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PubMed | Red Cross, Tokatsu Tsujinaka Hospital, Kyoundo Hospital, Kanto Central Hospital and 7 more.
Type: Journal Article | Journal: Journal of digestive diseases | Year: 2016

Vonoprazan is a potassium-competitive acid blocker, a new type of acid-suppressing drug, and has recently become available for peptic ulcers, gastroesophageal reflux disease, and Helicobacter pylori (H. pylori) eradication. Its efficacy for H. pylori eradication has been reported. However, the evidence for its efficacy and feasibility remains limited. We aimed to compare the feasibility, effectiveness and safety of vonoprazan-based triple therapy with conventional proton pump inhibitor (PPI)-based triple therapy in multicenter clinical practice.We performed a multicenter retrospective study on patients receiving first-line H. pylori eradication therapy between March 2013 and November 2015 with either vonoprazan-based triple therapy or conventional PPI-based triple therapy.A total of 2715 patients aged 63.012.1years (1412 [52.0%] males) were analyzed. Eradication rates were 87.2% (368/422) for vonoprazan-based therapy and 72.4% (1661/2293) for conventional PPI-based therapy (P<0.01). Among the former group, there were 10 cases of diarrhea, six of nausea/vomiting, and five of rash, but the rates of these adverse events were similar to those in the conventional PPI group.Vonoprazan-based triple therapy is feasible, and has a higher rate for H. pylori eradication than conventional PPI as a first-line regimen.


Nakarai H.,Hiroshima University | Yamashita A.,Hiroshima University | Nagayasu S.,Hiroshima University | Iwashita M.,Hiroshima University | And 8 more authors.
Innate Immunity | Year: 2012

Chronic low-grade infection has been suggested to be associated with metabolic disorder such as diabetes. However, the molecular mechanism underlying this important association is largely unknown. The only clue established so far is that many subjects exhibit elevated levels of C-reactive protein as measured by highly sensitive assay. Here, we hypothesized that adipocyte-macrophage interaction plays a key role in amplifying such low grade infection to the level of influencing metabolic disorders. The presence of macrophages in abdominal adipose tissues was investigated by immunohistochemistry. To see whether molecules associated with acute phase protein, LPS signaling, and persistent recruitment of monocytes, are produced at higher amounts in adipocytes co-cultured with macrophages stimulated with low concentration of LPS (1 ng/ml), we measured serum amyloid A (SAA), LPS binding protein (LBP), soluble CD14 (sCD14), and RANTES levels in culture supernatant of co-cultures. Lastly, we investigated in vivo effect of low-grade LPS infusion on the production of these molecules using obese model mice. The macrophages were certainly identified in abdominal adipose tissues. Investigated molecules, especially LBP, SAA, and RANTES were produced at higher amounts in co-cultures stimulated with LPS compared with the cells without LPS. The ob/ob, and high-fat diet-induced obesity mice produced higher amounts of LBP, SAA, and RANTES one day after LPS infusion (1 ng/ml/g body weight) compared with ob/- and normal-fat fed control mice. Thus, adipocytes and infiltrated macrophages, and their interaction with low endotoxin stimulation appear to play an important role in amplifying and maintaining LPS-induced low-grade inflammation. © The Author(s) 2011 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.


PubMed | Yakult Honsha Co., Tohoku University, University of Tokyo, Hiroshima University and 2 more.
Type: | Journal: Scientific reports | Year: 2016

Resistin-like molecule (RELM) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELM to non-alcoholic steatohepatitis (NASH) development. First, RELM knock-out (KO) mice were shown to be resistant to methionine-choline deficient (MCD) diet-induced NASH development. Since it was newly revealed that Kupffer cells in the liver express RELM and that RELM expression levels in the colon and the numbers of RELM-positive Kupffer cells were both increased in this model, we carried out further experiments using radiation chimeras between wild-type and RELM-KO mice to distinguish between the contributions of RELM in these two organs. These experiments revealed the requirement of RELM in both organs for full manifestation of NASH, while deletion of each one alone attenuated the development of NASH with reduced serum lipopolysaccharide (LPS) levels. The higher proportion of lactic acid bacteria in the gut microbiota of RELM-KO than in that of wild-type mice may be one of the mechanisms underlying the lower serum LPS level the former. These data suggest the contribution of increases in RELM in the gut and Kupffer cells to NASH development, raising the possibility of RELM being a novel therapeutic target for NASH.


Nakatsu Y.,Hiroshima University | Seno Y.,Hiroshima University | Kushiyama A.,Institute for Adult Disease | Sakoda H.,University of Miyazaki | And 9 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2015

Xanthine oxidase (XO) is an enzyme involved in the production of uric acid (UA) from purine nucleotides. Numerous recent studies have revealed the likelihood of metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) to be related to hyperuricemia. However, it remains unclear whether elevated serum UA during the development of NAFLD or NASH is a cause or a consequence of these diseases. In this study, the XO inhibitor febuxostat was administered to two types of NASH model mice. Febuxostat exerted a strong protective effect against NASH development induced by a high-fat diet containing trans fatty acid (HFDT). In contrast, methionine choline-deficient-diet-induced NASH development not accompanied by hyperuricemia showed no UA normalization, suggesting that the ameliorating effect of febuxostat occurs via the normalization of hyperuricemia itself and/or accompanying molecular mechanism(s) such as oxidative stress. In the HFDT-fed mice, hyperuricemia, elevated alanine aminotransferase, and increased Tunnelpositive cells in the liver were normalized by febuxostat administration. In addition, upregulation of fatty acid oxidation-related genes, fibrotic change, and increases in collagen deposition, inflammatory cytokine expressions, and lipid peroxidation in the HFDT-fed mice were also normalized by febuxostat administration. Taken together, these observations indicate that administration of febuxostat has a protective effect against HFDT-induced NASH development, suggesting the importance of XO in its pathogenesis. Thus XO inhibitors are potentially potent therapies for patients with NASH, particularly that associated with hyperuricemia. © 2015 the American Physiological Society.


Shinjo T.,Kyushu University | Nakatsu Y.,Hiroshima University | Iwashita M.,Kyushu University | Sano T.,Hiroshima University | And 9 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2015

Dipeptidyl peptidase IV (DPPIV) expression in visceral adipose tissue is reportedly increased in obese patients, suggesting an association of DPP-IV with inflammation. In this study, first, lipopolysaccharide (LPS)- or palmitateinduced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by coincubation with a DPP-IV inhibitor, anagliptin (10 μM), despite low DPP-IV expression in the RAW264.7 cells. Regarding the molecular mechanism, LPS-induced degradation of IκBα and phosphorylations of p65, JNK, and p38, as well as NF- κB and AP-1 promoter activities, were revealed to be suppressed by incubation with anagliptin, indicating suppressive effects of anagliptin on both NF- κB and AP-1 signaling pathways. Anagliptin also acted on 3T3-L1 adipocytes, weakly suppressing the inflammatory cytokine expressions induced by LPS and TNFα. When 3T3-L1 and RAW cells were cocultured and stimulated with LPS, the effects of anagliptin on the suppression of cytokine expressions in 3T3-L1 adipocytes were more marked and became evident at the 10 μM concentration. Anti-inflammatory effects of anagliptin were also observed in vivo on the elevated hepatic and adipose expressions and serum concentrations of inflammatory cytokines in association with the suppression of hepatic NF- κB transcriptional activity in LPS-infused mice. Taking these observations together, the anti-inflammatory properties of anagliptin may be beneficial in terms of preventing exacerbation of diabetes and cardiovascular events. © 2015 the American Physiological Society.


Okubo H.,Hiroshima University | Sakoda H.,University of Tokyo | Kushiyama A.,Institute for Adult Disease | Fujishiro M.,University of Tokyo | And 10 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2013

Gut microbiota alterations are associated with various disorders. In this study, gut microbiota changes were investigated in a methionine-choline-deficient (MCD) dietinduced nonalcoholic steatohepatitis (NASH) rodent model, and the effects of administering Lactobacillus casei strain Shirota (LcS) on the development of NASH were also investigated. Mice were divided into three groups, given the normal chow diet (NCD), MCD diet, or the MCD diet plus daily oral administration of LcS for 6 wk. Gut microbiota analyses for the three groups revealed that lactic acid bacteria such as Bifidobacterium and Lactobacillus in feces were markedly reduced by the MCD diet. Interestingly, oral administration of LcS to MCD diet-fed mice increased not only the L. casei subgroup but also other lactic acid bacteria. Subsequently, NASH development was evaluated based on hepatic histochemical findings, serum parameters, and various mRNA and/or protein expression levels. LcS intervention markedly suppressed MCD-diet-induced NASH development, with reduced serum lipopolysaccharide concentrations, suppression of inflammation and fibrosis in the liver, and reduced colon inflammation. Therefore, reduced populations of lactic acid bacteria in the colon may be involved in the pathogenesis of MCD diet-induced NASH, suggesting normalization of gut microbiota to be effective for treating NASH. © 2013 the American Physiological Society.


PubMed | Hiroshima University, University of Miyazaki, Institute for Adult Disease and University of Tokyo
Type: Comparative Study | Journal: American journal of physiology. Gastrointestinal and liver physiology | Year: 2015

Xanthine oxidase (XO) is an enzyme involved in the production of uric acid (UA) from purine nucleotides. Numerous recent studies have revealed the likelihood of metabolic syndrome including nonalcoholic fatty liver disease (NAFLD) or steatohepatitis (NASH) to be related to hyperuricemia. However, it remains unclear whether elevated serum UA during the development of NAFLD or NASH is a cause or a consequence of these diseases. In this study, the XO inhibitor febuxostat was administered to two types of NASH model mice. Febuxostat exerted a strong protective effect against NASH development induced by a high-fat diet containing trans fatty acid (HFDT). In contrast, methionine choline-deficient-diet-induced NASH development not accompanied by hyperuricemia showed no UA normalization, suggesting that the ameliorating effect of febuxostat occurs via the normalization of hyperuricemia itself and/or accompanying molecular mechanism(s) such as oxidative stress. In the HFDT-fed mice, hyperuricemia, elevated alanine aminotransferase, and increased Tunnel-positive cells in the liver were normalized by febuxostat administration. In addition, upregulation of fatty acid oxidation-related genes, fibrotic change, and increases in collagen deposition, inflammatory cytokine expressions, and lipid peroxidation in the HFDT-fed mice were also normalized by febuxostat administration. Taken together, these observations indicate that administration of febuxostat has a protective effect against HFDT-induced NASH development, suggesting the importance of XO in its pathogenesis. Thus XO inhibitors are potentially potent therapies for patients with NASH, particularly that associated with hyperuricemia.


PubMed | University of Miyazaki, Nihon University, University of Tokyo, Hiroshima University and 2 more.
Type: Journal Article | Journal: American journal of physiology. Endocrinology and metabolism | Year: 2015

Dipeptidyl peptidase IV (DPP-IV) expression in visceral adipose tissue is reportedly increased in obese patients, suggesting an association of DPP-IV with inflammation. In this study, first, lipopolysaccharide (LPS)- or palmitate-induced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by coincubation with a DPP-IV inhibitor, anagliptin (10 M), despite low DPP-IV expression in the RAW264.7 cells. Regarding the molecular mechanism, LPS-induced degradation of IB and phosphorylations of p65, JNK, and p38, as well as NF-B and AP-1 promoter activities, were revealed to be suppressed by incubation with anagliptin, indicating suppressive effects of anagliptin on both NF-B and AP-1 signaling pathways. Anagliptin also acted on 3T3-L1 adipocytes, weakly suppressing the inflammatory cytokine expressions induced by LPS and TNF. When 3T3-L1 and RAW cells were cocultured and stimulated with LPS, the effects of anagliptin on the suppression of cytokine expressions in 3T3-L1 adipocytes were more marked and became evident at the 10 M concentration. Anti-inflammatory effects of anagliptin were also observed in vivo on the elevated hepatic and adipose expressions and serum concentrations of inflammatory cytokines in association with the suppression of hepatic NF-B transcriptional activity in LPS-infused mice. Taking these observations together, the anti-inflammatory properties of anagliptin may be beneficial in terms of preventing exacerbation of diabetes and cardiovascular events.


Moriya T.,Kitasato University | Tanaka S.,Kyoto University | Kawasaki R.,Kyoto University | Ohashi Y.,University of Tokyo | And 5 more authors.
Diabetes Care | Year: 2013

OBJECTIVE-To examine the interactive relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in type 2 diabetic patients and to elucidate the role of DR and microalbuminuria on the onset of macroalbuminuria and renal function decline. RESEARCH DESIGN AND METHODS-We explored the effects of DR and microalbuminuria on the progression of DN from normoalbuminuria and low microalbuminuria (<150 mg/gCr) to macroalbuminuria or renal function decline in the Japan Diabetes Complications Study (JDCS), which is a nationwide randomized controlled study of type 2 diabetic patients focusing on lifestyle modification. Patients were divided into four groups according to presence or absence of DR and MA: normoalbuminuria without DR [NA(DR-)] (n = 773), normoalbuminuria with DR [NA(DR+)] (n = 279), microalbuminuria without DR [MA(DR2)] (n = 277), and microalbuminuria with DR [MA(DR+)] (n = 146). Basal urinary albumin-to-creatinine ratio and DR status were determined at baseline and followed for a median of 8.0 years. RESULTS-Annual incidence rates of macroalbuminuria were 1.6/1,000 person-years (9 incidences), 3.9/1,000 person-years (8 incidences), 18.4/1,000 person-years (34 incidences), and 22.1/1,000 person-years (22 incidences) in the four groups, respectively. Multivariate-adjusted hazard ratios of the progression to macroalbuminuria were 2.48 (95% CI 0.94-6.50; P = 0.07), 10.40 (4.91-22.03; P< 0.01), and 11.55 (5.24-25.45; P < 0.01) in NA(DR+), MA(DR-), and MA(DR+), respectively, in comparison with NA(DR-). Decline in estimated glomerular filtration rate (GFR) per year was two to three times faster in MA(DR+) (-1.92 mL/min/1.73m2/year) than in the other groups. CONCLUSIONS-In normo- and low microalbuminuric Japanese type 2 diabetic patients, presence ofmicroalbuminuria at baseline was associated with higher risk ofmacroalbuminuria in 8 years. Patients with microalbuminuria and DR showed the fastest GFR decline. Albuminuria and DR should be considered as risk factors of renal prognosis in type 2 diabetic patients. An open sharing of information will benefit both ophthalmologists and diabetologists. ©2013 by the American Diabetes Association.


Katayama S.,Saitama University | Moriya T.,Kitasato University | Tanaka S.,Kyoto University | Tanaka S.,Tokyo University of Science | And 6 more authors.
Diabetologia | Year: 2011

Aims/hypothesis: The aim of the study was to determine the transition rate and factors associated with the progression of normo- and low microalbuminuria to diabetic nephropathy (overt proteinuria). Methods: For 8 years we prospectively observed 1,558 Japanese patients with type 2 diabetes mellitus whose basal urinary albumin:creatinine ratio (UACR) had been measured as <17.0 mg/mmol at entry. The incidence of nephropathy (UACR >33.9 mg/mmol) was determined by measuring UACR twice a year. Results: Progression to nephropathy occurred in 74 patients. The annual transition rate was 0.67%, and was substantially higher for the low-microalbuminuric group than for the normoalbuminuric group (1.85% and 0.23%, respectively; hazard ratio for the low-microalbuminuric group 8.45, p<0.01). The hazard ratio for an HbA 1c of 7-9% or ≥9% was 2.72 (p<0.01) or 5.81 (p<0.01) relative to HbA1c <7.0%, respectively. In comparison with individuals with a systolic blood pressure (SBP) of <120 mmHg, the hazard ratios for patients with an SBP of 120-140 mmHg or ≥140 mmHg were 2.31 (p=0.06) and 3.54 (p<0.01), respectively. Smoking also affected progression to proteinuria (hazard ratio 1.99, p<0.01). In contrast, 30.3% of the low-microalbuminuric group returned to normoalbuminuria (i.e. were in remission). Conclusions/interpretation: These results suggest that if patients with type 2 diabetes mellitus are receiving treatment from diabetologists for hyperglycaemia and hypertension when they are in the early stages of nephropathy (i.e. normo- or low microalbuminuria), their rate of transition to proteinuria is considerably lowered, and that differentiating patients with low microalbuminuria from those with high microalbuminuria might be clinically useful. © The Author(s) 2011.

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