rare case of primary meningococcal arthritis of the knee joint without clinical features associated with meningococcemia, meningitis, or meningococcal complications. The patient suffered from diabetes mellitus and had experienced two episodes of joint trauma. Intravenous infusion of ampicillin/sulbactam for 18 consecutive days was successful.
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http://dx.doi.org/10.1002/ccr3.151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352356PMC
February 2015

Suppressed recruitment of alternatively activated macrophages reduces TGF-β1 and impairs wound healing in streptozotocin-induced diabetic mice.

Biomed Pharmacother 2015 Mar 31;70:317-25. Epub 2014 Oct 31.

Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan. Electronic address:

Background: Diabetes mellitus inhibits wound-induced angiogenesis, impairing the wound healing process and leading to the development of chronic wounds. Impaired healing of diabetic wounds is caused by persistent pro-inflammatory macrophages recruited to the granulation tissue; however, little is known about the phenotype of the macrophages involved in diabetic wound healing. The present study was conducted to examine the involvement of macrophages in impaired wound healing using streptozotocin (STZ)-induced diabetic mice.

Methods: Full-thickness skin wounds were created on the backs of mice treated with STZ or vehicle.

Results: Compared with controls, wound healing and angiogenesis were suppressed in STZ-treated mice, with attenuated expression of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-2 in wound granulation tissue. STZ-treated mice exhibited enhanced recruitment of classically activated macrophages (M1) expressing inducible nitric oxide synthase (iNOS) and suppressed recruitment of alternatively activated macrophages (M2) expressing transforming growth factor-beta-1 (TGF-β1). Treatment of diabetic mice with TGF-β1 restored wound healing and angiogenesis and normalized M1/M2 macrophage polarization in the granulation tissue.

Conclusions: These results suggest that an imbalance of macrophage phenotypes contributes to impaired wound healing in STZ-induced diabetic mice, and treatment with cytokines derived from M2 macrophages may be an effective therapeutic strategy to increase angiogenesis and promote healing of diabetic wounds.
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http://dx.doi.org/10.1016/j.biopha.2014.10.020DOI Listing
March 2015

Downregulation of the proangiogenic prostaglandin E receptor EP3 and reduced angiogenesis in a mouse model of diabetes mellitus.

Biomed Pharmacother 2014 Oct 31;68(8):1125-33. Epub 2014 Oct 31.

Department of Pharmacology, Kitasato University School of Medicine, Kanagawa 252-0374, Japan. Electronic address:

Vascular complications such as foot ulcers are a hallmark of diabetes mellitus (DM), although the molecular mechanisms that underlie vascular dysfunction remain unclear. Herein, we show that angiogenesis, which is indispensable to the healing of ulcers, is suppressed in polyurethane sponge implants in mice with DM and reduced proangiogenic signaling. DM was induced in male C57BL/6 mice by intraperitoneal injection of streptozotocin (100mg/kg). Polyurethane sponge disks were implanted into subcutaneous tissues on the backs of mice, and angiogenesis and expression of related factors were analyzed in sponge granulation tissues. Densities of platelet endothelial cell adhesion molecule-1 (PECAM-1)-positive vascular structures and PECAM-1 expression in sponge granulation tissues were increased over time in control mice and reduced in diabetic mice. The reductions in diabetic mice were accompanied by reduced expression of inducible cyclo-oxygenase-2 and microsomal prostaglandin E synthase-1. The prostaglandin E receptor subtype EP3 was downregulated in sponge granulation tissues in diabetic mice, whereas EP1, EP2, and EP4 were not. The expression of the proangiogenic growth factor vascular endothelial growth factor (VEGF)-A and the chemokine stromal cell-derived factor-1 (SDF-1) were both reduced in diabetic mice. Treatment of diabetic mice with a selective agonist of EP3, ONO-AE 248 (30 nmol/site/day, topical injection), reversed suppression of angiogenesis in diabetic mice. These results indicate that proangiogenic EP3 signaling is suppressed in diabetic mice with reduced expression of VEGF and SDF-1. Stimulation of EP3 signaling restored angiogenesis in a sponge implant model in mice with DM. This suggests that topical application of an EP3 agonist could be a novel strategy to treat foot ulcers in patients with DM.
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http://dx.doi.org/10.1016/j.biopha.2014.10.022DOI Listing
October 2014
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