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Pathogenesis of NSAID-induced gastric damage:Importance of cyclooxygenase inhibition and gastric hypermotility

World Journal of Gastroenterology 2012年第18期18卷 2147-2160页

作者： koji takeuchi Department of Pharmacology and Experimental Therapeutics Division of Pathological SciencesKyoto Pharmaceutical UniversityKyoto 607-8414Japan

This article reviews the pathogenic mechanism of nonsteroidal anti-inflammatory drug(NSAID)-induced gastric damage,focusing on the relation between cyclooxygenase(COX) inhibition and various functional events.NSAIDs,such as indomethacin,at a dose that inhibits prostaglandin(PG) production,enhance gastric motility,resulting in an increase in mucosal permeability,neutrophil infiltration and oxyradical production,and eventually producing gastric lesions.These lesions are prevented by pretreatment with PGE 2 and antisecretory drugs,and also via an atropine-sensitive mechanism,not related to antisecretory action.Although neither rofecoxib(a selective COX-2 inhibitor) nor SC-560(a selective COX-1 inhibitor) alone damages the stomach,the combined administration of these drugs provokes gastric lesions.SC-560,but not rofecoxib,decreases prostaglandin E 2(PGE 2) production and causes gastric hypermotility and an increase in mucosal permeability.COX-2 mRNA is expressed in the stomach after administration of indomethacin and SC-560 but not rofecoxib.The up-regulation of indomethacin-induced COX-2 expression is prevented by atropine at a dose that inhibits gastric hypermotility.In addition,selective COX-2 inhibitors have deleterious influences on the stomach when COX-2 is overexpressed under various conditions,including adrenalectomy,arthritis,and Helicobacter pylori-infection.In summary,gastric hypermotility plays a primary role in the pathogenesis of NSAID-induced gastric damage,and the response,causally related with PG deficiency due to COX-1 inhibition,occurs prior to other pathogenic events such as increased mucosal permeability;and the ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2,the inhibition of COX-1 upregulates COX-2 expression in association with gastric hypermotility,and PGs produced by COX-2 counteract the deleterious effect of COX-1 inhibition.

关键词：胃粘膜损伤非甾体抗炎药发病机理 COX-2抑制剂环氧化酶 COX-1 前列腺素E 致病机制

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Stimulation by nizatidine,a histamine H_2-receptor antagonist,of duodenal HCO_3^-secretion in rats:relation to anti-cholinesterase activity

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World Journal of Gastroenterology 2000年第5期6卷 651-658页

作者： koji takeuchi Shoji Kawauchi Hideo Araki Shigeru Ueki Osamu Furukawa Department of Pharmacology and Experimental Therapeutics Kyoto Pharmaceutical UniversityMisasagiYamashinaKyoto 607-8414Japan CURE Bldg.114Suite 217 West LA VAMC 11301 Wilshire Blvd.Los AngelesCA 90073

AIM To examine whether nizatidine stimulatesduodenal HCO3- secretion in rats by inhibitingAChE activity.METHODS Under pentobarbital anesthesia,aproximal duodenal loop was perfused withsaline,and the HCO3 secretion was measuredat pH 7.0 using a pH-stat method and by adding10mM HCI.Nizatidine,neostigmine,carbacholor famotidine was administered i.***.as a singleinjection.RESULTS Intravenous administration ofnizatidine（3-30 mg/kg）dose-dependentlyincreased duodenal HCO3- secretion,and theeffect at 10mg/kg was equivalent to thatobtained by carbachol at 0.01 mg/kg.Thisnizatidine action was observed at the same doserange that inhibited acid secretion and enhancedgastric motility,mimicked by i.***.injection ofneostigmine（0.03 mg/kg）,and significantlyattenuated by bilateral vagotomy and prior s.***.administration of atropine but not byindomethacin,a cyclooxygenase inhibitor,orNG-nitro-L-arginine methyl ester,a NO synthaseinhibitor.The HCO3- secretory response toacetylcholine（0.001 mg/kg）was significantlypotentiated by the concurrent administration ofnizatidine（3mg/kg,i.v.）.The IC50of nizatidine for AChE of rat erythrocytes was1.4×10-6M,about 12 times higher than that ofneostigmine.Neither famotidine(>10-3M,30mg/kg,i.v.)nor cisapride(> 10-3M,3mg/kg,i.v.)had any influence on AChEactivity or duodenal HCO3- secretion.Duodenaldamage induced by acid perfusion（100 mM HCIfor 4 h）in the presence of indomethacin wassignificantly prevented by nizatidine andneostigmine,at the doses that increased theHCO3- secretion.CONCLUSION Nizatidine stimulates duodenalHCO3- secretion,in both vagal-dependent andatropine-sensitive manners,and the action isassociated with the anti-AChE activity of thisagent.

关键词： nizatidine histamine H2 receptor blockaders duodenal HCO3-secretion cholinesterase inhibitors rats

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Gastro-protective action of lafutidine mediated by capsaicin-sensitive afferent neurons without interaction with TRPV1 and involvement of endogenous prostaglandins

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World Journal of Gastroenterology 2006年第19期12卷 3031-3037页

作者： Kazuhiro Fukushima Yoko Aoi Shinichi Kato koji takeuchi Department of Pharmacology and Experimental Therapeutics Kyoto Pharmaceutical University MisasagiYamashinaKyoto 607-8414Japan

瞄准：Lafutidine，一个组织安 H2 受体对手，展览胃保护的行动由 capsaicin 敏感的传入神经元(CSN ) 调停了。我们比较了在 lafutidine 和辣椒辣素之间的效果，关于和内长的前列腺素(PG ) 的相互作用，氮的氧化物(没有) 并且传入神经... 详细信息

瞄准：Lafutidine，一个组织安 H2 受体对手，展览胃保护的行动由 capsaicin 敏感的传入神经元(CSN ) 调停了。我们比较了在 lafutidine 和辣椒辣素之间的效果，关于和内长的前列腺素(PG ) 的相互作用，氮的氧化物(没有) 并且传入神经元，包括短暂受体潜力 vanilloid 子类型 1 (TRPV1 ) 。方法：男 SD 老鼠和 C57BL/6 老鼠，野类型并且 prostacyclin IP 受体大美人动物，在禁食的 18 h 以后被使用。胃的损害被 HCl/ethanol 的 po 管理导致(60% 在 150 mmol/L HCl ) 在为老鼠的 1 mL 或为老鼠的 0.3 mL 的体积。结果：lafutidine 和辣椒辣素(1-10 mg/kg， po ) 对在老鼠和老鼠的 HCl/ethanol 的负担得起的剂量依赖者保护。效果被两个稀释有 N (G)-nitro-L-arginine 甲基酉旨的 CSN 和预告的处理的脱离，然而，仅仅辣椒辣素的效果被 capsazepine， TRPV1 对手，以及消炎痛的优先的管理减轻。Lafutidine 在 IP 受体大美人老鼠保护了胃免于 HCl/ethanol，类似于野类型的动物，当辣椒辣素没能在缺乏 IP 受体的动物负担得起保护时。任何一个这些代理人都没在老鼠胃影响粘膜 PGE2 或 6-keto PGF (1alpha ) 内容。辣椒辣素唤起了增加在[Ca2+] 在老鼠 TRPV1-transfected HEK293 房间的 i 当时 lafutidine 不。结论：这些结果建议尽管 lafutidine 和辣椒辣素展出，胃保护的行动由 CSN 调停了，他们的效果的模式在内长的 PGs/IP 受体和 TRPV1 上关于相关性不同。lafutidine 在除 TRPV1 以外的还未辩别出的地点与 CSN 交往，这被假定。

关键词：保护作用辣椒素神经元前列腺素胃保护

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Measurement of shear wave velocities coupled with an evaluation of elasticity using ARFI elastography in diagnosis of papillary thyroid carcinoma

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Open Journal of Clinical Diagnostics 2013年第4期3卷 178-182页

作者： Ryuhei Okada Masami Suzuki koji takeuchi Hiroyuki Horikoshi Atsunobu Tsunoda Department of Head and Neck Surgery Gunma Prefectural Cancer Center Gunma Japan Department of Otolaryngology Tokyo Medical and Dental University Tokyo Japan Department of Radiological Diagnosis Gunma Prefectural Cancer Center Gunma Japan

This study aimed to evaluate the diagnostic value of measuring the shear wave velocities (Vs) of thyroid nodules in diagnosis of the thyroid carcinoma. Using Virtual Touch Tissue Quantification (VTTQ) of acoustic radiation force impulse (ARFI) elastography (ACUSON S2000®, Siemens Medical Solutions, Mountain View, CA, USA), we measured the Vs of thyroid nodules in 39 nodules from 34 patients (four males and 30 females) before surgery. Elasticity itself was also estimated by VTTI (Virtual Touch Tissue Imaging) using ARFI. The average Vs of normal thyroid tissue was 2.24 ± 0.68 m/s. Twenty-three out of 39 nodules showed an average 2.52 ± 1.33 m/s. However, 16 other nodules showed “X.XX m/s”. These 16 nodules showed either “black” or “honeycomb” patterns of elasticity in VTTI. This value suggested that the Vs of these nodules were too fast or heterogenous to measure by this device. After the surgery, the pathologies of these nodules were revealed to be papillary carcinoma (21 cases), adenomatous goiter (11), follicular carcinoma (4), follicular adenoma (2) and follicular lymphoma (1). Five papillary carcinomas were found within adenomatous goiters. Nodules from four follicular carcinomas showed average Vs of 1.92 ± 0.48 m/s, while two follicular adenomas and follicular lymphoma showed 2.19 ± 0.06 and 2.34 m/s respectively. Nodules of adenomatous goiter showed 2.14 ± 0.60 m/s. On the other hand, nodules from five out of 21 papillary carcinomas showed average Vs of 4.00 ± 2.37 m/s. In the nodules of 16 papillary carcinomas, Vs were measured as “X.XX m/s” and this value was only observed in nodules of papillary carcinoma. These data reflected high and/or heterogenous elasticity of papillary carcinoma, in other words, the tissue of papillary carcinoma was hard and/or heterogenous. It was notable that the Vs value of “X.XX m/s” strongly suggested papillary carcinoma.

关键词： ARFI Elastography Thyroid Thyroid Nodule

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Expression analyses of stress‑responsive genes in the hermatypic coral Acropora tenuis and its symbiotic dinofagellates after exposure to the herbicide Diuron

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Marine Life Science & Technology 2023年第3期5卷 289-299页

作者： Hiroshi Ishibashi Seigo Minamide Ichiro takeuchi Graduate School of Agriculture Ehime UniversityMatsuyamaEhime 790-8566Japan Center of Advanced Technology for the Environment Graduate School of AgricultureEhime UniversityMatsuyamaEhime 790-8566Japan

Diuron is one of the most frequently applied herbicides in sugarcane farming in southern Japan,and Australia.In addition,it is used as a booster substance in copper-based antifouling paints.Due to these various uses,Diuron is released into the marine environment;however,little information is available on gene expression in corals and their symbiotic algae exposed to Diuron.We investigated the efects of Diuron on stress-responsive gene expression in the hermatypic coral Acropora tenuis and its symbiotic dinofagellates.After seven days of exposure to 1µg/L and 10µg/L Diuron,no signifcant changes in the body colour of corals were observed.However,quantitative reverse transcription-polymerase chain reaction analyses revealed that the expression levels of stress-responsive genes,such as heat shock protein 90(HSP90),HSP70,and calreticulin(CALR),were signifcantly downregulated in corals exposed to 10µg/L of Diuron for seven days.Moreover,aquaglyceroporin was signifcantly downregulated in corals exposed to environmentally relevant concentrations of 1µg/L Diuron.In contrast,no such efects were observed on the expression levels of other stress-responsive genes,such as oxidative stress-responsive proteins,methionine adenosyltransferase,and green/red fuorescent proteins.Diuron exposure had no signifcant efect on the expression levels of HSP90,HSP70,or HSP40 in the symbiotic dinofagellates.These results suggest that stress-responsive genes,such as HSPs,respond diferently to Diuron in corals and their symbiotic dinofagellates and that A.tenuis HSPs and CALRs may be useful molecular biomarkers for predicting stress responses induced by the herbicide Diuron.

关键词： Acropora tenuis Calreticulin Coral bleaching Diuron Heat shock protein

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Disseminated carcinomatosis of the bone marrow caused by granulocyte colony-stimulating factor:A case report and review of literature

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World Journal of Gastrointestinal Oncology 2022年第10期14卷 2077-2084页

作者： Kengo Fujita Ayaka Okubo Toshitsugu Nakamura Nobumichi takeuchi Department of Medical Oncology Ina Central HospitalNagano 396-8555Japan Department of Diagnostic Pathology Ina Central HospitalNagano 396-8555Japan

BACKGROUND Disseminated carcinomatosis of the bone marrow(DCBM)is a widespread metastasis with a hematologic disorder that is mainly caused by gastric cancer.Although it commonly occurs as a manifestation of recurrence long after curative treatment,the precise mechanism of relapse from dormant status remains unclear.Granulocyte colony-stimulating factor(G-CSF)can promote cancer progression and invasion in various cancers.However,the potential of G-CSF to trigger recurrence from a cured malignancy has not been reported.CASE SUMMARY A 55-year-old Japanese woman was diagnosed with Ewing sarcoma localized on the fifth lumbar vertebrae 6 years after curative gastrectomy for T1 gastric cancer.After palliative surgery to release nerve compression,pathological diagnosis of the resected specimen was followed by curative radiation and chemotherapy.During treatment,G-CSF was administered 32 times for severe neutropenia prophylaxis.Eight months after completing definitive treatment,she complained of severe back pain and was diagnosed as multiple bone metastases with DCBM from gastric cancer.Despite palliative chemotherapy,she died of disseminated intravascular coagulation 13 d after the diagnosis.Immunohistochemical examination of the autopsied bone marrow confirmed a diffuse positive staining for the G-CSF receptor(G-CSFR)in the relapsed gastric cancer cell cytoplasm,whereas the primary lesion cancer cells showed negative staining for G-CSFR.In this case,G-CSF administration may have been the key trigger for the disseminated relapse of a dormant gastric cancer.CONCLUSIONWhen administering G-CSF to cancer survivors,recurrence of a preceding cancer should be monitored even after curative treatment.

关键词： Disseminated bone marrow carcinomatosis Gastric cancer Granulocyte colony-stimulating factor Cancer survivor Immunostaining Case report

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Drug-induced entero-colitis due to interleukin-17 inhibitor use;capsule endoscopic findings and pathological characteristics:A case report

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世界胃肠病学杂志:英文版 2023年第32期29卷 4912-4919页

作者： Keita Saito Kiichiro Yoza Shinichiro Takeda Yoshihiro Shimoyama Ken takeuchi Department of Gastroenterology Tsujinaka Hospital Kashiwano-HaKashiwa 277-0871Japan

BACKGROUND Interleukin-17(IL-17)inhibitors are known to cause exacerbation or new onset of inflammatory bowel disease upon administration.However,few reports have described characteristic endoscopic and histopathologic findings,and no small intestinal lesions have been reported so far.CASE SUMMARY A woman in her 60s with psoriasis was administered ixekizumab(IXE),an anti-IL-17A antibody,for the treatment of psoriasis.Twenty months after commencing treatment,the patient visited our hospital because of persistent diarrhea.Blood tests performed at the time of the visit revealed severe inflammation,and colonoscopy revealed multiple round ulcers throughout the colon.A tissue biopsy of the ulcer revealed infiltration of inflammatory cells and granuloma-like findings in the submucosal layer.Capsule endoscopy revealed multiple jejunal erosions.After the withdrawal of IXE,the symptoms gradually improved,and ulcer reduction and scarring of the colon were endoscopically confirmed.CONCLUSION To the best of our knowledge,17 reports have documented IL-17 inhibitorinduced entero-colitis with endoscopic images,endoscopic findings,and pathological characteristics,including the present case.Nine of these cases showed diffuse loss of vascular pattern,coarse mucosa/ulcer formation in the left colon,and endoscopic findings similar to those of ulcerative colitis.In the remaining eight cases,discontinuous erosions and ulcerations from the terminal ileum to the rectum were seen,with endoscopic findings similar to those of Crohn’s disease.In this case,the findings were confirmed by capsule endoscopy,which has not been previously reported.

关键词： Interleukin-17 inhibitor Ixekizumab Drug-induced entero-colitis Capsule endoscopy Case report

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In-silico clearing approach for deep refractive index tomography by partial reconstruction and wave-backpropagation

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Light(Science & Applications) 2023年第5期12卷 877-893页

作者： Osamu Yasuhiko Kozo takeuchi Central Research Laboratory Hamamatsu Photonics K.K5000 HirakuchiHamakita-kuHamamatsu 434-8601 ShizuokaJapan

Refractive index(RI)is considered to be a fundamental physical and biophysical parameter in biological imaging,as it governs light-matter interactions and light propagation while reflecting cellular properties.RI tomography enables volumetric visualization of RI distribution,allowing biologically relevant analysis of a sample.However,multiple scattering(MS)and sample-induced aberration(SIA)caused by the inhomogeneity in RI distribution of a thick sample make its visualization challenging.This paper proposes a deep RI tomographic approach to overcome MS and SIA and allow the enhanced reconstruction of thick samples compared to that enabled by conventional linear-model-based RI tomography.The proposed approach consists of partial RI reconstruction using multiple holograms acquired with angular diversity and their backpropagation using the reconstructed partial RI map,which unambiguously reconstructs the next partial volume.Repeating this operation efficiently reconstructs the entire RI tomogram while suppressing MS and SIA.We visualized a multicellular spheroid of diameter 140μm within minutes of reconstruction,thereby demonstrating the enhanced deep visualization capability and computational efficiency of the proposed method compared to those of conventional RI tomography.Furthermore,we quantified the high-RI structures and morphological changes inside multicellular spheroids,indicating that the proposed method can retrieve biologically relevant information from the RI distribution.Benefitting from the excellent biological interpretability of RI distributions,the label-free deep visualization capability of the proposed method facilitates a noninvasive understanding of the architecture and time-course morphological changes of thick multicellular specimens.

关键词： properties refractive overcome

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Association of anastomotic leakage with long-term oncologic outcomes of patients with esophagogastric junction cancer

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World Journal of Gastrointestinal Surgery 2022年第1期14卷 46-55页

作者： Masashi takeuchi Hirofumi Kawakubo Satoru Matsuda Shuhei Mayanagi Tomoyuki Irino Jun Okui Kazumasa Fukuda Rieko Nakamura Norihito Wada Hiroya takeuchi Yuko Kitagawa Department of Surgery Keio University School of MedicineTokyo 160-8582Japan Department of Preventive Medicine and Public Health Keio University School of MedicineTokyo 160-8582Japan Department of Surgery Hamamatsu University School of MedicineShizuoka 431-3192Japan

BACKGROUND Despite improvements in surgical procedures and peri-operative patients management,the postoperative complications in esophagogastric junction(EGJ)cancer remain high because of technical aspects.Several studies have indicated the negative influence of postoperative infectious complications on long-term survival after gastrointestinal surgery.However,no study has shown the association between postoperative complications and long-term survival of patients with EGJ cancer.AIM To elucidate influence of postoperative complications on the long-term outcomes of patients with EGJ cancer.METHODS A total of 122 patients who underwent surgery for EGJ cancer at the Keio University were included in this study.We examined the association between complications and long-term oncologic outcomes.RESULTS In all patients,the 3-year overall survival(OS)rate was 71.9%,and the recurrencefree survival(RFS)rate was 67.5%.Compared with patients without anastomotic leakage,those with anastomotic leakage had poor median OS(8 mo vs not reached,P=0.028)and median RFS(5 mo vs not reached,P=0.055).Among patients with cervical anastomosis,there were not significant differences between patients with and without anastomotic leakage.However,among patients who underwent intrathoracic anastomosis,patients with anastomotic leakage had significantly worse OS(P=0.002)and RFS(P=0.005).CONCLUSION Anastomotic leakage was significantly associated with long-term oncologic outcomes of patients with EGJ cancer,especially those who underwent intrathoracic anastomosis.Cervical anastomosis with subtotal esophagectomy may be an option for the patients who are at high risk for anastomotic leakage.

关键词： Esophagogastric junction cancer Complication Long-term outcome

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A Delayed HIV Infection Model with the Homeostatic Proliferation of CD4^(+)T Cells

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Acta Mathematicae Applicatae Sinica 2022年第2期38卷 441-462页

作者： Qiang-hui XU Ji-cai HUANG Yue-ping DONG Yasuhiro takeuchi School of Mathematics and Statistics and Hubei Key Laboratory of Mathematical Sciences Central China Normal UniversityWuhan 430079China College of Science and Engineering Aoyama Gakuin UniversityKanagawa 252-5258Japan

In this paper,we investigate a delayed HIV infection model that considers the homeostatic prolif-eration of CD4^(+)T cells.The existence and stability of uninfected equilibrium and infected equilibria(smaller and larger ones)are studied by analyzing the characteristic equation of the system.The intracellular delay does not affect the stability of uninfected equilibrium,but it can change the stability of larger positive equilibrium and Hopf bifurcation appears inducing stable limit cycles.Furthermore,direction and stability of Hopf bifur-cation are well investigated by using the central manifold theorem and the normal form theory.The numerical simulation results show that the stability region of larger positive equilibrium becomes smaller as the increase of time delay.Moreover,when the maximum homeostatic growth rate is very small,the larger positive equilibrium is always stable.On the contrary,when the rate of supply of T cells is very small,the larger positive equilibrium is always unstable.

关键词： HIV infection and persistence T cell homeostatic proliferation delayed model dynamics analysis Hopf bifurcation

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