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Clinical features of gastroduodenal injury associated with long-term low-dose aspirin therapy

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World Journal of Gastroenterology 2013年第11期19卷 1673-1682页

作者： Junichi Iwamoto Yoshifumi Saito Akira Honda Yasushi Matsuzaki Department of Gastroenterology Tokyo Medical UniversityIbaraki Medical CenterIbaraki 300-0395Japan

Low-dose aspirin(LDA) is clinically used for the prevention of cardiovascular and cerebrovascular events with the advent of an aging society.On the other hand,a very low dose of aspirin(10 mg daily) decreases the gastric mucosal prostaglandin levels and causes significant gastric mucosal damage.The incidence of LDAinduced gastrointestinal mucosal injury and bleeding has increased.It has been noticed that the incidence of LDA-induced gastrointestinal hemorrhage has increased more than that of non-aspirin non-steroidal anti-inflammatory drug(NSAID)-induced lesions.The pathogenesis related to inhibition of cyclooxygenase(COX)-1 includes reduced mucosal flow,reduced mucus and bicarbonate secretion,and impaired platelet aggregation.The pathogenesis related to inhibition of COX-2 involves reduced angiogenesis and increased leukocyte adherence.The pathogenic mechanisms related to direct epithelial damage are acid back diffusion and impaired platelet aggregation.The factors associated with an increased risk of upper gastrointestinal(GI) complications in subjects taking LDA are aspirin dose,history of ulcer or upper GI bleeding,age > 70 years,concomitant use of non-aspirin NSAIDs including COX-2-selective NSAIDs,and Helicobacter pylori(H.pylori) infection.Moreover,no significant differences have been found between ulcer and non-ulcer groups in the frequency and severity of symptoms such as nausea,acid regurgitation,heartburn,and bloating.It has been shown that the ratios of ulcers located in the body,fundus and cardia are significantly higher in bleeding patients than the ratio of gastroduodenal ulcers in patients taking LDA.Proton pump inhibitors reduce the risk of developing gastric and duodenal ulcers.In contrast to NSAIDinduced gastrointestinal ulcers,a well-tolerated histamine H2-receptor antagonist is reportedly effective in prevention of LDA-induced gastrointestinal ulcers.The eradication of H.pylori is equivalent to treatment with omeprazole in preventing recurrent bleeding.Continuous aspirin therapy for patients

关键词： Gastroduodenal ulcer Upper gastrointestinal bleeding Low-dose aspirin Non-steroidal antiinflammatory drugs

Small-bowel mucosal injuries in low-dose aspirin users with obscure gastrointestinal bleeding

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World Journal of Gastroenterology 2014年第36期20卷 13133-13138页

作者： Junichi Iwamoto Yuji Mizokami Yoshifumi Saito Koichi Shimokobe Akira Honda Tadashi Ikegami Yasushi Matsuzaki Department of Gastroenterology Tokyo Medical University Ibaraki Medical Center Ibaraki 300-0395 Japan Department of Gastroenterology University of Tsukuba Ibaraki 305-8576 Japan

AIM: To investigate the clinical differences between small intestinal injuries in low-dose aspirin(LDA) users and in non-steroidal anti-inflammatory drug(NSAID) users who were examined by capsule endoscopy(CE) for obscure gastrointestinal bleeding(OGIB). METHODS: A total of 181 patients who underwent CE for OGIB were included in this study. Based on clinical records, laboratory data such as hemoglobin levels, major symptoms, underlying diseases, the types and duration of LDA and NSAID use, and endoscopic characteristics of CE were reviewed.RESULTS: Out of a total of 45 cases of erosive lesions, 27 cases were taking LDA or NSAIDs(7 were on NSAIDs, 9 were on LDA alone, 9 were on LDA and thienopyridine, and 2 were on LDA and warfarin).The prevalence of ulcers or erosion during chronic use of LDA, LDA and the anti-platelet drug thienopyridine (clopidogrel or ticlopidine), and NSAIDs were 64.3%, 80.0%, and 75.0%, respectively. Erosive lesions were observed predominantly in chronic LDA users, while ulcerative lesions were detected mainly in NSAID users. However, concomitant use of thienopyridine such as clopidogrel with LDA increased the proportion of ulcers. The erosive lesions were located in the whole of the small intestine(jejunum and ileum), whereas ulcerative lesions were mainly observed in the ileum(P < 0.05). CONCLUSION: Our CE findings indicate that chronic LDA users and NSAID users show different types and locations of small-bowel mucosal injuries. The concomitant use of anti-platelet drugs with LDA tends to exacerbate the injuries from LDA-type to NSAID-type injuries.

关键词： Non-steroidal anti-inflammatory drugs Lowdose aspi

Bicarbonate Attenuates Irinotecan-Induced Cytotoxicity through Regulation of Both Extracellular and Intracellular <i>pHs</i>in Intestine Cell Line

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Journal of Cancer Therapy 2013年第5期4卷 944-952页

作者： Teruo Miyazaki Tadashi Ikegami Yoshiaki Nagai Amy Nguyen Yasushi Matsuzaki Kunihiko Kobayashi Susan Ceryak Department of Biochemistry and Molecular Biology The George Washington University Washington DC USA Department of Internal Medicine Division of Gastroenterology and Hepatology Tokyo Medical University Ibaraki Medical Center Ami Ibaraki Japan Department of Pharmacology The George Washington University Washington DC USA Department of Respiratory Medicine Saitama International Medical Center Saitama Medical University Hidaka Saitama Japan Joint Research Center Tokyo Medical University Ibaraki Medical Center Ami Ibaraki Japan

The anti-cancer therapy of irinotecan (CPT-11) is often limited due to severe late-onset diarrhea. Because the higher toxic form of CPT-11/its active metabolite (SN-38) is produced at acidification, the usefulness of oral sodium bicarbonate treatment against the CPT-11/SN-38-induced intestinal injuries and diarrhea has been confirmed. However, the roles of bicarbonate have been suggested to affect not only intestinal pH environment but also intracellular pH and CPT-11/SN-38 dynamics. The present study proposed to clarify the hypothesis in CPT-11/SN-38-exposed colon cell line in various pH conditions adjusted by bicarbonate. HT29 cell pre-exposed to ~1.0 μM SN-38 lactone or carboxylate forms was incubated at different pH adjusted by either bicarbonate or HCl/NaOH. The degrees of SN-38-induced cell injury depended on the higher proportion of the toxic form (lactone) of SN-38 rather than mere pH condition of medium. Apoptosis and cell injury induced by SN-38 were significantly inhibited by bicarbonate in a dose-dependent manner. Intercellular pH acidification induced by SN-38 was significantly prevented by 30 mM bicarbonate. Cell cytotoxicity of SN-38 depended on not only extracellular but also intracellular pH that converts the SN-38 form, while the intracellular acidification was prevented by bicarbonate. The multiple regulations of bicarbonate on both exracellular and intracellular pH would be essential mechanism against intestinal cell injury by CPT-11/SN-38.

关键词： Bicarbonate SN-38 CPT-11 pHi Anti-Cancer Drug Intestine

Spindle Cell Hemangioma and Decorin Expression

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Journal of Cosmetics, Dermatological Sciences and Applications 2012年第1期2卷 8-10页

作者： Daiki Rokunohe Hitoshi Takeda Takahide Kaneko Takayuki Aizu Eijiro Akasaka Yasushi Matsuzaki Hajime Nakano Daisuke Sawamura Department of Dermatology Graduate School of Medicine Hirosaki University Hirosaki Japan.

Spindle cell hemangioma (SCH) is a rare benign vascular tumor and we report 2 cases of SCH who are 50-year-old man and 16-year-old girl. A growing amount of evidence indicates that multifunctional ECM molecule decorin regulate endothelial cell-matrix interactions during angiogenesis. Furthermore, a current publication shows that no detectable decorin expression was found in the stromas of tumor nests in Kaposi’s sarcoma or angiosarcoma groups while the expression was clearly observed in the connective tissue stromas within benign vascular tumors. SCH exhibits spindle cell proliferation and resembles Kaposi’s sarcoma. Therefore, this study examined decorin expression in the tissues of our SCH cases by immunohistochemical analysis. The results demonstrated that immunoreactivity of decorin was clearly detectable in the connective tissue stroma within tumor nests. SCH was first perceived as sarcoma because of spindle cell proliferation, but this proliferation was subsequently found to be reactive. The presence of decorin expression in our cases also indicates that SCH have benign properties. Moreover, this study further increases the reliability of examination of decorin expression for differentiation between benign and malignant vascular tumors.

关键词： Proteoglycan Skin Endothelium Malignant Matrix

Amplification of Papillomavirus Oncogene Transcripts Assay for Bowenoid Papulosis

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International Journal of Clinical Medicine 2013年第10期4卷 428-431页

作者： Takahide Kaneko Gen Nakahishi Koji Nakajima Takayuki Aizu Kayo Jin Daiki Rokunohe Yasushi Matsuzaki Nakano Hajime Toshihiro Tanaka Daisuke Sawamura Department of Dermatology Shiga University of Medical Science Otsu Japan Department of Dermatology Hirosaki University Graduate School of Medicine Hirosaki Japan Department of Dermatology Hirosaki University Graduate School of Medicine Hirosaki Japan Department of Dermatology Shiga University of Medical Science Otsu Japan.

Human papillomavirus (HPV) is an important causative agent of cervical carcinoma and some malignant cutaneous tumors. The integration of HPV DNA into the host genome is one of the most important risk factors for malignant transformation. Here, we report the case of a 53-year-old man with multiple, black-brown genital macules and nodules. Histological findings resembled those for Bowen’s disease, and we made a diagnosis of bowenoid papulosis. This condition is generally benign, but invasive squamous cell carcinoma (SCC) arising from bowenoid papulosis has been previously reported. Therefore, we took biopsy specimens from 10 lesions and tested them for the presence of HPV DNA. DNA sequencing identified HPV type 16 (HPV-16) DNA in all samples. Next, we excised 4 different relatively large lesions and performed an amplification of papillomavirus oncogene transcripts (APOT) assay. This assay showed that all samples had only episome-derived viral transcripts, indicating no integration of HPV DNA into the host genome. We have followed this case for 3 years, and no progression to Bowen’s disease or SCC has so far been observed. We conclude that the APOT assay is a feasible method for evaluating the malignant potential of bowenoid papulosis.

关键词： HPV 16 Integration Malignant Transformation

A Case of Erythema Nodosum Associated with Subareolar Abscess

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Journal of Cosmetics, Dermatological Sciences and Applications 2012年第4期2卷 263-264页

作者： Satoko Minakawa Yasushi Matsuzaki Daiki Rokunoke Eijiro Akasaka Koji Nakajima Takayuki Aizu Takahide Kaneko Hajime Nakano Kazutoshi Takashima Daisuke Sawamura Departments of Dermatology Hirosaki University Graduate School of Medicine Departments of Dermatology Hirosaki University Graduate School of Medicine Hirosaki Japan Departments of Surgery Hiro- saki University Graduate School of Medicine Hirosaki Japan

While erythema nodosum is a nodular, erythematous eruption predominantly affecting the extensor aspects of the legs, breast abscesses are the result of relatively common bacterial infections, and only 2 studies have reported an association between erythema nodosum and breast abscesses. Here, we report the case of a patient with repeated erythema nodosum associated with subareolar abscesses. The patient was a 34-year-old woman with painful erythematous nodules on her right shin, accompanied by an indurated lesion on her right breast 4 days before the onset of the nodules. Therefore, the patient underwent circumareolar incision, and consequently the painful erythematous nodules disappeared. However, after 39 days, the patient developed another tender, painful lesion in her right breast and painful erythematous nodules on her right shin. After another circumareolar incision, the painful erythematous nodules disappeared again. Therefore, we suggested a significant association between erythema nodosum and breast abscess in this patient. The most common underlying causative organism in breast abscess is Staphylococcus aureus;however, erythema nodosum has rarely been proven to be associated with staphylococcal infections. Therefore, the relationship between S. aureus and erythema nodosum is rather controversial. However, the resistance to the usual treatment methods and prolonged clinical course in our case suggest that the pathogenesis of erythema nodosum associated with breast abscesses might be different from that of the common form of erythema nodosum.

关键词： Erythema Nodosum Subareolar Abscess Breast Staphylococcal Infections

Effect of cytokines and ultraviolet B radiation on the promoter activity of the metallothionein gene in keratinocytes

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Advances in Bioscience and Biotechnology 2013年第9期4卷 896-899页

作者： Hiromi Narumi Hajime Nakano Takahide Kaneko Koji Nakajima Yasushi Matsuzaki Takayuki Aizu Daisuke Sawamura Katsumi Hanada Department of Dermatology Hirosaki University Graduate School of Medicine Hirosaki Japan

Metallothionein (MT) has many functions that are modulated by several factors, including ultraviolet (UV) radiation and cytokines. We thought that these diverse functions of MT might reflect the specific regulatory mechanisms of its expression. To understand some of the molecular mechanisms underlying MT expression, we examined the effects of several cytokines and UVB on the promoter activity of the MT gene. First, we introduced the MT promoter construct into the HaCaT keratinocytes and treated them with various concentrations of interleukin-1α (IL-1α) and IL-6. The addition of IL-1α and IL-6 led to an increase in the promoter activity of the MT gene. UVB is known to induce MT expression in epidermal keratinocytes, and IL-6 is a possible mediator of MT induction by UV radiation. Therefore, we investigated whether UVB could induce MT promoter activity. Our results showed, interestingly, that UVB radiation has no or little effect on the promoter activity. This suggested a complex molecular regulation of the MT gene.

关键词： Sunburn Cytokine Epidermis Ultraviolet Light Promoter

胆汁酸对肝星状细胞增殖及细胞动能的调控作用(英文)

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临床儿科杂志 2010年第4期28卷 301-306页

作者：张一宁池上正杜红伟松崎靖司吉林大学第一医院东京医科大学茨城医疗中心

目的探讨胆汁酸如何通过调控肝星状细胞促进肝纤维化发生。方法采用BrdU掺入法测定胆汁酸和TGFβ-1对GFSC-2G细胞增殖的影响;利用Wound-healing检测法判定细胞的移动能力;同时利用Western blotting法检测与胆汁酸共同孵育的GFSC-2G细胞... 详细信息

目的探讨胆汁酸如何通过调控肝星状细胞促进肝纤维化发生。方法采用BrdU掺入法测定胆汁酸和TGFβ-1对GFSC-2G细胞增殖的影响;利用Wound-healing检测法判定细胞的移动能力;同时利用Western blotting法检测与胆汁酸共同孵育的GFSC-2G细胞的p38和JNK的表达。结果与50μmol/L甘氨鹅脱氧胆酸(GCDCA)共同孵育后,CFSC-2G细胞增殖明显增加,为对照组的152.0%±7.1%(P<0.05)。50μmol/L GCDCA诱导p38及JNK磷酸化的作用[在p38为对照组的450.0%±12.2%(P<0.01),在JNK为对照组的210.0%±15.2%(P<0.05)]。50μmol/L GCDCA促进培养细胞的伤痕愈合(剩余面积为原来的75.4%±5.8%,P<0.05),而JNK(SP600125)或p38(SB294002)的抑制因子能够抑制胆汁酸的这种作用。结论胆汁酸具有促进肝星状细胞增殖的作用,还能提高该细胞的运动能力,这种作用是通过促进p38和JNK的磷酸化而实现的。提示胆汁酸可能通过调控p38和JNK的信号转导而促进肝纤维化的形成。

关键词：肝纤维化胆汁酸肝星状细胞

去氢表雄酮通过Akt信号通路诱导肝癌细胞凋亡和细胞周期阻滞

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中华肝脏病杂志 2007年第6期15卷 441-444页

作者：姜艳芳赵平伟谭岩刘力华李明辉松崎静司牛俊奇吉林大学第一医院传染科长春130021 吉林大学第一医院中心研究室长春130021 吉林大学第四医院肝胆外科日本茨城县筑波大学消化内科

目的研究去氢表雄酮（DHEA）及其代谢物去氢表雄酮硫酸酯（DHEAs）对HepG2和HT-29细胞抑制增殖、促进凋亡及诱导细胞周期阻滞的作用。方法应用MTT比色法检测不同浓度（1、10、50、100、200μmol／L）的DHEA或DHEAs与HepG2和HT-29细胞... 详细信息

目的研究去氢表雄酮（DHEA）及其代谢物去氢表雄酮硫酸酯（DHEAs）对HepG2和HT-29细胞抑制增殖、促进凋亡及诱导细胞周期阻滞的作用。方法应用MTT比色法检测不同浓度（1、10、50、100、200μmol／L）的DHEA或DHEAs与HepG2和HT-29细胞孵育8、24、48、72 h对两种细胞系的生长抑制作用;应用流式细胞术检测不同浓度的DHEA或DHEAs对细胞凋亡及细胞周期的变化;采用Western blot检测细胞内磷酸化Akt（Ser473,Thr308）蛋白的水平。结果（1）不同浓度DHEA作用细胞24h时,HepG2的存活率24h时分别为92．7％±0．9%、84．7％±1．2％、62．4％±0．8％、49．5％±0．8％和50．7％±0．3％,HT-29细胞的存活率分别为92．5％±0.4％、89．5％±0．7％、80．5％±1．1％、67.5％±1.5％和70．6％±0．6％,与对照组相比,DHEA明显抑制HepG2和HT-29两种细胞的生长。在浓度为100μmol／L作用24 h时作用明显,而DHEAs对HepG2及HT-29细胞的增殖无明显影响。（2）100μmol／L的DHEA显著抑制两种细胞周期进程, HepG2细胞G0／G1期细胞比例显著升高,可以达到68．4％±2．0％,而对照组为48．6％±1．2％。HT-29细胞在100μmol／L时的G0／G1期的比率为90．3％±2．7％,而对照组仅为59．0％±1．2％,S及G2／M期细胞明显减少。（3）100μmol／L DHEA作用24 h时能显著诱导HepG2细胞凋亡（凋亡率为18．6％±2．2％）,而DHEAs却无此作用。（4）HepG2细胞在100μmol／L和200μmol／L DHEA作用24 h后,磷酸化Akt（Thr^308）、磷酸化Akt（Set^473）蛋白表达显著降低,这种作用在应用PI3K抑制剂和PI3K激活剂后分别被增强和消除。结论 DHEA对HepG2和HT-29两种肿瘤细胞系均具有较强的抗增殖作用。而对于不同的肿瘤细胞系,DHEA可能通过调节Akt的信号通路来诱导细胞凋亡,还可能通过阻滞细胞周期,使其阻滞在G0／G1期。DHEAs对细胞的生长没有明显的作用。

关键词：癌肝细胞细胞凋亡细胞周期肝细胞生长因子