Hajime Nagase

Oral administration of lactoferrin reduces colitis in rats via modulation of the immune system and correction of cytokine imbalance

Background and Aims : The natural immunomodulator, lactoferrin, is widespread among various biological fluids and is known to exert an anti‐inflammatory effect. However, there has been only one study that examined the mode of action of lactoferrin in reducing intestinal damage. We investigated the therapeutic role of lactoferrin and its effect on the levels of pro‐inflammatory and anti‐inflammatory cytokines, by using a rat model of dextran sulfate sodium (DSS) induced‐colitis.

Clinical characteristics of Japanese reflux esophagitis patients as determined by Los Angeles classification

Background:  Recent studies have shown that the number of patients with reflux esophagitis is increasing in Japan, but the prevalence and risk factors associated with reflux esophagitis in Japanese patients are not well defined.

Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial

BACKGROUND The prevalence of, and mortality from, colorectal cancer is increasing worldwide, and new strategies for prevention are needed to reduce the burden of this disease. The oral diabetes medicine metformin might have chemopreventive effects against cancer, including colorectal cancer. However, no clinical trial data exist for the use of metformin for colorectal cancer chemoprevention. Therefore, we devised a 1-year clinical trial to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence. METHODS This trial was a multicentre, double-blind, placebo-controlled, randomised phase 3 trial. Non-diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled into the study from five hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive oral metformin (250 mg daily) or identical placebo tablets by a stratified computer-based randomisation method, with stratification by institute, age, sex, and body-mass index. All patients, endoscopists, doctors, and investigators were masked to drug allocation until the end of the trial. After 1 year of administration of metformin or placebo, colonoscopies were done to assess the co-primary endpoints: the number and prevalence of adenomas or polyps. Our analysis included all participants who underwent random allocation, according to the intention-to-treat principle. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000006254. FINDINGS Between Sept 1, 2011, and Dec 30, 2014, 498 patients who had had single or multiple colorectal adenomas resected by endoscopy were enrolled into the study. After exclusions for ineligibility, 151 patients underwent randomisation: 79 were assigned to the metformin group and 72 to the placebo group. 71 patients in the metformin group and 62 in the placebo group underwent 1-year follow-up colonoscopy. The prevalence of total polyps (hyperplastic polyps plus adenomas) and of adenomas in the metformin group was significantly lower than that in the placebo group (total polyps: metformin group 27 [38·0%; 95% CI 26·7-49·3] of 71 patients, placebo group 35 [56·5%; 95% CI 44·1-68·8] of 62; p=0·034, risk ratio [RR] 0·67 [95% CI 0·47-0·97]; adenomas: metformin group 22 [30·6%; 95% CI 19·9-41·2] of 71 patients, placebo group 32 [51·6%; 95% CI 39·2-64·1] of 62; p=0·016, RR 0·60 [95% CI 0·39-0·92]). The median number of polyps was zero (IQR 0-1) in the metformin group and one (0-1) in the placebo group (p=0·041). The median number of adenomas was zero (0-1) in the metformin group and zero (0-1) in the placebo group (p=0·037). 15 (11%) of patients had adverse events, all of which were grade 1. We recorded no serious adverse events during the 1-year trial. INTERPRETATION The administration of low-dose metformin for 1 year to patients without diabetes was safe. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of colorectal cancer. However, further large, long-term trials are needed to provide definitive conclusions. FUNDING Ministry of Health, Labour and Welfare, Japan.

Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial

BackgroundColorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients.Methods/DesignThis study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation.DiscussionThis is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been reported to be at a lower risk of cancer development than those not taking under treatment with metformin. We showed in a previous study that metformin suppressed the formation of human colorectal ACF. We therefore decided to conduct a study to determine whether metformin might suppress the formation of human colorectal polyps.Trial registrationThis trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000006254

Hepatic glucose-sensitive unit regulation of glucose-induced insulin secretion in rats

Vagal glucose receptors, or glucose-sensitive units which modulate insulin secretion, exist in the liver. This study sought to determine the pathway of portal glucose-sensitive unit-regulated insulin secretion by measuring plasma insulin after intraperitoneal (IP) injection of glucose under unanesthetized and unrestrained conditions (Experiment 1), and by recording electrical discharge after intraportal injection of glucose (Experiment 2) in rats with hepatic and/or celiac vagotomy. In Experiment 1, plasma insulin was significantly reduced and plasma glucose elevated after IP glucose injection (1 g/kg) in the three groups of hepatic-, celiac-, and hepatic- and celiac-vagotomized rats in comparison with a sham-vagotomized group. There were no significant differences among the four groups in plasma insulin or glucose after IV glucose injection (0.5 g/kg). In Experiment 2, intraportal injection of 400 mg/dl of glucose solution, a similar concentration to that produced by 1 g/kg of IP glucose injection, caused a reduction in the discharge rate of hepatic vagal afferents and an increase in that of pancreatic vagal efferents. This increase was blocked by prior sectioning of the hepatic branch of the vagus nerve. These results suggested that hepatic glucose-sensitive units enhanced glucose-induced insulin secretion via the hepatic vagal afferents and the pancreatic vagal efferents mediated by the brain stem center in vivo. The physiological role of these hepatic glucose-sensitive units is assumed to maintain blood glucose homeostasis by enhancing glucose-induced insulin secretion.

Modulation of insulin secretion by hepatic vagotomy in cirrhotic rats

There is evidence that glucose sensors and arginine sensors are present in the hepato-portal system and exert a reflex regulation of the pancreatic neuroendocrine system in normal rats. To investigate the function of these sensor systems in liver cirrhosis, we examined the effect of hepatic vagotomy on plasma glucose and insulin concentrations after intraperitoneal (IP) injection of glucose or L-arginine in carbon tetrachloride (CCl4)-induced cirrhotic rats. After IP glucose injection, hepatic vagotomy decreased plasma insulin with elevation of plasma glucose in control rats; however, in cirrhotic rats, this procedure did not affect either plasma glucose or insulin concentrations. After IP arginine injection, hepatic vagotomy increased plasma insulin and reduced plasma glucose in control rats, although in cirrhotic rats, this procedure did not affect plasma glucose but did increase plasma insulin concentrations. These results suggest that function of the glucose sensor in CCl4-induced cirrhotic rats is disturbed, although that of the arginine sensor is retained.

Risk factors for small-bowel mucosal breaks in chronic low-dose aspirin users: data from a prospective multicenter capsule endoscopy registry

BACKGROUND To develop appropriate management strategies for patients who take low-dose aspirin, it is important to identify the risk factors for GI injury. However, few studies have described the risk factors for small-bowel injury in these patients. OBJECTIVE To investigate factors influencing the risk of small-bowel mucosal breaks in individuals taking continuous low-dose aspirin. DESIGN Capsule endoscopy data were collected prospectively from 5 institutions. SETTING Yokohama City University Hospital and 4 other hospitals. PATIENTS A total of 205 patients receiving treatment with low-dose aspirin for over 3 months. INTERVENTIONS Colonoscopic and upper GI endoscopy had been performed in all of the patients before the capsule endoscope evaluation. MAIN OUTCOME MEASUREMENTS Risk factors for small-bowel mucosal breaks. RESULTS Of the 198 patients (141 male; mean age 71.9 years) included in the final analysis, 114 (57.6%) had at least 1 mucosal break. Multivariate analysis identified protein pump inhibitor (PPI) use (OR 2.04; 95% confidence interval [CI], 1.05-3.97) and use of enteric-coated aspirin (OR 4.05; 95% CI, 1.49-11.0) as independent risk factors for the presence of mucosal breaks. LIMITATIONS Cross-sectional study. CONCLUSION PPI use appears to increase the risk of small-bowel injury in patients who take continuous low-dose aspirin. Clinicians should be aware of this effect of PPIs; new strategies are needed to treat aspirin-induced gastroenteropathy.

Factors predicting the presence of small bowel lesions in patients with obscure gastrointestinal bleeding

To identify the predictive factors for the presence of small bowel lesions in patients with obscure gastrointestinal bleeding (OGIB).

Role of the efferent and afferent vagus nerve in the development of ventromedial hypothalamic (VMH) obesity

Hyperactivity of the vagus nerve and hypoactivity of the sympathetic nerves after VMH lesions both cooperatively contribute to the development of VMH obesity, mainly through hyperinsulinemia. Recently it has turned out that we should discriminate the role of the efferent vagus from that of the afferent vagus in the pancreatic hormone secretion. The hepatic branch is the main pathway of afferent fibers in the vagus, while the celiac (pancreatic) branch is the main pathway of efferent fibers. We investigated the role of the afferent and efferent vagus on the development of VMH obesity using the sectioning of the hepatic and celiac branch. Celiac vagotomy decreased insulin secretion and food intake, while hepatic vagotomy did not change them. The results suggested that the efferent vagus plays the main role in the development of VMH obesity, while the role of afferent vagus seems less apparent.

Chemoprevention of precursors to colon cancer by dehydroepiandrosterone (DHEA).

Although dehydroepiandrosterone (DHEA) is recognized as one of the major adrenal androgens, its precise physiological role in the human endocrine system remains to be elucidated. In particular, the effect of DHEA on carcinogenesis has not been fully characterized. We undertook this study to determine whether DHEA has a chemopreventative effect on the precursors of colon cancer in a murine model of azoxymethane (AOM)-induced aberrant crypt foci (ACF). The number of ACF was significantly decreased in mice treated with 0.4% (p < 0.001) and 0.8% DHEA (p < 0.001), but there were no significant differences between DHEA-treated and control mice in terms of the ACF size, 3-catenin expression or level of dysplasia. This is the first study of colon cancer carcinogenesis demonstrating that DHEA treatment can decrease the number of ACF without apparently modifying their malignant potential. These data strongly suggest that DHEA might be a potential chemopreventative agent against human colon cancer.