Publications by authors named "Yasushi Fukushima"

45 Publications

Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial.

Lancet Diabetes Endocrinol 2021 09 21;9(9):563-574. Epub 2021 Jul 21.

Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

Background: Semaglutide is an effective treatment for type 2 diabetes; however, 20-30% of patients given semaglutide 1·0 mg do not reach glycaemic treatment goals. We aimed to investigate the efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in adults with inadequately controlled type 2 diabetes on a stable dose of metformin with or without a sulfonylurea.

Methods: We did a 40-week, randomised, active-controlled, parallel-group, double-blind, phase 3B trial (SUSTAIN FORTE) at 125 outpatient clinics in ten countries. Participants (≥18 years) with inadequately controlled type 2 diabetes (HbA 8·0-10·0%) with metformin and with or without sulfonylurea were randomly assigned (1:1) by an interactive web-response system to 2·0 mg or 1·0 mg once-weekly semaglutide. Participants, site personnel, the clinical study group, and investigators were masked to the randomised treatment. Outcomes included change from baseline at week 40 in HbA (primary outcome) and bodyweight (secondary confirmatory outcome), evaluated through trial product estimand (no treatment discontinuation or without rescue medication) and treatment policy estimand (regardless of treatment discontinuation or rescue medication) strategies. This study is registered with ClinicalTrials.gov, NCT03989232; EudraCT, 2018-004529-96; and WHO, U1111-1224-5162.

Findings: Between June 19 and Nov 28, 2019, of 1515 adults assessed for eligibility, 961 participants (mean age 58·0 years [SD 10·0]; 398 [41%] women) were included. Participants were randomly assigned to once-weekly semaglutide 2·0 mg (n=480 [50%]) or 1·0 mg (n=481 [50%]); 462 (96%) patients in the semaglutide 2·0 mg group and 471 (98%) in the semaglutide 1·0 mg group completed the trial. Mean baseline HbA was 8·9% (SD 0·6; 73·3 mmol/mol [SD 6·9]) and BMI was 34·6 kg/m (SD 7·0). Mean change in HbA from baseline at week 40 was -2·2 percentage points with semaglutide 2·0 mg and -1·9 percentage points with semaglutide 1·0 mg (estimated treatment difference [ETD] -0·23 percentage points [95% CI -0·36 to -0·11]; p=0·0003; trial product estimand) and -2·1 percentage points with semaglutide 2·0 mg and -1·9 percentage points with semaglutide 1·0 mg (ETD -0·18 percentage points [-0·31 to -0·04]; p=0·0098; treatment policy estimand). Mean change in bodyweight from baseline at week 40 was -6·9 kg with semaglutide 2·0 mg and -6·0 kg with semaglutide 1·0 mg (ETD -0·93 kg [95% CI -1·68 to -0·18]; p=0·015; trial product estimand) and -6·4 kg with semaglutide 2·0 mg and -5·6 kg with semaglutide 1·0 mg (ETD -0·77 kg [-1·55 to 0·01]; p=0·054; treatment policy estimand). Gastrointestinal disorders were the most commonly reported adverse events (163 [34%] in the 2·0 mg group and 148 [31%] in the 1·0 mg group). Serious adverse events were similar between treatment groups, reported for 21 (4%) participants given semaglutide 2·0 mg and 25 (5%) participants given semaglutide 1·0 mg. Three deaths were reported during the trial (one in the semaglutide 1·0 mg group and two in the semaglutide 2·0 mg group).

Interpretation: Semaglutide 2·0 mg was superior to 1·0 mg in reducing HbA, with additional bodyweight loss and a similar safety profile. This higher dose provides a treatment intensification option for patients with type 2 diabetes treated with semaglutide in need of additional glycaemic control.

Funding: Novo Nordisk.
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http://dx.doi.org/10.1016/S2213-8587(21)00174-1DOI Listing
September 2021

Long-Term Safety and Efficacy of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Japanese Patients with COPD.

Int J Chron Obstruct Pulmon Dis 2019 23;14:2993-3002. Epub 2019 Dec 23.

AstraZeneca, Durham, NC, USA.

Background: Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) is a triple fixed-dose combination for COPD. The long-term safety of triple therapy for COPD has not been investigated in Japanese patients. In this 28-week extension study (NCT03262012), we investigated the long-term safety and tolerability of BGF MDI in Japanese patients with moderate-to-very severe COPD who completed the 24-week Phase III randomized, double-blind, multicenter KRONOS study (NCT02497001).

Materials And Methods: Patients randomized to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily in KRONOS continued treatment for up to 28 additional weeks. Safety was evaluated over 52 weeks via adverse event (AE) monitoring, electrocardiograms, clinical laboratory testing, and vital sign measurements.

Results: The safety population included 416 patients who received BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Treatment-emergent AE (TEAE) rates were similar across treatment groups (range: 82.6-82.9%). The most frequent TEAEs overall were nasopharyngitis (32.2%) and bronchitis (9.9%). The incidence of major adverse cardiovascular events was low across groups (range: 0.0-2.9%). Over 52 weeks, the incidence of confirmed pneumonia was 9.4% (BGF MDI), 3.6% (GFF MDI), 5.7% (BFF MDI), and 2.9% (BUD/FORM DPI); in the 28-week extension period, rates were comparable across groups (range: 2.9-5.7%). Six deaths were reported (0.7-2.2% per group); none were considered treatment-related. No clinically meaningful trends were observed in electrocardiograms, laboratory parameters, or vital signs over time in any of the treatment groups.

Conclusion: All treatments were well tolerated over 52 weeks, and the safety profile of BGF MDI was generally comparable to dual long-acting muscarinic antagonist (LAMA)/long-acting β-agonist (LABA) and inhaled corticosteroid (ICS)/LABA therapies. These findings support the long-term tolerability of BGF MDI in Japanese patients with COPD.
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http://dx.doi.org/10.2147/COPD.S220861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934178PMC
July 2020

Efficacy and Safety of Budesonide/Glycopyrrolate/Formoterol Fumarate Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Japanese Patients with COPD: A Subgroup Analysis of the KRONOS Study.

Int J Chron Obstruct Pulmon Dis 2019 23;14:2979-2991. Epub 2019 Dec 23.

AstraZeneca, Morristown, NJ, USA.

Background: KRONOS, a Phase III, multicenter, randomized, double-blind study (NCT02497001) conducted in Canada, China, Japan, and the USA, assessed the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), a triple fixed-dose combination therapy, relative to dual therapies in patients with moderate-to-very severe COPD. Here we present findings from the Japanese subgroup of KRONOS.

Methods: Patients received BGF MDI 320/18/9.6μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12μg twice-daily for 24 weeks. The primary endpoint was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV) over Weeks 12-24. Symptoms, quality of life, exacerbations, and safety were also assessed.

Results: In total, 416 Japanese patients (21.9% of the global KRONOS population) were randomized and treated with BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Nominally significant improvements in the change from baseline in morning pre-dose trough FEV over Weeks 12-24 were observed for BGF MDI vs GFF MDI (least squares mean [LSM] difference 37 mL, 95% confidence interval [CI] 3, 72; =0.0337) and BFF MDI (67 mL; 95% CI 25, 109; =0.0020). Treatment with BGF MDI led to a nominally significant reduction in the rate of moderate/severe exacerbations vs GFF MDI (rate ratio 0.40, 95% CI 0.19, 0.83; =0.0142). Compared with dual therapies, numerical improvements were observed with BGF MDI for Transition Dyspnea Index focal score and the change from baseline in Evaluating Respiratory Symptoms in COPD total score (≤0.3899). All treatments were generally well tolerated.

Conclusion: BGF MDI nominally significantly improved lung function and numerically improved symptoms vs GFF MDI and BFF MDI. BGF MDI nominally significantly reduced exacerbations vs GFF MDI in Japanese patients with COPD. Efficacy and safety findings were generally comparable to those in the global KRONOS population.
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http://dx.doi.org/10.2147/COPD.S220850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939402PMC
July 2020

Clinical Efficacy of Telemedicine Compared to Face-to-Face Clinic Visits for Smoking Cessation: Multicenter Open-Label Randomized Controlled Noninferiority Trial.

J Med Internet Res 2019 04 26;21(4):e13520. Epub 2019 Apr 26.

CureApp Institute, Karuizawa, Japan.

Background: Tobacco is a major public health concern. A 12-week standard smoking cessation program is available in Japan; however, it requires face-to-face clinic visits, which has been one of the key obstacles to completing the program, leading to a low smoking cessation success rate. Telemedicine using internet-based video counseling instead of regular clinic visits could address this obstacle.

Objective: This study aimed to evaluate the efficacy and feasibility of an internet-based remote smoking cessation support program compared with the standard face-to-face clinical visit program among patients with nicotine dependence.

Methods: This study was a randomized, controlled, open-label, multicenter, noninferiority trial. We recruited nicotine-dependent adults from March to June 2018. Participants randomized to the telemedicine arm received internet-based video counseling, whereas control participants received standard face-to-face clinic visits at each time point in the smoking cessation program. Both arms received a CureApp Smoking Cessation smartphone app with a mobile exhaled carbon monoxide checker. The primary outcome was a continuous abstinence rate (CAR) from weeks 9 to 12. Full analysis set was used for data analysis.

Results: We randomized 115 participants with nicotine dependence: 58 were allocated to the telemedicine (internet-based video counseling) arm and 57, to the control (standard face-to-face clinical visit) arm. We analyzed all 115 participants for the primary outcome. Both telemedicine and control groups had similar CARs from weeks 9 to 12 (81.0% vs 78.9%; absolute difference, 2.1%; 95% CI -12.8 to 17.0), and the lower limit of the difference between groups (-12.8%) was greater than the prespecified limit (-15%).

Conclusions: The application of telemedicine using internet-based video counseling as a smoking cessation program had a similar CAR from weeks 9 to 12 as that of the standard face-to-face clinical visit program. The efficacy of the telemedicine-based smoking cessation program was not inferior to that of the standard visit-based smoking cessation program.

Trial Registration: University Hospital Medical Information Network Clinical Trials Registry: UMIN000031620; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000035975.
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http://dx.doi.org/10.2196/13520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660118PMC
April 2019

Randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of three doses of co-suspension delivery technology glycopyrronium MDI in Japanese patients with moderate-to-severe COPD.

Int J Chron Obstruct Pulmon Dis 2018;13:1187-1194. Epub 2018 Apr 13.

Pearl - a member of the AstraZeneca Group, Morristown, NJ, USA.

Purpose: Due to the burden of COPD in Japan, new pharmacologic treatments are needed to meet patient requirements. This study assessed the efficacy and safety of glycopyrronium (GP) delivered via metered dose inhaler (MDI) in Japanese patients with moderate-to-severe COPD.

Methods: This Phase IIb, multicenter, randomized, double-blind, 7-day, crossover study compared GP MDI 28.8, 14.4, and 7.2 μg with placebo MDI (all administered as two inhalations, twice daily). The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV) on Day 8. Secondary endpoints included FEV area under the curve from 0 to 2 hours (AUC) and peak change from baseline in FEV on Days 1 and 8 and forced vital capacity AUC on Day 8. Safety was also assessed. ClinicalTrials.gov Identifier: NCT03256552; http://www.ClinicalTrials.gov.

Results: Sixty-six patients were randomized and 62 were included in the modified intent-to-treat population (mean age 67.5 years). All three GP MDI doses significantly improved change from baseline in morning pre-dose trough FEV on Day 8 compared with placebo MDI (least squares mean differences 108-131 mL; all <0.0001). Significant improvements in secondary efficacy endpoints were also observed for all three GP MDI doses compared with placebo MDI (all <0.0001). Dose-response plateaued at GP MDI 14.4 μg. No significant safety findings were observed with any GP MDI dose or placebo MDI.

Conclusions: The results of this study suggest that GP MDI 14.4 μg (7.2 μg per inhalation) is the most appropriate dose for use in Phase III studies in Japanese patients with moderate-to-severe COPD.
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http://dx.doi.org/10.2147/COPD.S159246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905841PMC
October 2018

Efficacy and safety of twice-daily rabeprazole maintenance therapy for patients with reflux esophagitis refractory to standard once-daily proton pump inhibitor: the Japan-based EXTEND study.

J Gastroenterol 2018 Jul 29;53(7):834-844. Epub 2017 Nov 29.

Department of Gastroenterology, Gunma University Hospital, Maebashi, Gunma, Japan.

Background: Rabeprazole at 10 or 20 mg twice daily (b.i.d.) has been reported to be highly effective in the treatment of proton pump inhibitor (PPI)-resistant reflux esophagitis (RE) that is refractory to the standard once-daily PPI regimen. We evaluated the efficacy and safety of rabeprazole maintenance therapy at 10 mg once daily (q.d.) or b.i.d. for longer than 8 weeks.

Methods: Patients with RE refractory to standard PPI regimens for at least 8 weeks were enrolled. They were treated with rabeprazole at 10 or 20 mg b.i.d. for 8 weeks during the open-label treatment period. After endoscopic examination, those with confirmed healing entered the subsequent double-blind maintenance therapy. During this period, the subjects were randomized to receive rabeprazole 10 mg q.d. (control) or 10 mg b.i.d. The primary endpoint was the endoscopic no-recurrence rate at Week 52.

Results: In total, 517 subjects entered the treatment, and 359 subjects continued on maintenance therapy. The full analysis set for central assessment included 343 subjects. The no-recurrence rate at Week 52 was significantly higher in the b.i.d. group (73.9%; p < 0.001, χ test) than in the q.d. group (44.8%). In particular, the b.i.d. regimen was more effective in all subgroups with Los Angeles Classification Grade B to D at treatment entry.

Conclusions: In the maintenance treatment of PPI-resistant RE, rabeprazole at 10 mg b.i.d. exerted a stronger recurrence-preventing effect than 10 mg q.d. over 52 weeks. No particular safety issues were noted during long-term administration. ClinicalTrials.gov number: NCT02135107.
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http://dx.doi.org/10.1007/s00535-017-1417-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006226PMC
July 2018

Association of baseline plasma des-acyl ghrelin level with the response to rikkunshito in patients with functional dyspepsia.

J Gastroenterol Hepatol 2016 Feb;31(2):334-41

Rikkunshito Study Group, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Background And Aim: We recently conducted a randomized placebo-controlled trial on the efficacy and safety of rikkunshito, a standardized Japanese herbal medicine, for the treatment of functional dyspepsia (FD). The present post-hoc study aimed to evaluate the differences in clinical characteristics between responders and non-responders among FD patients who received rikkunshito for 8 weeks.

Methods: Rikkunshito responders were defined by using a global patient assessment. Candidate predictors included age, gender, smoking, alcohol consumption, body mass index, comorbidity, Helicobacter pylori infection, plasma levels of acyl ghrelin and des-acyl ghrelin, severity of dyspeptic symptoms, FD subgroup, previous medication, and the type of recruiting institution (clinic or hospital). We calculated hazard ratios (HRs) by using Cox regression analysis with the factors that were indicated to be associated with responders.

Results: We assigned 83 and 42 patients to responder and non-responder categories, respectively. Lack of alcohol consumption (HR, 2.04; 95% confidence interval, 1.08-3.88) and low plasma des-acyl ghrelin levels (< 177 fmol/mL; HR, 2.42; 95% confidence interval, 1.24-4.73) were significantly associated with the efficacy of rikkunshito. Lack of alcohol consumption was associated with the efficacy of rikkunshito especially among H. pylori-infected participants. On the other hand, the low plasma des-acyl ghrelin was associated with the efficacy of rikkunshito especially among H. pylori-negative participants.

Conclusions: A low baseline level of plasma des-acyl ghrelin was associated with an increased treatment efficacy of rikkunshito against FD. Lack of alcohol consumption was also clinically useful for predicting the response to rikkunshito.
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http://dx.doi.org/10.1111/jgh.13074DOI Listing
February 2016

Mucosal expression of aquaporin-4 in the stomach of histamine type 2 receptor knockout mice and Helicobacter pylori-infected mice.

J Gastroenterol Hepatol 2014 Dec;29 Suppl 4:53-9

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

Background And Aim: Basolateral water channel, aquaporin-4 (AQP4), is known to be expressed in gastric parietal cells, especially in the basal side of gastric mucosa. However, the role of AQP4 in the stomach is still unknown. Histamine type 2 receptor (H2R) knockout mice, which are characterized by suppressed gastric acid secretion, are known as formation of mucosal hyperplasia with cystic dilatation and spasmolytic polypeptide-expressing metaplasia (SPEM) in the stomach. The aim of the present study is to investigate whether the expression of AQP4 is changed by the condition of acid suppression and Helicobacter pylori infection.

Methods: Male H2 R knockout mice and their controls (C57BL/6) were used. H. pylori was orally infected at the age of 5 weeks. The distributions of AQP4 and H+/K+-ATPase in the gastric mucosa were investigated by fluorescent immunohistochemistry. The mRNA expressions of AQP4, H+/K+-ATPase, sonic hedgehog (Shh), and trefoil factor-2 (TFF2) were investigated by quantitative reverse transcription polymerase chain reaction (RT-PCR).

Results: In the H2 R knockout mice, the distribution of AQP4-positive parietal cells was extended toward the surface of the fundic glands. Although the mRNA expression levels of AQP4 and H+/K+ATPase were elevated in H2 R knockout mice at the age of 20 weeks, the elevations were not maintained by aging or H. pylori infection. In H2 R knockout mice with H. pylori infection, the expression level of TFF2 mRNA was elevated while the ratio between AQP4 and H+/K+ ATPase mRNA expression was decreased compared with the H2 R knockout mice without H. pylori infection.

Conclusions: In the H2 R knockout mice, massive SPEM was induced by H. pylori colonization and the ratio between AQP4 and H+/K+ATPase mRNA expression was decreased.
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http://dx.doi.org/10.1111/jgh.12771DOI Listing
December 2014

Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis.

Clin Sci (Lond) 2014 Oct;127(7):435-48

*The State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Histamine H2 receptor (H2R) blockade has been reported to be beneficial for patients with chronic heart failure (CHF), but the mechanisms involved are not entirely clear. In the present study, we assessed the influences of H2R disruption on left ventricular (LV) dysfunction and the mechanisms involved in mitochondrial dysfunction and calcineurin-mediated myocardial fibrosis. H2R-knockout mice and their wild-type littermates were subjected to transverse aortic constriction (TAC) or sham surgery. The influences of H2R activation or inactivation on mitochondrial function, apoptosis and fibrosis were evaluated in cultured neonatal rat cardiomyocytes and fibroblasts as well as in murine hearts. After 4 weeks, H2R-knockout mice had higher echocardiographic LV fractional shortening, a larger contractility index, a significantly lower LV end-diastolic pressure, and more importantly, markedly lower pulmonary congestion compared with the wild-type mice. Similar results were obtained in wild-type TAC mice treated with H2R blocker famotidine. Histological examinations showed a lower degree of cardiac fibrosis and apoptosis in H2R-knockout mice. H2R activation increased mitochondrial permeability and induced cell apoptosis in cultured cardiomyocytes, and also enhanced the protein expression of calcineurin, nuclear factor of activated T-cell and fibronectin in fibroblasts rather than in cardiomyocytes. These findings indicate that a lack of H2R generates resistance towards heart failure and the process is associated with the inhibition of cardiac fibrosis and apoptosis, adding to the rationale for using H2R blockers to treat patients with CHF.
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http://dx.doi.org/10.1042/CS20130716DOI Listing
October 2014

Multinational, double-blind, randomised, placebo-controlled, prospective study of esomeprazole in the prevention of recurrent peptic ulcer in low-dose acetylsalicylic acid users: the LAVENDER study.

Gut 2014 Jul 10;63(7):1061-8. Epub 2013 Dec 10.

Research & Development, AstraZeneca, Osaka, Japan.

Objectives: To evaluate if esomeprazole prevents recurrent peptic ulcer in adult patients with a history of peptic ulcer receiving low-dose acetylsalicylic acid (ASA, aspirin) for cardiovascular protection in East Asia.

Methods: In this prospective, randomised, double-blind, placebo-controlled trial conducted in Japan, Korea and Taiwan, eligible patients receiving low-dose ASA for cardiovascular protection (81-324 mg/day) were randomised to esomeprazole 20 mg/day or placebo for ≤72 weeks. All patients received concomitant mucosal protection (gefarnate 100 mg/day). The primary endpoint was time to ulcer recurrence (Kaplan-Meier analysis). Efficacy findings are presented up to week 48, as per a planned interim analysis within the study protocol.

Results: A total of 364 patients (79.9% men; mean age, 67.1 years) comprised the full analysis set (esomeprazole, n=182; placebo, n=182). There was a statistically significant difference in the time to ulcer recurrence between esomeprazole and placebo (HR 0.09; 96.65% CI 0.02 to 0.41; p<0.001). The estimated ulcer-free rate at week 12 was 99.3% (esomeprazole) and 89.0% (placebo). The high estimated ulcer-free rate for esomeprazole was maintained through to week 48 (98.3% vs. 81.2% of placebo-treated patients). No factors, other than female gender, reduced time to ulcer recurrence in addition to the effect of esomeprazole (p<0.001). Treatment with esomeprazole was generally well tolerated.

Conclusions: Daily esomeprazole 20 mg is efficacious and well tolerated in reducing the recurrence of peptic ulcer in East-Asian patients with a history of ulcers who are taking low-dose ASA for cardiovascular protection.

Clinicaltrialgov Identifier: NCT01069939.
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http://dx.doi.org/10.1136/gutjnl-2013-304722DOI Listing
July 2014

Histamine H2 receptor activation exacerbates myocardial ischemia/reperfusion injury by disturbing mitochondrial and endothelial function.

Basic Res Cardiol 2013 May 7;108(3):342. Epub 2013 Mar 7.

Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, 510515, Guangzhou, China.

There is evidence that H2R blockade improves ischemia/reperfusion (I/R) injury, but the underlying cellular mechanisms remain unclear. Histamine is known to increase vascular permeability and induce apoptosis, and these effects are closely associated with endothelial and mitochondrial dysfunction, respectively. Here, we investigated whether activation of the histamine H2 receptor (H2R) exacerbates myocardial I/R injury by increasing mitochondrial and endothelial permeability. Serum histamine levels were measured in patients with coronary heart disease, while the influence of H2R activation was assessed on mitochondrial and endothelial function in cultured cardiomyocytes or vascular endothelial cells, and myocardial I/R injury in mice. The serum histamine level was more than twofold higher in patients with acute myocardial infarction than in patients with angina or healthy controls. In neonatal rat cardiomyocytes, histamine dose-dependently reduced viability and induced apoptosis. Mitochondrial permeability and the levels of p-ERK1/2, Bax, p-DAPK2, and caspase 3 were increased by H2R agonists. In cultured human umbilical vein endothelial cells (HUVECs), H2R activation increased p-ERK1/2 and p-moesin levels and also enhanced permeability of HUVEC monolayer. All of these effects were abolished by the H2R blocker famotidine or the ERK inhibitor U0126. After I/R injury or permanent ischemia, the infarct size was reduced by famotidine and increased by an H2R agonist in wild-type mice. In H2R KO mice, the infarct size was smaller; myocardial p-ERK1/2, p-DAPK2, and mitochondrial Bax were downregulated. These findings indicate that H2R activation exaggerates myocardial I/R injury by promoting myocardial mitochondrial dysfunction and by increasing cardiac vascular endothelial permeability.
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http://dx.doi.org/10.1007/s00395-013-0342-4DOI Listing
May 2013

Efficacy of Solifenacin on Irritable Bowel Syndrome With Diarrhea: Open-label Prospective Pilot Trial.

J Neurogastroenterol Motil 2012 Jul 10;18(3):317-23. Epub 2012 Jul 10.

Department of Internal Medicine, Tokyo-Eki Center-Building Clinic, Tokyo, Japan.

Background/aims: Solifenacin, a muscarinic type 3 receptor antagonist, is used to treat overactive bladder in adults. The aim of this study is to examine the efficacy of solifenacin on the symptomatic relief of diarrhea predominant irritable bowel syndrome (IBS-D).

Methods: A total of 20 patients with IBS-D were enrolled. After a 2-week observation period, all participants received solifenacin for 6 weeks. Subsequently, the administration of solifenacin was discontinued and ramosetron, a serotonin 3 receptor antagonist, was administered for 4 weeks. Overall improvement, the IBS-symptom severity scale (IBS-SSS), and frequency of defecation were assessed.

Results: Six weeks after initiation of solifenacin treatment and 4 weeks after initiation of ramosetron treatment, overall improvement was observed in 19 out of 20 (95%) and 17 out of 20 (85%) participants, respectively. At 2 weeks after initiation of solifenacin, overall improvement was observed in 16 out of 20 participants (80%). Total IBS-SSS scores at 2 and 6 weeks after the administration of solifenacin, and at 4 weeks after administration of ramosetron, were significantly lower than those at week 0. Compared to before administration, the participants' quality of life and frequency of defecation were significantly lower in all participants at 2 and 6 weeks after the administration of solifenacin and at 4 weeks after administration of ramosetron.

Conclusions: The efficacy of solifenacin in the treatment of IBS with diarrhea was not inferior to that of ramosetron. Further placebo-controlled parallel studies are needed.
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http://dx.doi.org/10.5056/jnm.2012.18.3.317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3400820PMC
July 2012

Influences of CYP2C19 polymorphism on recurrence of reflux esophagitis during proton pump inhibitor maintenance therapy.

Hepatogastroenterology 2009 May-Jun;56(91-92):703-6

Department of Internal Medicine, Tokyo Women's Medical University, Medical Center East, Tokyo, Japan.

Background/aims: Patients with erosive gastroesophageal reflux disease (GERD) have rapid recurrence after treatment withdrawal. The aim is to study the influences of CYP2C19 polymorphism on recurrence of GERD during proton pump inhibitor maintenance therapy.

Methodology: Ninety-nine patients with initial healing of GERD (judged by endoscopy) after 8 wk of treatment with PPIs were enrolled into maintenance therapy for 6 mo with rabeprazole (10 mg/day), omeprazole (20 mg/day) or lansoprazole (15 mg/day). The recurrence of GERD symptoms in the maintenance therapy was assessed by a QUEST questionnaire.

Results: The recurrence rate of GERD symptoms in the group of CYP2C19 homozygous extensive metabolizers (38.5%) was significantly greater than those in groups of heterozygous extensive metabolizers (10.9%) and poor metabolizers (5.6%). The recurrence rates in patients treated with omeprazole (25%) and lansoprazole (30.8%) were significantly greater than that with rabeprazole (4.4%). The gender, age and H. pylori did not significantly affect the rate.

Conclusions: The CYP2C19 genotypes affected the recurrence rate of GERD symptoms during PPI maintenance therapy. The reason for the low recurrence rate with 10 mg/day rabeprazole possibly is due to its sufficient acid suppression independent of CYP2C19 genotypes in Japanese patients.
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September 2009

Alterations in gastric mucosal lineages before or after acute oxyntic atrophy in gastrin receptor and H2 histamine receptor-deficient mice.

Dig Dis Sci 2009 Aug 9;54(8):1625-35. Epub 2009 Jun 9.

Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

Spasmolytic polypeptide (SP/TFF2)-expressing metaplasia (SPEM) is induced by oxyntic atrophy and is known as a precancerous or paracancerous lesion. We seek to determine whether the gastrin receptor or H(2) histamine receptor influence the development of SPEM. DMP-777 was administered to gastrin receptor and/or H(2) receptor-deficient mice and wild-type mice. Gastric mucosal lineage changes were analyzed. The mucosa from double knockout mice and H(2) receptor knockout mice contained elevated numbers of dual TFF2 and intrinsic factor immunoreactive cells even before DMP-777 treatment. All genotypes of mice showed SPEM after 7-day treatment. In all types of knockout mice, the number of TFF2 immunoreactive cells remained elevated after cessation of treatment. The H(2) receptor and gastrin receptor do not affect emergence of SPEM. However, it is suggested that the absence of H(2) receptor signaling causes a delay in the maturation of chief cells from mucous neck cells.
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http://dx.doi.org/10.1007/s10620-009-0832-2DOI Listing
August 2009

Agonist-induced internalization of histamine H2 receptor and activation of extracellular signal-regulated kinases are dynamin-dependent.

J Neurochem 2008 Oct 7;107(1):208-17. Epub 2008 Aug 7.

Departments of Pharmacology, Tohoku University School of Medicine, Seiryo-machi, Aoba-ku, Sendai, Japan.

Histamine H2 receptor (H2R) is a member of G protein-coupled receptor family. Agonist stimulation of H2R results in several cellular events including activation of adenylate cyclase and phospholipase C, desensitization of the receptor, activation of extracellular signal-regulated kinases ERK1/2, and receptor endocytosis. In this study, we identified a GTPase dynamin as a binding partner of H2R. Dynamin could associate with H2R both in vitro and in vivo. Functional analyses using dominant-negative form of dynamin (K44E-dynamin) revealed that cAMP production and the following H2R desensitization are independent of dynamin. However, the agonist-induced H2R internalization was inhibited by co-expression of K44E-dynamin. Furthermore, activation of extracellular-signal regulated kinases ERK1/2 in response to dimaprit, an H2R agonist, was attenuated by K44E-dynamin. Although H2R with truncation of 51 amino acids at its carboxy-terminus did not internalize after agonist stimulation, it still activated ERK1/2, but the degree of this activation was less than that of the wild-type receptor. Finally, K44E dynamin did not affect ERK1/2 activation induced by internalization-deficient H2R. These results suggest that the agonist-induced H2R internalization and ERK1/2 activation are partially dynamin-dependent. Furthermore, ERK1/2 activation via H2R is likely dependent of the endocytotic process rather than dynamin itself.
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http://dx.doi.org/10.1111/j.1471-4159.2008.05608.xDOI Listing
October 2008

Hepatic overexpression of a dominant negative form of raptor enhances Akt phosphorylation and restores insulin sensitivity in K/KAy mice.

Am J Physiol Endocrinol Metab 2008 Apr 12;294(4):E719-25. Epub 2008 Feb 12.

Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

Several serine/threonine kinases reportedly phosphorylate serine residues of IRS-1 and thereby induce insulin resistance. In this study, to investigate the effect of mTOR/raptor on insulin signaling and metabolism in K/KAy mice with genetic obesity-associated insulin resistance, a dominant negative raptor, COOH-terminally deleted raptor (raptor-DeltaC(T)), was overexpressed in the liver via injection of its adenovirus into the circulation. Hepatic raptor-DeltaC(T) expression levels were 1.5- to 4-fold that of endogenously expressed raptor. Glucose tolerance in raptor-DeltaC(T)-overexpressing mice improved significantly compared with that of LacZ-overexpressing mice. Insulin-induced activation of p70S6 kinase (p70(S6k)) was significantly suppressed in the livers of raptor-DeltaC(T) overexpressing mice. In addition, insulin-induced IRS-1, Ser(307), and Ser(636/639) phosphorylations were significantly suppressed in the raptor-DeltaC(T)-overexpressing liver, whereas tyrosine phosphorylation of IRS-1 was increased. PI 3-kinase activation in response to insulin stimulation was increased approximately twofold, and Akt phosphorylation was clearly enhanced under both basal and insulin-stimulated conditions in the livers of raptor-DeltaC(T) mice. Thus, our data indicate that suppression of the mTOR/p70(S6k) pathway leads to improved glucose tolerance in K/KAy mice. These observations may contribute to the development of novel antidiabetic agents.
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http://dx.doi.org/10.1152/ajpendo.00253.2007DOI Listing
April 2008

Regulation of gut-derived resistin-like molecule beta expression by nutrients.

Diabetes Res Clin Pract 2008 Jan 23;79(1):2-10. Epub 2007 Oct 23.

Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Resistin was initially identified as a protein, secreted by adipocytes, which inhibits insulin action and adipose differentiation. The three proteins homologous to resistin were identified and given the names resistin-like molecules (RELM) alpha, beta and gamma. Resistin and RELMalpha are abundantly expressed in adipose, but RELMbeta and RELMgamma are secreted mainly from the gut. Since nutrient composition greatly affects insulin sensitivity, we investigated the regulatory effects of various nutritional factors in food on the expressions of resistin family proteins. First, mice were given diets with different nutritional compositions (high-carbohydrate, high-protein and high-fat) for 2 weeks. RELMbeta mRNA expression in the intestines was markedly suppressed by the high-protein and high-carbohydrate diets, while slightly but not significantly upregulated by the high-fat diet. In the epididymal fat, resistin expression was unchanged, while RELMalpha expression was markedly decreased by the high-carbohydrate diet. Taking into consideration that humans have neither RELMalpha nor RELMgamma, our subsequent studies focused on RELMbeta expression. We used the human colon cancer cell line LS174T. Treatments with insulin and TNFalpha as well as stearic acid, a saturated free fatty acid, upregulated RELMbeta expression, while d-glucose downregulated RELMbeta. These results suggest RELMbeta expression to be regulated directly by nutrients such as glucose and saturated free fatty acids including stearic acid, as well as by hormones including insulin and TNFalpha. These regulations may play an important role in the nutrient-associated induction of insulin resistance.
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http://dx.doi.org/10.1016/j.diabres.2007.04.015DOI Listing
January 2008

Enhanced ghrelin expression and subsequent acid secretion in mice with genetic H(2)-receptor knockout.

J Gastroenterol 2007 Sep 25;42(9):711-8. Epub 2007 Sep 25.

Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan.

Background: Ghrelin, an appetite-promoting peptide secreted from the stomach, is reported to enhance preprandial acid output, possibly through stimulation of the cephalic phase. The present study was designed to clarify the dynamics of ghrelin in H(2) receptor (H(2)R)-null mice by genetic H(2)R knockout.

Methods: Fifteen-week- and 54-week-old H(2)R-null mice and their littermates were used. After evaluating the levels of food intake and body-weight increments, mice were killed, and the plasma and gastric active and total ghrelin levels were examined by radioimmunoassay, and gastric preproghrelin mRNA expression was examined by quantitative reverse transcriptase-polymerase chain reaction. Furthermore, each stomach specimen was evaluated by immunohistochemistry and transmission electron microscopy for ghrelin.

Results: The levels of food intake and body-weight gain of the H(2)R-null mice were higher than those of wild-type mice. The gastric pH of the 54-week-old H(2)R-null mice was lower than that of the 15-week-old mice. Gastric preproghrelin mRNA expression, plasma ghrelin level, and density of ghrelin-immunoreactive cells in the gastric mucosa of the H(2)R-null mice were significantly increased compared with those of the wild-type mice. Ghrelin-positive immunogold density seen in the electron micrograph was significantly reduced in A-like cells of the H(2)R-null mouse stomach.

Conclusions: Ghrelin production and secretion from A-like cells in the gastric fundus are upregulated in H(2)R-null mice, a genetic H(2)R knockout model.
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http://dx.doi.org/10.1007/s00535-007-2084-2DOI Listing
September 2007

Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways.

Am J Physiol Cell Physiol 2007 Nov 5;293(5):C1576-85. Epub 2007 Jul 5.

Department of Endocrinology and Metabolism, Institute for Adult Disease, Asahi Life Foundation, Tokyo.

Carboxy-terminal modulator protein (CTMP) was identified as binding to the carboxy terminus of Akt and inhibiting the phosphorylation and activation of Akt. In contrast to a previous study, we found CTMP overexpression to significantly enhance Akt phosphorylation at both Thr(308) and Ser(473) as well as the kinase activity of Akt, while phosphatidylinositol 3-kinase (PI3-kinase) activity was unaffected. Translocation of Akt to the membrane fraction was also markedly increased in response to overexpression of CTMP, with no change in the whole cellular content of Akt. Furthermore, the phosphorylations of GSK-3beta and Foxo1, well-known substrates of Akt, were increased by CTMP overexpression. On the other hand, suppression of CTMP with small interfering RNA partially but significantly attenuated this Akt phosphorylation. The cellular activities reportedly mediated by Akt activation were also enhanced by CTMP overexpression. UV-B-induced apoptosis of HeLa cells was significantly reversed not only by overexpression of the active mutant of Akt (myr-Akt) but also by that of CTMP. Increases in glucose transport activity and glycogen synthesis were also induced by overexpression of either myr-Akt or CTMP in 3T3-L1 adipocytes. Taking these results into consideration, it can be concluded that CTMP induces translocation of Akt to the membrane and thereby increases the level of Akt phosphorylation. As a result, CTMP enhances various cellular activities that are principally mediated by the PI3-kinase/Akt pathway.
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http://dx.doi.org/10.1152/ajpcell.00570.2006DOI Listing
November 2007

Role of hepatic AMPK activation in glucose metabolism and dexamethasone-induced regulation of AMPK expression.

Diabetes Res Clin Pract 2006 Aug 28;73(2):135-42. Epub 2006 Feb 28.

Department of Sports Medicine, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

To elucidate the role of AMPK in hepatic glucose metabolism, dominant negative (DN), constitutively active (CA) forms of the AMPKalpha1 subunit and control vector LacZ were overexpressed by means of adenovirus-mediated gene transfer. Five days after virus injection, hepatic AMPK activity was five-fold higher in CA mice than in DN mice. DN mice were apparently glucose intolerant with a higher fasting plasma glucose level (DN 82.3+/-0.7mg/dl, CA 42.5+/-4.8mg/dl and LacZ 54.3+/-2.4mg/dl). PEPCK, a gluconeogenic key enzyme, mRNA was increased 131.54% and 48.92% in DN mice compared to that of CA and LacZ, respectively. Thus, hepatic AMPK activation plays a role in the suppression of gluconeogenesis and this might be the cause of decreased fasting plasma glucose level in CA mice. We also investigated the effects of dexamethasone on hepatic AMPK expression and activity in rat liver, mice liver, as well as primary cultured hepatocytes. Subcutaneously injecting mice with dexamethasone (1mg/day) for 5 days significantly upregulated hepatic AMPKalpha1 and alpha2 expressions. Similarly, the treatment of primary cultured rat hepatocytes with dexamethasone (1microM) increased expression of the AMPKalpha1 subunit, AICAR-induced AMPK phosphorylation and kinase activity. Although increased AMPK expression cannot be attributed to dexamethasone-induced glucose intolerance, taken together our results raise the possibility that AMPK control liver glucose output and its expression in liver might be modulated by various hormones and growth factors.
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http://dx.doi.org/10.1016/j.diabres.2005.12.011DOI Listing
August 2006

TRAIL-induced cell death cooperates with IFN-gamma activation in the graft-versus-tumor effect against colon tumors.

Int J Cancer 2006 May;118(9):2237-46

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.

The graft-versus-tumor (GVT) effect that occurs following allogeneic bone marrow transplantation (BMT) and donor lymphocyte infusion (DLI) is currently being subjected to intensive investigation because of clinical evidence for GVT efficacy against leukemia. In this report, we investigate the efficacy and molecular mechanisms of GVT against solid tumors, using a modification of the mouse parent-to-F1 BMT model. Mouse Colon26 cells in which tumor necrosis factor related apoptosis-inducing ligand (TRAIL) receptor expression was stably knocked down were transplanted to investigate the role of the TRAIL-TRAIL receptor system in the GVT effect. In addition, Fas ligand-(FasL) deficient mice on a C57BL6 (B6) background were used as donors, to determine the significance of the Fas-FasL system for the antitumor effect. The group that received B6 DLI followed by preconditioning with 950 rad irradiation underwent tumor reduction associated with the induction of IFN-gamma, TRAIL and tumor-cell apoptosis. In vitro cultured Colon26 cells were resistant to TRAIL but susceptible to the combination of IFN-gamma and TRAIL in a TRAIL-dose-dependent manner. The infusion of lymphocytes from FasL-defective donors reduced the tumor progression, although efficacy was decreased in the TRAIL receptor knockdown tumors but not in wild-type ones, compared with infusion of B6-derived lymphocytes. The findings indicate that GVT activity against subcutaneous colon tumors is efficiently induced by preconditioning with irradiation and allogeneic DLI, and that TRAIL and IFN-gamma act cooperatively in the antitumor effect.
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http://dx.doi.org/10.1002/ijc.21658DOI Listing
May 2006

Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet.

J Biol Chem 2005 Dec 21;280(51):42016-25. Epub 2005 Oct 21.

Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655.

Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. Because the serum concentration and intestinal expression level of RELMbeta were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELMbeta on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELMbeta overexpression were shown to exhibit significant hyperglycemia, hyperlipidemia, fatty liver, and pancreatic islet enlargement when fed a high fat diet. Hyperinsulinemic glucose clamp showed a decreased glucose infusion rate due to increased hepatic glucose production. In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELMbeta transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELMbeta, suggesting the insulin resistance-inducing effect of RELMbeta to be direct. Furthermore, it was shown that RELMbeta acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. This increased basal p38 phosphorylation level was also observed in the livers of RELMbeta transgenic mice. In conclusion, RELMbeta, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELMbeta may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELMbeta is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.
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http://dx.doi.org/10.1074/jbc.M503065200DOI Listing
December 2005

Cancer-derived VEGF plays no role in malignant ascites formation in the mouse.

World J Gastroenterol 2005 Sep;11(35):5455-9

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo Hospital, 7-3-1 Hongo, Tokyo 113-8655, Japan.

Aim: Vascular endothelial growth factor (VEGF) is a potent mediator of peritoneal fluid accumulation following tumor progression. This study investigated the role of VEGF secreted by cancerous cells in the formation of malignant ascites.

Methods: VEGF expression was eliminated by knockdown in the pancreas cancer cell-line PancO2 using vector-based short-hairpin type RNA interference (RNAi). Malignant ascites formation in the mouse was analyzed by intraperitoneal injection of PancO2 cells expressing VEGF or with expression knockdown.

Results: The VEGF knockdown PancO2 cell was successfully established. Knockdown of VEGF did not affect cancer cell proliferation in vitro or in vivo. The volume of ascites following peritoneal expansion of the tumor in VEGF knockdown cells and control cells did not differ statistically in this in vivo study. Moreover, the VEGF concentration in the ascites did not differ statistically.

Conclusion: Malignant ascites formation might be mediated by VEGF production in noncancerous tissues, such as stromal compartments. An anti-VEGF strategy against malignant ascites could be applied to various tumors regardless of whether they secrete VEGF.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4320353PMC
http://dx.doi.org/10.3748/wjg.v11.i35.5455DOI Listing
September 2005

Nasal allergic response mediated by histamine H3 receptors in murine allergic rhinitis.

Laryngoscope 2005 Oct;115(10):1778-84

Department of Otolaryngology, Faculty of Medicine, University of Tokyo, Japan.

Background: Histamine is one of the most important chemical mediators causing nasal allergic symptoms, and H1 receptor antagonist have been used as the treatment first choice in nasal allergy. The presence of H3 receptors has also been determined in the human nasal mucosa, but few studies have investigated the involvement of H3 receptors in nasal allergy.

Objective: We used a murine allergic model to investigate the presence of nasal mucosa H3 receptor mRNA and any H3 receptor agonist or antagonist influences on clinical nasal allergic symptoms.

Methods: H3 receptor mRNA in nasal mucosa was investigated by reverse-transcription polymerase chain reaction. OVA-sensitized mice were given an intraperitoneal injection of H3 receptor agonist or antagonist, and clinical nasal allergic symptoms were scored over 10 minutes after nasal provocation of OVA. Inhibition of nasal allergic symptoms was also examined using an H1 receptor antagonist alone and using a both an H3 receptor agonist and an H1 receptor antagonist.

Results: H3 receptor mRNA was identified in the murine nasal mucosa. The H3 receptor agonist (R)-alpha-metylhistamine significantly inhibited clinical nasal allergic symptoms of OVA-sensitized mice. The H3 receptor agonist and H1 receptor antagonist inhibited clinical nasal allergic symptoms in the murine allergic model more strongly than the single drug.

Conclusion: The foregoing results indicate that H3 receptors are involved in modulation of nasal allergy. H3 receptor agonists can also be useful as a novel therapeutic approach in nasal allergy. Both H3 receptor agonist and H1 receptor antagonist may be more effective than a single drug.
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http://dx.doi.org/10.1097/01.mlg.0000176537.41105.bcDOI Listing
October 2005

Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner.

Cancer Res 2005 Jul;65(13):5864-71

Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, Hongo, Japan.

The interaction between the chemokine receptor CXCR4 and its specific ligand, stromal cell-derived factor-1 (SDF-1/CXCL12), mediates several cellular functions. In cancer, SDF-1-positive or CXCR4-positive cells of various lineages are detected within tumor tissues. Recent intensive research has indicated the possibility that blocking CXCR4 could reduce the metastatic potential of cancer cells. Here, we show that the inhibition of the SDF-1/CXCR4 axis decreases the growth of s.c. gastrointestinal tumors through the suppression of tumor neoangiogenesis. The neutralization of CXCR4 suppressed the growth in vivo of tumors derived from mouse Colon38 and PancO2 cells, whereas it did not affect the growth of Colon38 and PancO2 cells in vitro. This attenuation of tumor growth was found to be independent of the expression of CXCR4 by the cancer cells themselves, because CXCR4 knocked-down Colon38 cells grew similarly to control cells. Furthermore, CD31-positive tumor capillaries were reduced to 45% (P < 0.001) and intratumor blood flows were decreased to 65% (P < 0.01) by blockade of CXCR4. The vascular endothelial growth factor (VEGF) concentration in the tumors was not affected by the neutralization of CXCR4. Taken together with the detection of CXCR4-positive endothelial cells in the tumor tissues, the findings suggest that the antiangiogenic effects of the blockade of CXCR4 are related to a reduction of the establishment of tumor endothelium independently of VEGF inhibition. Our data indicate that the SDF-1/CXCR4 pathway might be a general target for anticancer strategies and that blocking this system could be cooperatively effective in combination with other antiangiogenic therapies, such as blockade of VEGF.
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http://dx.doi.org/10.1158/0008-5472.CAN-04-3833DOI Listing
July 2005

Outbreak of hepatitis C virus infection in an outpatient clinic.

J Gastroenterol Hepatol 2005 Jul;20(7):1087-93

Department of Internal Medicine, University of Tokyo, Tokyo, Japan.

Background: From January through September 2001, seven patients were admitted to Fukaya Red Cross Hospital with typical clinical manifestations of acute hepatitis. Six were outpatients of the clinic, which is located near the hospital. An extensive survey of clinic outpatients conducted by the local health department revealed six more new acute hepatitis cases during this period.

Methods: A case control study was carried out to identify potential risk factors for infection. In total, 1946 outpatients with clinic records were scheduled to undergo hepatitis C virus (HCV)-antibody testing. For the HCV-Ab positive patients, HCV-RNA was subtyped and quantified, and sequences of HCV hypervariable region 1 were determined.

Results: Ultimately, 12 patients with acute hepatitis and two asymptomatic subjects were found to be a part of this outbreak. HCV isolates were divided into three major groups using phylogenetic tree analysis. Only a past history of visiting the clinic was significantly associated with acute hepatitis. The timing of the parenteral medical procedure at the clinic and the onset of acute hepatitis strongly suggested association of the two events.

Conclusions: Our findings suggest that nosocomial HCV infection can occur in an outpatient clinic, even in countries where post-transfusion hepatitis has been almost entirely eliminated.
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http://dx.doi.org/10.1111/j.1440-1746.2005.03883.xDOI Listing
July 2005

Glycogen debranching enzyme association with beta-subunit regulates AMP-activated protein kinase activity.

Am J Physiol Endocrinol Metab 2005 Sep 10;289(3):E474-81. Epub 2005 May 10.

Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

AMP-activated protein kinase (AMPK) regulates both glycogen and lipid metabolism functioning as an intracellular energy sensor. In this study, we identified a 160-kDa protein in mouse skeletal muscle lysate by using a glutathione-S-transferase (GST)-AMPK fusion protein pull-down assay. Mass spectrometry and a Mascot search revealed this protein to be a glycogen debranching enzyme (GDE). The association between AMPK and GDE was observed not only in the overexpression system but also endogenously. Next, we showed the beta1-subunit of AMPK to be responsible for the association with GDE. Furthermore, experiments using deletion mutants of the beta1-subunit of AMPK revealed amino acids 68-123 of the beta1-subunit to be sufficient for GDE binding. W100G and K128Q, both beta1-subunit mutants, are reportedly incapable of binding to glycogen, but both bound GDE, indicating that the association between AMPK and GDE does not involve glycogen. Rather, the AMPK-GDE association is likely to be direct. Overexpression of amino acids 68-123 of the beta1-subunit inhibited the association between endogenous AMPK and GDE. Although GDE activity was unaffected, basal phosphorylation and kinase activity of AMPK, as well as phosphorylation of acetyl-CoA carboxylase, were significantly increased. Thus it is likely that the AMPK-GDE association is a novel mechanism regulating AMPK activity and the resultant fatty acid oxidation and glucose uptake.
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http://dx.doi.org/10.1152/ajpendo.00003.2005DOI Listing
September 2005

A novel protein kinase B (PKB)/AKT-binding protein enhances PKB kinase activity and regulates DNA synthesis.

J Biol Chem 2005 May 7;280(18):18525-35. Epub 2005 Mar 7.

Department of Internal Medicine, Institute for Adult Diseases, Asahi Life Foundation, 1-6-1, Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan.

Protein kinase B (PKB)/Akt reportedly plays a role in the survival and/or proliferation of cells. We identified a novel protein, which binds to PKB, using a yeast two-hybrid screening system. This association was demonstrated not only in vivo by overexpressing both proteins or by coimmunoprecipitation of the endogenous proteins, but also in vitro using glutathione S-transferase fusion proteins. Importantly, this protein specifically associates with the C terminus of PKB but not with other AGC kinases and enhances PKB phosphorylation and kinase activation without growth factor stimulation. Thus, we termed this Akt-specific binding protein APE (Akt-phosphorylation enhancer). Since APE-induced phosphorylation of PKB did not occur in cells treated with wortmannin or LY294002, APE itself is not a kinase but seems to enhance or prolong the phosphoinositide 3-kinase-dependent phosphorylation of PKB. In cells in which APE was suppressed by small interfering RNA, DNA synthesis was significantly reduced with suppression of PKB phosphorylation, suggesting a synergistic role of APE in PKB-induced proliferation. On the other hand, in cells overexpressing both PKB and APE, despite markedly increased basal phosphorylation of PKB, both DNA rereplication and subsequent Chk2 phosphorylation and apoptosis were seen, suggesting the involvement of APE in the regulation of cell cycling replication licensing. Taking these observations together, APE appears to be a novel regulator of PKB phosphorylation. Furthermore, the interaction between APE and PKB, possibly dependent on the expression levels of both proteins, may be a novel molecular mechanism leading to proliferation and/or apoptosis.
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http://dx.doi.org/10.1074/jbc.M500586200DOI Listing
May 2005

Unique roles of G protein-coupled histamine H2 and gastrin receptors in growth and differentiation of gastric mucosa.

Eur J Pharmacol 2004 Oct;502(3):243-52

Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.

Disruption of histamine H2 receptor and gastrin receptor had different effects growth of gastric mucosa: hypertrophy and atrophy, respectively. To clarify the roles of gastrin and histamine H2 receptors in gastric mucosa, mice deficient in both (double-null mice) were generated and analyzed. Double-null mice exhibited atrophy of gastric mucosae, marked hypergastrinemia and higher gastric pH than gastrin receptor-null mice, which were unresponsive even to carbachol. Comparison of gastric mucosae from 10-week-old wild-type, histamine H2 receptor-null, gastrin receptor-null and double-null mice revealed unique roles of these receptors in gastric mucosal homeostasis. While small parietal cells and increases in the number and mucin contents of mucous neck cells were secondary to impaired acid production, the histamine H2 receptor was responsible for chief cell maturation in terms of pepsinogen expression and type III mucin. In double-null and gastrin receptor-null mice, despite gastric mucosal atrophy, surface mucous cells were significantly increased, in contrast to gastrin-null mice. Thus, it is conceivable that gastrin-gene product(s) other than gastrin-17, in the stimulated state, may exert proliferative actions on surface mucous cells independently of the histamine H2 receptor. These findings provide evidence that different G-protein coupled-receptors affect differentiation into different cell lineages derived from common stem cells in gastric mucosa.
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http://dx.doi.org/10.1016/j.ejphar.2004.09.013DOI Listing
October 2004

[Functional analyses of gastric mucosa using mice deficient in both histamine H2 receptor and CCKB/gastrin receptor].

Nihon Rinsho 2004 Mar;62(3):551-5

Department of Gastroenterology, University of Tokyo.

Histamine H2 and cholecystokinin (CCK)-B/gastrin receptors are very important in both acid secretion and growth and differentiation of the gastric mucosa. Generations of mice deficient in each of these receptors have provided information on the structure and function of the gastric mucosa, respectively. To examine the gastric mucosa in further detail, we generated mice deficient in both receptors. This review discusses the roles of histamine H2 and CCK-B/gastrin receptors in gastric mucosa based on data from our double-null mice.
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March 2004
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