Journal of Clinical Biochemistry and Nutrition
Online ISSN : 1880-5086
Print ISSN : 0912-0009
Advance online publication
Showing 1-24 articles out of 24 articles from Advance online publication
  • Tomohisa Takagi, Yuji Naito, Katsura Mizuhima, Yasuko Hirai, Akihito H ...
    Type: Original Article
    Article ID: 17-133
    Published: 2018
    [Advance publication] Released: July 12, 2018
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    Heme oxygenases (HOs) are rate-limiting enzymes catabolizing heme to biliverdin, ferrous iron, and carbon monoxide, and of the three HO isoforms identified, HO-1 plays a protective role against inflammatory processes. In this study, we investigated the possible role of HO-1 in intestinal inflammation. Acute colitis was induced in male C57BL/6 (wild-type) and homozygous BTB and CNC homolog 1 (Bach1)-deficient mice, which show high HO-1 expression in the colonic mucosa, using dextran sodium sulfate. The disease activity index, myeloperoxidase activity, and inflammatory cytokines in the colonic mucosa were evaluated 7 days after dextran sodium sulfate-dependent colitis induction. We also evaluated the impact of HO-1 inhibition using zinc protoporphyrin IX (25 mg/kg i.p., daily). After dextran sodium sulfate administration, HO-1 mRNA and protein expression increased in a time-dependent manner. Disease activity index score, myeloperoxidase activity, and colonic production of TNF-α and IFN-γ were increased after dextran sodium sulfate administration, and co-administration of zinc protoporphyrin IX enhanced their increase. In addition, disease activity index in Bach1-deficient was significantly lower after dextran sodium sulfate administration than that in wild type mice. These results indicate that HO-1 plays a protective role against dextran sodium sulfate-induced intestinal inflammation, possibly by regulating pro-inflammatory cytokines in intestinal tissues.

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  • Agustin Martin Morales, Rie Mukai, Kaeko Murota, Junji Terao
    Type: Original Article
    Article ID: 18-38
    Published: 2018
    [Advance publication] Released: July 12, 2018
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    To determine the preventive effect of dietary rutin on oxidative damages occurring in the digestive tract, 13-hydroperoxyoctadecadienoic acid and hemoglobin were exposed to Caco-2 intestinal cells after the pretreatment with colonic rutin metabolites. Among four catechol-type metabolites, quercetin and 3,4-dihydroxytoluene exerted significant protection on 13-hydroperoxyoctadecadienoic and hemoglobin-dependent lipid peroxidation of this epithelial cell. Compared with quercetin, a much lower concentration allowed 3,4-dihydroxytoluene to maximize the protective effect, though it needed a longer pre-incubation period. Neither quercetin nor 3,4-dihydroxytoluene affected the expression of peroxiredoxin-6 protein, which comprises the cellular antioxidant defense system. It is concluded that 3,4-dihydroxytoluene is a plausible rutin colonic metabolite that can suppress oxidative damages of intestinal epithelial cells by directly inhibiting lipid peroxidation. This result may illuminate the preventive role of dietary rutin against colorectal cancer incidence in relation to the consumption of red and processed meat.

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  • Yukiko Imi, Norie Yabiki, Maerjianghan Abuduli, Masashi Masuda, Hisami ...
    Type: Original Article
    Article ID: 17-141
    Published: 2018
    [Advance publication] Released: July 11, 2018
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    Excessive phosphate intake has been positively associated with renal and vascular dysfunction, conversely negatively associated with body fat accumulation. We investigated the effect of a high-phosphate diet on the expression of lipid metabolic genes in white adipose tissue and liver. Male 8-week-old Sprague–Dawley rats were fed a control diet containing 0.6% phosphate or a high-phosphate diet containing 1.5% phosphate for 4 weeks. In comparison to the control group, the HP group showed a significantly lower body fat mass and fasting plasma insulin level alongside decreased lipogenic and increased lipolytic gene expression in visceral fat. Additionally, the expression of genes involved in hepatic lipogenesis, hepatic glycogenesis, and triglyceride accumulation decreased in the high-phosphate group. Exogenous phosphate, parathyroid hormone, and fibroblast growth factor 23 did not directly affect the expression of lipolytic or lipogenic genes in 3T3-L1 adipocytes and HepG2 hepatocytes. Thus, the high-phosphate diet suppressed the activity of white adipose tissue by increasing lipolytic gene expression and decreasing lipogenic gene expression. These effects could have been caused by the lowered fasting plasma insulin level that occurred in response to the high-phosphate diet, but were not directly caused by the increases in plasma phosphate or phosphaturic hormones.

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  • Sayaka Iida, Yorihiro Yamamoto, Chisato Susa, Kana Tsukui, Akio Fujisa ...
    Type: Original Article
    Article ID: 18-6
    Published: 2018
    [Advance publication] Released: July 11, 2018
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    Although uric acid is known to react with many reactive oxygen species, its specific oxidation products have not been fully characterized. We now report that 5-N-carboxyimino-6-N-chloroaminopyrimidine-2,4(3H)-dione (CCPD) is a hypochlorite (ClO)-specific oxidation product of uric acid. The yield of CCPD was 40–70% regardless of the rate of mixing of ClO with uric acid. A previously reported product, allantoin (AL), was a minor product. Its yield (0–20%) decreased with decreasing rate of mixing of ClO with uric acid, indicating that allantoin is less important in vivo. Kinetic studies revealed that the formation of CCPD required two molecules of ClO per uric acid reacted. The identity of CCPD was determined from its molecular formula (C5H3ClN4O4) measured by LC/time-of-flight mass spectrometry and a plausible reaction mechanism. This assumption was verified by the fact that all mass fragments (m/z −173, −138, −113, and −110) fit with the chemical structure of CCPD and its tautomers. Isolated CCPD was stable at pH 6.0–8.0 at 37°C for at least 6 h. The above results and the fact that uric acid is widely distributed in the human body at relatively high concentrations indicate that CCPD is a good marker of ClO generation in vivo.

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  • Toshihiro Nishizawa, Hidekazu Suzuki, Masahide Arita, Yosuke Kataoka, ...
    Type: Original Article
    Article ID: 18-5
    Published: 2018
    [Advance publication] Released: June 20, 2018
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    Nausea and vomiting after esophagogastroduodenoscopy have not been studied in detail. The aim of this study was to evaluate the risk factors for post-endoscopic nausea. We performed a case-control study at the Toyoshima Endoscopy Clinic. Eighteen patients with post-endoscopic nausea and 190 controls without post-endoscopic nausea were analyzed. We conducted univariate and multivariate logistic regression analyses with respect to patient age; sex; body height; body weight; the use of psychotropic drugs as baseline medications; and the dosing amounts of midazolam, pethidine, flumazenil and naloxone. On univariate analysis, post-endoscopic nausea was significantly related with patient age (odds ratio = 0.946); female sex (odds ratio = 10.85); body weight (odds ratio = 0.975); and the dose per kg body weight of pethidine (odds ratio = 53.03), naloxone (odds ratio = 1.676), and flumazenil (odds ratio = 1.26). On multivariate analysis, the dose per kg body weight of pethidine (odds ratio = 21.67, p = 0.004) and female sex (odds ratio = 13.12, p = 0.047) were the factors independently associated with post-endoscopic nausea. The prevalence of nausea after esophagogastroduodenoscopy was 0.49% (18/3,654). In conclusion, post-endoscopic nausea was associated with the dose of pethidine and female sex.

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  • Bing Li, Junqing Zheng, Xia Zhang, Shan Hong
    Type: Original Article
    Article ID: 17-117
    Published: 2018
    [Advance publication] Released: June 08, 2018
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    The aim of the present study was to investigate the efficacy of oral administration of probiotic Lactobacillus casei Shirota and amoxicillin-sulbactam in treating childhood fast breathing pneumonia. 518 children diagnosed of fast breathing pneumonia were enrolled and randomly assigned to be administered either amoxicillin-sulbactam + Lactobacillus casei Shirota or amoxicillin-sulbactam + placebo. Primary outcome was defined as treatment failure before day 3, and secondary outcome was defined as treatment failure during follow-ups on day 6 and 12. Serum levels of tumor necrosis factor-α and interferon-γ were also examined at the end of day 3. Treatment failure rate before day 3 was significantly reduced in amoxicillin-sulbactam + Lactobacillus casei Shirota group compared to amoxicillin-sulbactam + placebo group. Serum levels of tumor necrosis factor-α and interferon-γ were both significantly reduced in amoxicillin-sulbactam + placebo group on day 3. On day 6 and 12, although treatment failure rates were higher than on day 3 in both groups, it was still significantly reduced in amoxicillin-sulbactam + Lactobacillus casei Shirota group. No severe adverse effects were observed in either treatment group. In conclusion, Probiotic Lactobacillus casei Shirota, in combination with amoxicillin-sulbactam, is more effective in treating childhood fast breathing pneumonia, which supports the potential clinical application of Lactobacillus casei Shirota as a safe supplement to amoxicillin-sulbactam therapy against childhood fast breathing pneumonia.

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  • Midori Nagase, Yorihiro Yamamoto, Jun Mitsui, Shoji Tsuji
    Type: Original Article
    Article ID: 17-131
    Published: 2018
    [Advance publication] Released: June 08, 2018
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    The redox balance of coenzyme Q10 in human plasma is a good marker of oxidative stress because the reduced form of coenzyme Q10 (ubiquinol-10) is very sensitive to oxidation and is quantitatively converted to its oxidized form (ubiquinone-10). Here we describe an HPLC method for simultaneous detection of ubiquinol-10 and ubiquinone-10 in human cerebral spinal fluid to meet a recent demand for measuring local oxidative stress. Since the levels of coenzyme Q10 in human cerebral spinal fluid are less than 1/500 of those in human plasma, cerebral spinal fluid extracted with 2-propanol requires concentration for electrochemical detection. Using human plasma diluted 500-fold with physiological saline as a pseudo-cerebral spinal fluid, we found that addition of tert-butylhydroquinone was effective in preventing the oxidation of ubiquinol-10. The optimized tert-butylhydroquinone concentration in the extraction solvent was 20 µM. The addition of 20 µM ascorbic acid or co-addition of tert-butylhydroquinone and ascorbic acid (20 µM each) were also effective in preventing the oxidation of ubiquinol-10, but ascorbic acid alone gave poor reproducibility. Good within day reproducibility was observed, and day-to-day analytical variance was excellent.

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  • Yujiro Henmi, Kazuki Kakimoto, Takuya Inoue, Kei Nakazawa, Minori Kubo ...
    Type: Original Article
    Article ID: 18-14
    Published: 2018
    [Advance publication] Released: June 08, 2018
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    We investigated the risk factors of and appropriate treatment for cytomegalovirus colitis in patients with ulcerative colitis, using quantitative polymerase chain reaction analysis to detect cytomegalovirus in the colonic mucosa. Between February 2013 and January 2017, patients with exacerbated ulcerative colitis who were admitted to our hospital were consecutively enrolled in this retrospective, single-center study. Patients were evaluated for cytomegalovirus using serology (antigenemia) and quantitative polymerase chain reaction analyses of the colonic mucosa, which were sampled during colonoscopy. Of 86 patients, 26 (30.2%) had positive quantitative polymerase chain reaction results for cytomegalovirus; only 4 were also positive for antigenemia. The ages of the cytomegalovirus DNA-positive patients were significantly higher than those of negative patients (p = 0.002). The mean endoscopic score of cytomegalovirus DNA-positive patients was significantly higher than that of cytomegalovirus DNA-negative patients. Treatment with combined immunosuppressants was associated with an increased risk of cytomegalovirus. Fourteen of 15 (93.3%) cytomegalovirus DNA-positive patients who were negative for antigenemia showed a clinical response to treatment with additional oral tacrolimus, without ganciclovir. cytomegalovirus reactivation in active ulcerative colitis is associated with age and combined immunosuppressant therapy. Because additional treatment with tacrolimus was effective, patients who are negative for antigenemia and cytomegalovirus DNA-positive colonic mucosa may recover without antiviral therapy.

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  • Takashi Himoto, Koji Fujita, Teppei Sakamoto, Takako Nomura, Asahiro M ...
    Type: Original Article
    Article ID: 18-30
    Published: 2018
    [Advance publication] Released: June 08, 2018
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    The role of free testosterone, that not bound to sex hormone-binding globulin, in male patients with HCV infection remains uncertain. We investigated whether free testosterone is involved in the progression to hepatic fibrosis/steatosis or insulin resistance in male patients with HCV-related chronic liver disease or not. Free androgen indices, which reflect circulating free testosterone levels, were calculated as 100 × total testosterone levels/sex hormone-binding globulin levels in 30 male patients with HCV-related chronic liver disease. Degrees of hepatic fibrosis and steatosis were evaluated by the New Inuyama Classification and the classification proposed by Brunt and colleagues, respectively. Insulin resistance was estimated by HOMA-IR values. Serum total testosterone levels were independent of hepatic fibrosis staging in the enrolled patients. However, circulating sex hormone-binding globulin levels were significantly increased in proportion to the severity of hepatic fibrosis. Therefore, free androgen indices were inversely correlated with the severity of hepatic fibrosis. Moreover, free androgen indices were inversely correlated with the grades of hepatic steatosis and HOMA-IR values in those patients. Our data suggest that lower circulating free testosterone levels may be recognized as the risk factor for more advanced hepatic fibrosis, steatosis and/or higher insulin resistance in male patients with HCV-related chronic liver disease.

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  • Shigeki Sakai, Atsushi Nishida, Masashi Ohno, Osamu Inatomi, Shigeki B ...
    Type: Original Article
    Article ID: 18-42
    Published: 2018
    [Advance publication] Released: June 08, 2018
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    We examined the effect of bortezomib, a proteasome inhibitor, on the development of dextran sulfate sodium (DSS)-induced colitis in mice. DSS-colitis was induced by the administration of 3% DSS in water in C57BL/6J mice. Bortezomib was intraperitoneally administered daily for 9 days from the start of DSS. Ubiquitination of IκBα was evaluated by immunoblot. Bortezomib significantly ameliorated DSS-induced body weight loss and reduced the disease activity. The translocation of NF-κBp65 into the nucleus was markedly suppressed in the DSS + bortezomib group compared to the DSS group, but this difference was not detected in submucosal tissue. Ubiquitinated IκBα in the cytoplasm of colon epithelial cells was increased in the DSS + bortezomib group compared to the DSS group. In HT-29 cells, bortezomib blocked tumor necrosis factor-α (TNF-α)-induced nuclear translocation of NF-κB and this was accompanied by an increase in ubiquitinated IκBα in the cytoplasm. The mRNA expression of inflammatory mediators in colonic epithelial cells was significantly reduced by the treatment of bortezomib. Bortezomib inhibited the nuclear translocation of NF-κB in colonic epithelial cells by suppressing the degradation of IκBα and contributed to an improvement in DSS colitis. Our study suggests that bortezomib may be a new treatment option for IBD.

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  • Azusa Hara, Kazuhiro Ota, Toshihisa Takeuchi, Yuichi Kojima, Yuki Hira ...
    Type: Original Article
    Article ID: 18-16
    Published: 2018
    [Advance publication] Released: May 25, 2018
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    Although low-dose aspirin (LDA) is known to induce small intestinal mucosal injury, the effect of dual antiplatelet therapy (DAPT; LDA + clopidogrel) on small intestinal mucosa in patients after percutaneous coronary intervention (PCI) for coronary stenosis is unknown. Fifty-one patients with a history of PCI and LDA use were enrolled, and 45 eligible patients were analyzed. Patients were grouped based on DAPT (DAPT: n = 10 and non-DAPT: n = 35) and proton pump inhibitor (PPI) use (PPI user: n = 22 and PPI-free patients: n = 23) to compare small intestinal endoscopic findings. The relationship between LDA-use period and small intestinal endoscopic findings was also examined. Multivariate analysis was performed to identify risk factors for LDA-induced mucosal injury using age, sex, DAPT, PPI, gastric mucoprotective drug, and LDA-use period. The rate of small intestinal mucosal injury incidence did not significantly differ between DAPT and non-DAPT patients (50% vs 51.1%, respectively; p = 0.94), or PPI users and PPI-free patients (50% vs 52.2%, respectively; p = 0.88). Additionally, LDA-use period of ≤24 months (n = 15) yielded a significantly higher rate of small intestinal mucosal injury incidence than LDA-use period >24 months (n = 30) (80% vs 36.7%, respectively; p = 0.006). Multivariate analysis revealed that a LDA-use period of ≤24 months was a significant risk factor for small intestinal mucosal injury (odds ratio: 19.5, 95% confidence interval: 2.48–154.00, p = 0.005). Following PCI for coronary stenosis, neither DAPT nor PPI affected LDA-induced small intestinal mucosal injury. Moreover, patients who used LDA within the last 24 months were at a greater risk of small intestinal mucosal injury.

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  • Susan Park, Woori Na, Cheongmin Sohn
    Type: Original Article
    Article ID: 18-10
    Published: 2018
    [Advance publication] Released: May 12, 2018
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    Osteosarcopenic obesity syndrome is a condition including osteopenia, sarcopenia and obesity. A pro-inflammatory dietary pattern has been reported to be associated with obesity and osteoporosis. However, studies on the association of dietary inflammatory index with osteosarcopenic obesity syndrome in the Korean population are lacking. The aim of this study was to analyze the relationship between dietary inflammatory index and osteosarcopenic obesity syndrome among Korean postmenopausal women. We analyzed the 2009–2011 Korea National Health and Nutrition Examination Survey, consisting of 1,344 postmenopausal women aged 50 years or older. Body composition was evaluated by dual-energy X-ray absorptiometry. Dietary inflammatory index was estimated after analyzing 36 nutrients and 9 foods using a 24-h dietary recall data. The association between dietary inflammatory index levels and the body composition was analyzed by logistic regression models with dietary inflammatory index fit as a dichotomous variable. The dietary inflammatory index was −0.96 ± 0.22 in the normal group, 0.12 ± 0.16 in the osteopenic obesity group, 0.00 ± 0.18 in the osteosarcopenia group, 0.12 ± 0.33 in the sarcopenic obesity group, and −0.02 ± 0.14 in the osteosarcopenic obesity group (p<0.001). After adjusting for potential covariates, women with higher dietary inflammatory index scores were more likely to have risk of osteopenic obesity (OR = 2.757, 95% CI: 1.398–5.438, p<0.01) and that of osteosarcopenic obesity (OR = 2.186, 95% CI: 1.182–4.044, p<0.05). The results indicate that pro-inflammatory diet was associate with increased odds of the osteosarcopenic obesity in postmenopausal Korean women. Therefore, studies are needed to identify the effects of anti-inflammatory diets, which can reduce the degree of inflammation through dietary intake.

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  • Yuji Matsui, Hideo Iwahashi
    Type: Original Article
    Article ID: 18-8
    Published: 2018
    [Advance publication] Released: May 09, 2018
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    This study examines oxidizability in individual aqueous solutions of oleic acid, linoleic acid, α-linolenic acid, γ-linolenic acid and arachidonic acid, and in their mixtures. We used electron spin resonance (ESR), high performance liquid chromatography-electron spin resonance (HPLC-ESR) and high performance liquid chromatography-electron spin resonance-mass spectrometries (HPLC-ESR-MS). We detected 4-carboxybutyl radical derived from γ-linolenic acid, ethyl and 7-carboxyheptyl radicals derived from α-linolenic acid, and pentyl and 7-carboxyheptyl radicals derived from linoleic acid. HPLC-ESR analyses for the individual aqueous solutions of linoleic acid, α-linolenic acid, γ-linolenic acid and arachidonic acid showed less radical form for polyunsaturated fatty acids with more double bonds. On the other hand, HPLC-ESR peak height of 4-carboxybutyl radical, which form through hydrogen atom abstraction at the carbon close to the carboxy end, increased for linoleic acid/γ-linolenic acid, α-linolenic acid/γ-linolenic acid, and γ-linolenic acid/oleic acid mixtures compared to before mixing. Conversely, HPLC-ESR peak heights of ethyl, 7-carboxyheptyl and pentyl radicals, which form through hydrogen atom abstraction at the carbons close to the methyl end, decreased for linoleic acid/α-linolenic acid, linoleic acid/γ-linolenic acid, linoleic acid/oleic acid, linoleic acid/arachidonic acid, α-linolenic acid/γ-linolenic acid, and α-linolenic acid/oleic acid mixtures compared to before mixing.

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  • Daisuke Chinda, Tadashi Shimoyama, Kuniaki Miyazawa, Tetsu Arai, Shiro ...
    Type: Original Article
    Article ID: 18-12
    Published: 2018
    [Advance publication] Released: April 11, 2018
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    The aim of this study was to assess the perioperative invasiveness of endoscopic submucosal dissection for colorectal cancer quantitatively by using energy metabolism. In fifty-three patients who underwent endoscopic submucosal dissection for colorectal cancer, resting energy expenditure using an indirect calorimeter, body weight and basal energy expenditure using the Harris–Benedict equation before and after endoscopic submucosal dissection. Resting energy expenditure/body weight and resting energy expenditure/basal energy expenditure were 19.7 ± 2.5 kcal/kg/day and 0.96 ± 0.12 on the day of endoscopic submucosal dissection, whereas one day after the endoscopic submucosal dissection they increased to 21.0 ± 2.9 kcal/kg/day and 1.00 ± 0.13 (p<0.001 and p<0.05, respectively). The stress factor on the postoperative day 1 was computed as 1.06. The increase was lower comparing with that experienced for surgery, suggesting that the perioperative invasiveness of colorectal endoscopic submucosal dissection is lower in comparison to that during surgery. Furthermore, in spite of technical difficulty, stress factor of colorectal endoscopic submucosal dissection was approximately equal to that of gastric endoscopic submucosal dissection. (The study of the resting energy metabolism and stress factor using an indirect calorimeter in the perioperative period of endoscopic operation: UMIN000027135)

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  • Shoji Yamada, Masaki Kimura, Yoshimasa Saito, Hidetsugu Saito
    Type: Original Article
    Article ID: 17-125
    Published: 2018
    [Advance publication] Released: April 03, 2018
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    The exact mechanisms of hepatocellular carcinoma development in non-alcoholic steatohepatitis remain unclear. In this study, we used a new class of high-fat diet, which could induce hepatocellular carcinoma development without the use of general chemical carcinogens or knockout mice. We investigated the correlation between hepatocellular carcinoma and oxidative stress/anti-oxidant effects after depletion of the gut microbiota by treatment with antibiotics. Mice fed with the steatohepatitis-inducing high-fat diet (STHD-01) for 41 weeks developed hepatocellular carcinoma. Antibiotic-treatment in mice fed with STHD-01 significantly depleted the gut microbiota and significantly ameliorated liver injury/histology. The tumor numbers of hepatocellular carcinoma were dramatically decreased by the antibiotics-treatment. We analyzed the factors involved in oxidative stress and anti-oxidant effects. Oxidative stress was elevated in mice fed with STHD-01, whereas some anti-oxidant factors were significantly elevated after antibiotics treatment. These results suggest that the gut microbiota is a key factor in improving oxidative stress induced by STHD-01 feeding.

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  • Shiro Nakamura, Toshio Watanabe, Sunao Shimada, Yuji Nadatani, Koji Ot ...
    Type: Original Article
    Article ID: 17-142
    Published: 2018
    [Advance publication] Released: April 03, 2018
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    A large proportion of patients demonstrating obscure gastrointestinal bleeding (OGIB) are antithrombotic users and need to undergo small bowel capsule endoscopy (SBCE). We examined the effect of discontinuation of antithrombotics on the diagnostic yield of SBCE. Additionally, we assessed predictive factors associated with positive SBCE findings. Our study included 130 patients using antithrombotics who underwent SBCE for overt OGIB. The primary endpoint was the difference in the rate of positive SBCE findings between patients who continued and those who discontinued antithrombotics. Secondary endpoints were to investigate the effect of discontinuation of antithrombotics using a propensity score analysis, and to assess predictive factors associated with a positive SBCE. Among the 73 patients who continued use of antithrombotics, 36 (49.3%) patients demonstrated positive findings, while among the 57 patients who discontinued antithrombotics, 35 (61.4%) patients showed positive findings. Rates of positive SBCE findings didn’t differ between the two groups. After we performed propensity score matching, discontinuation didn’t affect the rate of positive SBCE findings. The lowest hemoglobin level was the only independent predictive factor associated with positive SBCE findings. In conclusion, discontinuation of antithrombotic therapy didn’t affect the diagnostic yield of SBCE in patients presenting with overt OGIB.

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  • Noriyuki Kitagawa, Masahide Hamaguchi, Saori Majima, Takuya Fukuda, To ...
    Type: Original Article
    Article ID: 17-64
    Published: 2018
    [Advance publication] Released: April 03, 2018
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    Dipeptidyl peptidase-4 (DPP-4) is a critical molecule for the metabolism of incretins. In addition, DPP-4 is known as CD26, the receptor of T cells, and plays important role in activation of T cells. Recently, DPP-4 inhibitors (DPP4i) are reported to have several immunologic effects beyond glycemic control. DPP4i seem to have anti-inflammatory effects in patients with type 2 diabetes. This might be direct effects on T cells. However, the close mechanism is not clear. To evaluate the possibility, we performed ex vivo assays by using primarily human CD4+ T cells (CD4) and CD8+ T cells (CD8). We purified primary naïve CD4 and CD8 from human peripheral blood. Then, we evaluated the effect of DPP4i on the proliferation of naïve T cells and the cytokine production in ex vivo experiments. The proliferation of CD4 and CD8 were suppressed by adding DPP4i in a dose dependent manner. However, DPP4i did not inhibit cytokine production from CD4. It was revealed by phospho-flow that the T cell receptor (TCR) signaling was attenuated in the presence of DPP4i. Taken together, DPP4i modulated TCR signaling, which contributed to attenuate the proliferation of CD4 and CD8. DPP4i have adverse effects for the proliferation of human T cells.

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  • Keisuke Nakai, Jiro Watari, Katsuyuki Tozawa, Akio Tamura, Ken Hara, T ...
    Type: Original Article
    Article ID: 18-11
    Published: 2018
    [Advance publication] Released: April 03, 2018
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    To investigate sex differences in the associations among metabolic syndrome, obesity, adipose tissue-related biomarkers, and colorectal adenomatous polyps, a cross-sectional, multicenter study was conducted on 489 consecutive individuals who underwent their first colonoscopy at 3 hospitals. Plasma concentrations of adiponectin and leptin, as well as homeostatic model assessment of insulin resistance were also evaluated. The presence and number of adenomatous polyps, including advanced adenoma, were higher in men than in women. Metabolic syndrome was a risk factor for adenomatous polyps in both sexes. Large waist circumference was an independent risk factor for adenomatous polyps in men, and high BMI and large waist circumference were risk factors for adenomatous polyps in women. Interestingly, low BMI was associated with large adenomatous polyps (≥10 mm) and advanced adenoma, and waist-hip ratio was involved in proximal adenomatous polyp development only in women. In contrast, the highest quartile of leptin concentration had a 3.67-fold increased adenomatous polyp risk compared with the lowest quartile only in men. These results indicate that regarding colorectal pathogenesis, sex differences were identified in obesity but not in metabolic syndrome. Visceral obesity and a high serum leptin level may be risk factors for colorectal adenomatous polyp development in Japanese men.

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  • Yukihiro Ogawa, Emiko Sekine-Suzuki, Megumi Ueno, Ikuo Nakanishi, Ken- ...
    Type: Original Article
    Article ID: 18-15
    Published: 2018
    [Advance publication] Released: April 03, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    The generation of localized hydroxyl radical (OH) in aqueous samples by low linear energy transfer irradiation was investigated. Several concentrations of 5,5-dimethyl-1-pyrroline-N-oxid solution (from 0.5 to 1,680 mmol/L) were prepared and irradiated with an identical dose of X-ray or γ-ray. The density of OH generation in aqueous solution was evaluated by the electron paramagnetic resonance spin-trapping technique using 5,5-dimethyl-1-pyrroline-N-oxid as an electron paramagnetic resonance spin-trapping agent. The relationship between the molecular density of 5,5-dimethyl-1-pyrroline-N-oxid in the samples and the concentration of 5,5-dimethyl-1-pyrroline-N-oxid-OH generated in the irradiated samples was analyzed. Two different characteristic linear trends were observed in the 5,5-dimethyl-1-pyrroline-N-oxid-OH/5,5-dimethyl-1-pyrroline-N-oxid plots, which suggested OH generation in two fashions, i.e., mmol/L- and mol/L-level local concentrations. The dose, dose rate, and/or the energy of photon irradiation did not affect the shapes of the 5,5-dimethyl-1-pyrroline-N-oxid-OH/5,5-dimethyl-1-pyrroline-N-oxid plots. Moreover, the addition of 5 mmol/L caffeine could cancel the contribution of mmol/L-level OH generation, leaving a trace of mol/L-level OH generation. Thus, the localized mmol/L- and mol/L-level generations of OH, which were independent of experimental parameters such as dose, dose rate, and/or the energy of photon of low linear energy transfer radiation, were established.

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  • Ingrid Žitňanová, Pavel Šiarnik, Matej Füllöp, Stanislav Oravec, Adela ...
    Type: Original Article
    Article ID: 17-105
    Published: 2018
    [Advance publication] Released: March 30, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    The aim of our study was to examine gender differences of LDL- and HDL-cholesterol subfractions in patients after the acute ischemic stroke with focus on small LDL and HDL subfractions, and their association with oxidative stress markers. In addition, we have monitored the 7-day effect of cholesterol-lowering drugs administered to patients after the acute ischemic stroke, on these subfractions. Eighty two stroke patients and 81 age matched controls were included in this study. Blood was collected from patients within 24 h after the stroke (group A) and re-examined at the 7-day follow-up (group B). We have found gender differences in LDL- and HDL-subfractions in stroke patients, lipid-lowering drugs administered to acute ischemic stroke patients significantly reduced all measured parameters of lipoprotein profile. In the group A LDL1 subfraction positively correlated with activity of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) indicating a protective role of this subfraction. On the contrary, small HDL subfractions positively correlated with lipoperoxide levels and negatively with trolox equivalent antioxidant capacity in plasma suggesting a negative role of these subfractions. In this work we have confirmed the hypothesis of atherogenic properties of small HDL subfractions and anti-atherogenic properties of large LDL1-subfractions.

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  • Takanari Nakano, Ikuo Inoue, Yasuhiro Takenaka, Yuichi Ikegami, Norihi ...
    Type: Original Article
    Article ID: 17-116
    Published: 2018
    [Advance publication] Released: March 30, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Plant sterols are used as food additives to reduce intestinal cholesterol absorption. They also increase fecal neutral sterol (FNS) excretion irrespective of the absorption inhibition. Intestine-mediated reverse cholesterol transport, or trans-intestinal cholesterol efflux (TICE), provides the major part of the increase of FNS excretion. However, it is unknown whether plant sterols stimulate TICE or not. We have shown previously that TICE can be evaluated by brush border membrane (BBM)-to-lumen cholesterol efflux. Thus, we examined whether luminal plant sterols stimulate BBM-to-lumen cholesterol efflux in the intestinal tract or not in mice. Cannulated upper jejunum that had been pre-labeled with orally given 3H-cholesterol, was flushed and perfused to collect 3H-cholesterol effluxed back into the lumen from the BBM to estimate the efflux efficiency. Adding 0.5 mg/ml of plant sterols, but not cholesterol, in the perfusion solution doubled the efflux. Plant sterols enter the BBM and are effluxed back to the lumen rapidly, in which process cholesterol transporters in the BBM are involved. We thus speculate that phytosterols alter cholesterol flux in the BBM; thereby, increases BBM-to-lumen cholesterol efflux, resulting in the increased TICE.

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  • Midori Nagase, Yorihiro Yamamoto, Nozomi Matsumoto, Yasumichi Arai, No ...
    Type: Original Article
    Article ID: 17-124
    Published: 2018
    [Advance publication] Released: March 17, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Aging populations are expanding worldwide, and the increasing requirement for nursing care has become a serious problem. Furthermore, successful aging is one of the highest priorities for individuals and societies. Centenarians are an informative cohort to study and inflammation has been found to be a key factor in predicting cognition and physical capabilities. Inflammation scores have been determined based on the levels of cytokines and C-reactive protein, however, serum antioxidants and lipid profiles have not been carefully examined. We found that the redox balance of coenzyme Q10 significantly shifted to the oxidized form and levels of strong antioxidants, such as ascorbic acid and unconjugated bilirubin, decreased significantly compared to 76-year-old controls, indicating an increased oxidative stress in centenarians. Levels of uric acid, an endogenous peroxynitrite scavenger, remained unchanged, suggesting that centenarians were experiencing moderate, chronic inflammatory conditions. Centenarians exhibited a hypocholesterolemic condition, while an increase in the ratio of free cholesterol to cholesterol esters suggests some impairment of liver function. Serum free fatty acids and monoenoic acid composition, markers of tissue oxidative damage, were significantly decreased in centenarians, indicating an impairment in the tissue repair system. Despite an elevation of the coenzyme Q10 binding protein Psap, serum total coenzyme Q10 levels decreased in centenarians. This suggests a serious deficiency of coenzyme Q10 in tissues, since tissue levels of coenzyme Q10 significantly decrease with age. Therefore, coenzyme Q10 supplementation could be beneficial for centenarians.

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  • Junko Yamaguchi, Midori Nagase, Yorihiro Yamamoto, Atsushi Sakurai, Ai ...
    Type: Original Article
    Article ID: 17-130
    Published: 2018
    [Advance publication] Released: March 17, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Sepsis remains one of the leading causes of death in intensive care units. The early phase of sepsis is characterized by a massive formation of reactive oxygen and nitrogen species such as superoxide and nitric oxide. However, few comprehensive studies on plasma antioxidants have been reported. Increased oxidative stress was confirmed in sepsis patients (n = 18) at the time of hospitalization by a significant decrease in plasma ascorbic acid and a significant increase in the percentage of oxidized form of coenzyme Q10 in total coenzyme Q10 compared to age-matched healthy controls (n = 62). Tissue oxidative damage in patients was suggested by a significant decrease in polyunsaturated fatty acid contents and a significant increase in oleic acid contents in total free fatty acids. Thus, it is reasonable that plasma uric acid (end product of purines) would be significantly elevated. However, uric acid levels were continuously decreased during hospitalization for 7 days, indicating a continuous formation of peroxynitrite. A greater decrease in free cholesterol (FC) compared to cholesterol esters (CE) was observed. Thus, the FC/CE ratio significantly increased, suggesting deficiency of lecithin-cholesterol acyltransferase secreted from the liver. Plasma levels of prosaposin, a coenzyme Q10 binding protein, significantly decreased as compared to healthy controls. This may be correlated with renal injury in sepsis patients, since the kidney is thought to be a major secretor of prosaposin.

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  • Keiichi Koshinaka, Rie Ando, Akiko Sato
    Type: Original Article
    Article ID: 17-98
    Published: 2018
    [Advance publication] Released: March 17, 2018
    JOURNALS FREE ACCESS ADVANCE PUBLICATION

    Dietary intervention for preventing postprandial increases in glucose level by replacing high-glycemic index (GI) carbohydrates with lower-GI carbohydrate has been proposed as a strategy for treating insulin-resistant metabolic disorders such as type II diabetes. In this study, we examined the effect of short-term replacement of starch with a low-GI disaccharide, isomaltulose, on insulin action in skeletal muscle. Male Wistar rats were fed isomaltulose for 12 h during their dark cycle. In isolated epitrochlearis muscle, insulin-induced glucose uptake was greater in tissue from rats treated with isomaltulose than from those treated with starch. This insulin-sensitizing effect occurred independently of changes visceral fat mass. To determine whether this sensitization was specific to insulin stimulation, we also measured glucose uptake in response to exercise. In isolated epitrochlearis muscles from rats that performed swimming exercise, exercise-induced glucose uptake was higher in isomaltulose-treated than starch-treated animals. This amplification was associated with increased phosphorylation of exercise-induced AMP-activated protein kinase. In conclusion, our results demonstrate that short-term replacement of starch with isomaltulose enhances both insulin-dependent and -independent glucose uptake in isolated skeletal muscle. This transient replacement of carbohydrate with isomaltulose, together with exercise, represents a potentially effective approach for the management of insulin resistance.

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