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Antithrombin Ⅲ injection via the portal vein suppresses liver damage

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World Journal of Gastroenterology 2012年第16期18卷 1884-1891页

作者： Masayuki Miyazaki Masaki Kato Masatake Tanaka Kosuke Tanaka Shinichiro Takao Motoyuki Kohjima Tetsuhide Ito Munechika Enjoji Makoto Nakamuta Kazuhiro Kotoh ryoichi takayanagi Department of Medicine and Bioregulatory Science Graduate School of Medical SciencesKyushu UniversityFukuoka 812-8582Japan Department of Gastroenterology Kyushu Medical CenterNational Hospital OrganizationFukuoka 810-0065Japan Department of Clinical Pharmacology Faculty of Pharmaceutical SciencesFukuoka UniversityFukuoka 814-0180Japan

AIM:To investigate the effects of antithrombin Ⅲ(AT Ⅲ) injection via the portal vein in acute liver failure.METHODS:Thirty rats were intraperitoneally challenged with lipopolysaccharide(LPS) and D-galactosamine(GalN) and divided into three groups:a control group;a group injected with AT Ⅲ via the tail vein;and a group injected with AT Ⅲ via the portal vein.AT Ⅲ(50 U/kg body weight) was administrated 1 h after challenge with LPS and GalN.Serum levels of inflammatory cytokines and fibrin degradation products,hepatic fibrin deposition,and hepatic mRNA expression of hypoxiarelated genes were analyzed.RESULTS:Serum levels of alanine aminotransferase,tumor necrosis factor-α and interleukin-6 decreased significantly following portal vein AT Ⅲ injection compared with tail vein injection,and control rats.Portal vein AT Ⅲ injection reduced liver cell destruction and decreased hepatic fibrin deposition.This treatment also significantly reduced hepatic mRNA expression of lactate dehydrogenase and heme oxygenase-1.CONCLUSION:A clinically acceptable dose of AT Ⅲ injection into the portal vein suppressed liver damage,probably through its enhanced anticoagulant and antiinflammatory activities.

关键词：静脉注射抗凝血酶肝损伤 mRNA表达水平 D-半乳糖纤维蛋白血红素加氧酶肝功能衰竭

Retroperitoneal fibrosis associated with immunoglobulin G4-related disease

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World Journal of Gastroenterology 2013年第1期19卷 35-41页

作者： Nao Fujimori Tetsuhide Ito Hisato Igarashi Takamasa Oono Taichi Nakamura Yusuke Niina Masayuki Hijioka Lingaku Lee Masahiko Uchida ryoichi takayanagi Department of Medicine and Bioregulatory Science Graduate School of Medical SciencesKyushu UniversityFukuoka 812-8582Japan

Retroperitoneal fibrosis is a rare disease characterized by the development of inflammation and fibrosis in the soft tissues of the retroperitoneum and other abdominal organs.Retroperitoneal fibrosis can be of 2 types:idiopathic and secondary.The recently advocated concept and diagnostic criteria of immunoglobulin G4(IgG4)-related disease,derived from research on autoimmune pancreatitis(AIP),has led to widespread recognition of retroperitoneal fibrosis as a condition caused by IgG4-related disease.We now know that previously diagnosed idiopathic retroperitoneal fibrosis includes IgG4-related disease;however,the actual prevalence is unclear.Conversely,some reports on AIP suggest that retroperitoneal fibrosis is concurrently found in about 10% of IgG4-related disease.Because retroperitoneal fibrosis has no specific symptoms,diagnosis is primarily based on diagnostic imaging(computed tomography and magnetic resonance imaging),which is also useful in evaluating the effect of therapy.Idiopathic retroperitoneal fibrosis can occur at different times with other lesions of IgG4-related disease including AIP.Thus,the IgG4 assay is recommended to diagnose idiopathic retroperitoneal fibrosis.High serum IgG4 levels should be treated and monitored as a symptom of IgG4-related disease.The first line of treatment for retroperitoneal fibrosis is steroid therapy regardless of its cause.For patients with concurrent AIP,i.e.,IgG4-related retroperitoneal fibrosis,the starting dose of steroid is usually 30-40 mg/d.The response to steroid therapy is generally favorable.In most cases,the pancreatic lesion and retroperitoneal fibrosis improve after the initial treatment.However,the epidemiology,treatment for recurring retroperitoneal fibrosis,and long-term prognosis are still largely unknown.Further analysis of such cases and research are necessary.

关键词： Autoimmune pancreatitis Extrapancreatic lesion Immunoglobulin G4 Immunoglobulin G4related disease Retroperitoneal fibrosis

Lysophosphatidic acid induced nuclear translocation of nuclear factor-κB in Panc-1 cells by mobilizing cytosolic free calcium

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World Journal of Gastroenterology 2008年第28期14卷 4473-4479页

作者： Yoshiyuki Arita Tetsuhide Ito Takamasa Oono Ken Kawabe Terumasa Hisano ryoichi takayanagi Department of Medicine and Bioregulatory Science Graduate School of Medical SciencesKyushu UniversityFukuoka 812-8582Japan

AIM: To clarify whether Lysophosphatidic acid (LPA) activates the nuclear translocation of nuclear factor-κB (NF-κB) in pancreatic cancer. METHODS: Panc-1, a human pancreatic cancer cell line, was used throughout the study. The expression of LPA receptors was confirmed by reverse-transcript polymerase chain reaction (RT-PCR). Cytosolic free calcium was measured by fluorescent calcium indicator fura-2, and the localization of NF-κB was visualized by immunofluorescent method with or without various agents, which effect cell signaling. RESULTS: Panc-1 expressed LPA receptors, LPA1, LPA2 and LPA3. LPA caused the elevation of cytosolic free calcium dose-dependently. LPA also caused the nuclear translocation of NF-κB. Cytosolic free calcium was attenuated by pertussis toxin (PTX) and U73122, an inhibitor of phospholipase C. The translocation of NF-κB was similarly attenuated by PTX and U73122, but phorbol ester, an activator of protein kinase C, alone did not translocate NF-κB. Furthermore, the translocation of NF-κB was completely blocked by Ca2+ chelator BAPTA-AM. Thapsigargin, an endoplasmic- reticulum Ca2+-ATPase pump inhibitor, also promoted the translocation of NF-κB. Staurosporine, a proteinkinase C inhibitor, attenuated translocation of NF-κB induced by LPA. CONCLUSION: These findings suggest that protein kinase C is activated endogenously in Panc-1, and protein kinase C is essential for activating NF-κB with cytosolic calcium and that LPA induces the nuclear translocation of NF-κB in Panc-1 by mobilizing cytosolic free calcium.

关键词：核因子-κB 治疗方法基因表达胰腺癌

Chemoradiotherapy with twice-weekly administration of low-dose gemcitabine for locally advanced pancreatic cancer

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World Journal of Gastroenterology 2008年第34期14卷 5311-5315页

作者： Hisato Igarashi Tetsuhide Ito Ken Kawabe Terumasa Hisano Yoshiyuki Arita Toyoma Kaku ryoichi takayanagi Department of Medicine and Bioregulatory Science Graduate School of Medical ScienceKyushu University

AIM:To evaluate the chemoradiotherapy for locally advanced pancreatic cancer utilizing low dose gemcitabine as a radiation sensitizer administered twice weekly. METHODS: We performed a retrospective analysis of chemoradiotherapy utilizing gemcitabine administered twice weekly at a dose of 40 mg/m2. After that, maintenance systemic chemotherapy with gemcitabine, at a dose of 1000 mg/m2, was administered weekly for 3 wk with 1-wk rest until disease progression or unacceptable toxicity developed. RESULTS: Eighteen patients with locally advanced unresectable pancreatic cancer were enrolled. Three of those patients could not continue with the therapy; one patient had interstitial pneumonia during radiation therapy and two other patients showed liver metastasis or peritoneal metastasis during an early stage of the therapy. The median survival was 15.0 mo and the overall 1-year survival rate was 60%, while the median progression-free survival was 8.0 mo. The subgroup which showed the reduction of tumor development, more than 50% showed a tendency for a better prognosis; however, other parameters including age, gender and performance status did not correlate with survival. The median survival of the groups that died of liver metastasis and peritoneal metastasis were 13.0 mo and 27.7 mo, respectively.CONCLUSION: Chemoradiotherapy with low-dose gemcitabine administered twice weekly could be effective to patients with locally advanced pancreatic cancer; however, patients developing liver metastases had a worse prognosis. Another chemoradiotherapy strategy might be needed for those patients, such as administrating one or two cycles of chemotherapy initially, followed by chemoradiotherapy for the cases with no distant metastases.

关键词：胰腺癌化学疗法肿瘤标志物药物剂量管理

Fractalkine and TGF-β1 levels reflect the severity of chronic pancreatitis in humans

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World Journal of Gastroenterology 2008年第42期14卷 6488-6495页

作者： Mikihiko Yasuda Tetsuhide Ito Takamasa Oono Ken Kawabe Toyoma Kaku Hisato Igarashi Taichi Nakamura ryoichi takayanagi Department of Medicine and Bioregulatory Science Graduate School of Medical Sciences Kyushu University Fukuoka 812-8582 Japan

AIM: To clarify whether serum chemokine and cytokine levels can become useful biological and functional markers to assess the severity of chronic pancreatitis (CP). This study aimed at clarifying whether serum chemokine and cytokine levels can become useful biological and functional markers to assess the severity of CP. METHODS: Serum monocyte chemoattractant protein-1 (MCP-1), transforming growth factor beta-1 (TGF-β1), and soluble type fractalkine (s-fractalkine) concentrations were examined in patients with CP (n = 109) and healthy controls (n = 116). Severity of disease was classified in patients with CP by a staging system. Relationships between stage-specifi c various clinical factors and serum MCP-1, TGF-β1, and s-fractalkine levels were investigated. Furthermore, 57 patients with non-alcoholic CP were similarly evaluated in order to exclude in? uence of alcohol intake. RESULTS: Patients with CP showed signifi cant higher levels of serum TGF-β1 and s-fractalkine, but not MCP-1, compared to the controls. Serum TGF-β1 in the severe stage and s-fractalkine in the mild and thesevere stage of CP significantly increased compared to those of controls. However, it was observed that both TGF-β1 and s-fractalkine levels were affected by alcohol intake. In patients with non-alcoholic CP, serum TGF-β1 showed significant increase in the moderate stage of CP, and serum s-fractalkine revealed signifi cant increase in the early stage of CP. CONCLUSION: It is suggested that the measurement of serum F-fractalkine is useful to diagnose early-stage CP. Moreover, the combined determination of both, s-fractalkine and TGF-β1, in human sera may be helpful in evaluating the severity status of CP.

关键词：慢性胰腺炎生长因子转换单核细胞化学诱导物

Exenatide improves hepatic steatosis by enhancing lipid use in adipose tissue in nondiabetic rats

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World Journal of Gastroenterology 2014年第10期20卷 2653-2663页

作者： Kosuke Tanaka Yuko Masaki Masatake Tanaka Masayuki Miyazaki Munechika Enjoji Makoto Nakamuta Masaki Kato Masatoshi Nomura Toyoshi Inoguchi Kazuhiro Kotoh ryoichi takayanagi Department of Medicine and Bioregulatory Science Graduate School of Medical Sciences Kyushu University Fukuoka 812-8582 Japan Department of Clinical Pharmacology Faculty of Pharmaceutical Science Fukuoka University Fukuoka 814-0180 Japan Department of Gastroenterology Kyushu Medical Center National Hospital Organization Fukuoka 810-8563 Japan Innovation Center for Medical Redox Navigation Kyushu University Fukuoka 812-8582 Japan

AIM:To investigate the metabolic changes in skeletal muscle and/or adipose tissue in glucagon-like peptide-1-induced improvement of nonalcoholic fatty liver disease(NAFLD).METHODS:Male Wistar rats were fed either a control diet(control group)or a high-fat diet(HFD).After 4wk,the HFD-fed rats were subdivided into two groups;one group was injected with exenatide[HFD-Ex(+)group]and the other with saline[HFD-Ex(-)group]every day for 12 wk.The control group received saline and were fed a control diet.Changes in weight gain,energy intake,and oxygen consumption were analyzed.Glucose tolerance tests were performed after 8 wk of treatment.Histological assessments were performed in liver and adipose tissue.RNA expression levels of lipid metabolism related genes were evaluated in liver,skeletal muscle,and adipose tissue.RESULTS:Exenatide attenuated weight gain[HFDEx(-)vs HFD-Ex(+)]and reduced energy intake,which was accompanied by an increase in oxygen consumption and a decrease in the respiratory exchange ratio[HFD-Ex(-)vs HFD-Ex(+)].However,exenatide did not affect glucose tolerance.Exenatide reduced lipid content in the liver and adipose tissue.Exenatide did not affect the expression of lipid metabolism-related genes in the liver or skeletal muscle.In adipose tissue,exenatide significantly upregulated lipolytic genes,including hormone-sensitive lipase,carnitine palmitoyltransferase-1,long-chain acyl-CoA dehydrogenase,and acyl-CoA oxidase 1[HFD-Ex(-)vs HFD-Ex(+)].Exenatide also upregulated catalase and superoxide dismutase 2[HFD-Ex(-)vs HFD-Ex(+)].CONCLUSION:In addition to reducing appetite,enhanced lipid use by exenatide in adipose tissue may reduce hepatic lipid content in NAFLD,most likely by decreasing lipid influx into the liver.

关键词： Adipose tissue Energy expenditure Exenatide Glucag

Continuous regional arterial infusion therapy with gabexate mesilate for severe acute pancreatitis

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World Journal of Gastroenterology 2008年第41期14卷 6382-6387页

作者： Yoshifumi Ino Yoshiyuki Arita Tetsuro Akashi Toshinari Kimura Hisato Igarashi Takamasa Oono Masayuki Furukawa Ken Kawabe Keiichiro Ogoshi Jiro Ouchi Toshihiko Miyahara ryoichi takayanagi Tetsuhide Ito Department of Medicine and Bioregulatory Science Graduate School of Medical Sciences Kyushu University Department of Social Insurance Nakabaru Hospital Department of Gastroenterology Saiseikai Fukuoka General Hospital Department of Gastroenterology Fukuoka Higashi Medical Center Division of Gastroenterology National Kyushu Cancer Center National Hospital Organization Kyushu Medical Center

AIM: To evaluate the effi cacy of continuous regional arterial infusion therapy (CRAI) with gabexate mesilate and antibiotics for severe acute pancreatitis (SAP). METHODS: We conducted a prospective study on patients who developed SAP with or without CRAI. Out of 18 patients fulf illed clinical diagnostic criteria for SAP in Japan, 9 patients underwent CRAI, while 9 patients underwent conventional systemic protease inhibitor and antibiotics therapy (non-CRAI). CRAI was initiated within 72 h of the onset of pancreatitis. Gabexate mesilate (2400 mg/d) was continuously administered for 3 to 5 d. The clinical outcome including serum infl ammation-related parameters were examined. RESULTS: The duration of abdominal pain in the CRAI group was 1.9 ± 0.26 d, whereas that in the non-CRAI group was 4.3 ± 0.50. The duration of SIRS in the CRAI group was 2.2 ± 0.22 d, whereas that in the non- CRAI group was 3.2 ± 0.28. Abdominal pain and SIRS disappeared signifi cantly in a short period of time after the initiation of CRAI using gabexate mesilate. The average length of hospitalization signifi cantly differed between the CRAI and non-CRAI groups, 53.3 ± 7.9 d and 87.4 ± 13.9 d, respectively. During the first two weeks, levels of serum CRP and the IL6/IL10 ratio in the CRAI group tended to have a rapid decrease compared to those in the non-CRAI group. CONCLUSION: The present results suggest that CRAI using gabexate mesilate was effective against SAP.

关键词：急性胰腺炎动脉输液抗生素疗效

Vasoactive Intestinal Peptide (VIP) and VIP Receptors-Elucidation of Structure and Function for Therapeutic Applications

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International Journal of Clinical Medicine 2011年第4期2卷 500-508页

作者： Hisato Igarashi Nao Fujimori Tetsuhide Ito Taichi Nakamura Takamasa Oono Kazuhiko Nakamura Koichi Suzuki Robert T Jensen ryoichi takayanagi 不详

Vasoactive intestinal peptide (VIP) is a 28-amino acid polypeptide first isolated from swine duodenum. VIP is a neurotransmitter that is extensively distributed in tissues. According to published reports, VPAC1 and VPAC2 act as VIP receptors and are widely present in the central nervous system and peripheral tissues. VIP exerts diverse actions on the cardiovascular system, pancreas, digestive tract, respiratory system, and urological system. Recent reports indicated that VIP has immunological and neuroprotective effects and also affects cell growth. While primary investigations for developing therapeutic applications for various pathological conditions and diseases are underway, the structure and function of VIP should be analyzed in more detail.

关键词： Vasoactive Intestinal Peptide VIP VPAC

Mucosal-incision assisted biopsy for suspected gastric gastrointestinal stromal tumors

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World Journal of Gastrointestinal Endoscopy 2013年第4期5卷 191-196页

作者： Eikichi Ihara Hiroshi Matsuzaka Kuniomi Honda Yoshitaka Hata Yorinobu Sumida Hirotada Akiho Tadashi Misawa Satoshi Toyoshima Yoshiharu Chijiiwa Kazuhiko Nakamura ryoichi takayanagi Department of Medicine and Bioregulatory Science Graduate School of Medical Sciences Kyushu University Department of Gastroenterology Hara-Sanshin General Hospital Department of Gastroenterology Kita-kyushu Municipal Medical Center Department of Pathology Kitakyushu Municipal Medical Center

To evaluate the diagnostic yield of the procedure, mucosal-incision assisted biopsy (MIAB), for the histological diagnosis of gastric gastrointestinal stromal tumor (GIST), we performed a retrospective review of the 27 patients with suspected gastric GIST who underwent MIAB in our hospitals. Tissue samples obtained by MIAB were sufficient to make a histological diagnosis (diagnostic MIAB) in 23 out of the 27 patients, where the lesions had intraluminal growth patterns. Alternatively, the samples were insufficient (non-diagnosticMIAB) in remaining 4 patients, three of whom had gastric submucosal tumor with extraluminal growth patterns. Although endoscopic ultrasound and fine needle aspiration is the gold standard for obtaining tissue specimens for histological and cytological analysis of suspected gastric GISTs, MIAB can be used as an alternative method for obtaining biopsy specimens of lesions with an intraluminal growth pattern.

关键词： Endoscopic ultrasound-guided fine-needle aspiration Gastrointestinal stromal tumor Mucosalincision assisted biopsy Submucosal tumor Endoscopic submucosal dissection