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Connection between inflammation and carcinogenesis in gastrointestinal tract: Focus on TGF-β signaling

World Journal of Gastroenterology 2010年第17期16卷 2080-2093页

作者： Suntaek Hong Ho-Jae Lee Seong Jin kim ki-baik hahm Laboratory of Cancer Cell Biology Lee Gil Ya Cancer and Diabetes InstituteGachon University of Medicine and ScienceIncheon 406-840South Korea Laboratory of Chemoprevention Lee Gil Ya Cancer and Diabetes InstituteGachon University of Medicine and ScienceIncheon 406-840South Korea Laboratory of Cell Regulation and Carcinogenesis Lee Gil Ya Cancer and Diabetes InstituteGachon University of Medicine and ScienceIncheon 406-840South Korea Laboratory of Translational Medicine Lee Gil Ya Cancer and Diabetes InstituteGachon University of Medicine and ScienceIncheon 406-840South Korea Department of Gastroenterology Gachon Graduate School of MedicineIncheon 406-840South Korea

Inflammation is a primary defense process against various extracellular stimuli,such as viruses,pathogens,foods,and environmental pollutants.When cells respond to stimuli for short periods of time,it results in acute or physiological inflammation.However,if the stimulation is sustained for longer time or a pathological state occurs,it is known as chronic or pathological inflammation.Several studies have shown that tumorigenesis in the gastrointestinal (GI) tract is closely associated with chronic inflammation,for which abnormal cellular alterations that accompany chronic inflammation such as oxidative stresses,gene mutations,epigenetic changes,and inflammatory cytokines,are shared with carcinogenic processes,which forms a critical cross-link between chronic inflammation and carcinogenesis.Transforming growth factor (TGF)-β is a multi-potent cytokine that plays an important role in regulation of cell growth,apoptosis and differentiation.Most importantly,TGF-β is a strong anti-inflammatory cytokine that regulates the development of effector cells.TGF-β has a suppressive effect on carcinogenesis under normal conditions by inhibiting abnormal cell growth,but on the other hand,many GI cancers originate from uncontrolled cell growth and differentiation by genetic loss of TGF-β signaling molecules or perturbation of TGF-β adaptors.Once a tumor has developed,TGF-β exerts a promoting effect on the tumor itself and stromal cells to enhance cell growth,alter the responsiveness of tumor cells to stimulate invasion and metastasis,and inhibited immune surveillance.Therefore,novel development of therapeutic agents to inhibit TGF-β-induced progression of tumor and to retain its growth inhibitory activities,in addition to anti-inflammatory actions,could be useful in oncology.In this review,we discuss the role of TGF-β in inflammation and carcinogenesis of the GI tract related to abnormal TGF-β signaling.

关键词： Inflammation Carcinogenesis Transforming growth factor-β Gastrointestinal tract

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8-Hydroxydeoxyguanosine:Not mere biomarker for oxidative stress,but remedy for oxidative stress-implicated gastrointestinal diseases

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World Journal of Gastroenterology 2012年第4期18卷 302-308页

作者： Chan-Young Ock Eun-Hee kim Duck Joo Choi Ho Jae Lee ki-baik hahm Myung Hee Chung Lab of Translational Medicine Gachon University of Medicine and ScienceLee Gil Ya Cancer and Diabetes Institute Department of Gastroenterology Gachon Graduate School of MedicineGil Hospital Sungkyunkwan University Samsung Advanced Institute for Biomedical Research

Reactive oxygen species (ROS) attack guanine bases in DNA easily and form 8-hydroxydeoxyguanosine (8-OHdG),which can bind to thymidine rather than cytosine,based on which,the level of 8-OHdG is gen-erally regarded as a biomarker of mutagenesis conse-quent to oxidative stress.For example,higher levels of 8-OHdG are noted in Helicobacter pylori-associated chronic atrophic gastritis as well as gastric cancer.However,we have found that exogenous 8-OHdG can paradoxically reduce ROS production,attenuate thenuclear factor-κB signaling pathway,and ameliorate the expression of proinflammatory mediators such as interleukin (IL)-1,IL-6,cyclo-oxygenase-2,and induc-ible nitric oxide synthase in addition to expression of nicotinamide adenine dinucleotide phosphate oxidase (NOX)-1,NOX organizer-1 and NOX activator-1 in vari-ous conditions of inflammation-based gastrointestinal (GI) diseases including gastritis,inflammatory bowel disease,pancreatitis,and even colitis-associated carci-nogenesis.Our recent finding that exogenous 8-OHdG was very effective in either inflammation-based or oxidative-stress-associated diseases of stress-related mucosal damage has inspired the hope that synthetic 8-OHdG can be a potential candidate for the treatment of inflammation-based GI diseases,as well as the pre-vention of inflammation-associated GI cancer.In this editorial review,the novel fact that exogenous 8-OHdG can be a functional molecule regulating oxidative-stress-induced gastritis through either antagonizing Rac-guanosine triphosphate binding or blocking the signals responsible for gastric inflammatory cascade is introduced.

关键词：胃肠道疾病氧化应激生物标志物补救办法羟基烟酰胺腺嘌呤二核苷酸信号转导通路炎症介质

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A case of Cowden syndrome diagnosed from multiple gastric polyposis

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World Journal of Gastroenterology 2012年第8期18卷 861-864页

作者： Minsu Ha Jun Won Chung ki baik hahm Yoon Jae kim Dong Kyu kim Myeong Gun kim Woochang Lee Jungsuk An Division of Gastroenterology Department of Internal MedicineGachon Graduate School of MedicineGil Medical CenterIncheon 405-760South Korea Woocharlo LeeDepartment of Laboratory MedicineAsan Medical CenterSeoul 138-736South Korea Department of Laboratory Medicine Asan Medical CenterSeoul 138-736South Korea Department of Patholgy Gachon University Gil HospitalIncheon 405-760South Korea

Cowden syndrome is a rare autosomal dominant disorder that is characterized by multiple hamartomas in a variety of tissues and this is associated with germline mutations in the phosphatase and tensin homologue (PTEN) gene, which is the tumor suppressor gene located on chromosome 10q23.3. It is characterized by multiple hamartomatous neoplasms of the skin, oral mucosa, gastrointestinal (GI) tract, bones, central nervous system, eyes, and genitourinary tract. Cowden syndrome does not have increased risk of GI malignancy; however, it has an increased risk of breast, thyroid and endometrial cancer development. Herethe authors report a rare case of Cowden syndrome incidentally diagnosed from multiple gastric polyposis. A 29-year-old woman presented with multiple gastric polyps. The laboratory results were normal except for mild anemia, with a hemoglobin level of 11.9 g/dL. Esophagogastroduodenoscopy revealed multiple gastric, duodenal polyps and esophageal acanthosis. Colonoscopy revealed possible hamartomatous polyps in the rectum. Under the suspicion of Cowden syndrome, sonography of the thyroid and breasts was carried out, which revealed multiple thyroid masses. Subsequent fine-needle aspiration biopsy revealed the presence of clusters of follicular epithelial cells, and due to the possibility of malignancy, the patient underwent total thyroidectomy. The pathology was reported as invasive follicular carcinoma. A gene study by direct sequencing showed the presence of a PTEN mutation (c.633C > A /p.Cys211*).

关键词：胃肠道综合征 PTEN基因多发性肉甲状腺癌确诊中枢神经系统

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Gastric angiodysplasia in a hereditary hemorrhagic telangiectasia type 2 patient

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World Journal of Gastroenterology 2012年第15期18卷 1840-1844页

作者： Minsu Ha Yoon Jae kim Kwang An Kwon ki baik hahm Mi-Jung kim Dong Kyu kim Young Jae Lee S Paul Oh Department of Gastroenterology Gachon University Gil Medical CenterIncheon 402-751South Korea World Class University program Lee Gil Ya Cancer and Diabetes InstituteGachon University of Medicine and ScienceIncheon 402-751South Korea Lee Gil Ya Cancer and Diabetes Institute Gachon University of Medicine and ScienceIncheon 402-751South Korea

Hereditary hemorrhagic telangiectasia(HHT)is a rare autosomal-dominantly inherited disease that occurs in approximately one in 5000 to 8000 people.Clinical diagnosis of HHT is made when a person presents three of the following four criteria:family history,recurrent nosebleeds,mucocutaneous telangiectasis,and arteriovenous malformations(AVM)in the brain,lung,liver and gastrointestinal(GI)tract.Although epistaxis is themost common presenting symptom,AVMs affecting the lungs,brain and GI tract provoke a more serious outcome.Heterozygous mutations in endoglin,activin receptor-like kinase 1(ACVRL1;ALK1),and SMAD4,the genes involved in the transforming growth factor-βfamily signaling cascade,cause HHT.We report here the case of a 63 year-old male patient who presented melena and GI bleeding episodes,proven to be caused by bleeding from multiple gastric angiodysplasia.Esophagogastroduodenoscopy revealed multiple angiodysplasia throughout the stomach.Endoscopic argon plasma coagulation was performed to control bleeding from a gastric angiodysplasia.The patient has been admitted several times with episodes of hemoptysis and hematochezia.One year ago,the patient was hospitalized due to right-sided weakness,which was caused by left basal ganglia hemorrhage as the part of HHT presentation.In family history,the patient's mother and elder sister had died,due to intracranial hemorrhage,and his eldest son has been suffered from recurrent epistaxis for 20 years.A genetic study revealed a mutation in exon 3 of ALK1(c.199C>T;p.Arg67Trp)in the proband and his eldest son presenting epistaxis.

关键词：毛细血管扩张发育不良出血性遗传性胃癌动静脉畸形基因家族 Smad4

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Non-microbial approach for Helicobacter pylori as faster track to prevent gastric cancer than simple eradication

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World Journal of Gastroenterology 2013年第47期19卷 8986-8995页

作者： Sang-Ho Park Napapan Kangwan Jong-Min Park Eun-Hee kim ki baik hahm CHA Cancer Prevention Research Center CHA Cancer InstituteCHA UniversitySeoul 135-081South Korea

Although the International Agency for Research on Cancer declared Helicobacter pylori(H.pylori)as a definite human carcinogen in 1994,the Japanese Society for Helicobacter Research only recently(February 2013)adopted the position that H.pylori infection should be considered as an indication for either amelioration of chronic gastritis or for decreasing gastric cancer mortality.Japanese researchers have found that H.pylori eradication halts progressive mucosal damage and that successful eradication in patients with non-atrophic gastritis most likely prevents subsequent development of gastric cancer.However,those who have already developed atrophic gastritis/gastric atrophy retain potential risk factors for gastric cancer.Because chronic perpetuated progression of H.pylori-associated gastric inflammation is associated with increased morbidity culminating in gastric carcinogenesis,a non-microbial approach to treatment that provides long-term control of gastric inflammation through nutrients and other interventions may be an effective way to decrease this morbidity.This non-microbial approach might represent a new form of prerequisite"rescue"therapy that provides a quicker path to the prevention of gastric cancer as compared to simple eradication.

关键词： Helicobacter pylori Gastric cancer Prevention Atrophic gastritis Non-microbial approach

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Antioxidative phytoceuticals to ameliorate pancreatitis in animal models: An answer from nature

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World Journal of Gastroenterology 2014年第44期20卷 16570-16581页

作者： Jong-Min Park Sooyeon Lee Mi Kyung Chung Sung-Hun Kwon Eun-Hee kim Kwang Hyun Ko Chang Il Kwon ki baik hahm CHA Cancer Prevention Research Center CHA University Digestive Disease Center CHA University Bundang Medical Center

Despite enthusiastic efforts directed at elucidating critical underlying mechanisms towards the identification of novel therapeutic targets for severe acute pancreatitis(SAP), the disease remains without a specific therapy to be executed within the first hours to days after onset of symptoms. Although earlier management for SAP should aim to either treat organ failure or reduce infectious complications, the current standard of care for the general management of AP in the first hours to days after onset of symptoms include intravenous fluid replacement, nutritional changes, and the use of analgesics with a close monitoring of vital signs. Furthermore, repeated evaluation of severity is very important, as the condition is particularly unstable in the early stages. In cases where biliary pancreatitis is accompanied by acute cholangitis or in cases where biliary stasis is suspected,an early endoscopic retrograde cholangiopancreatography is recommended.However,practice guidelines regarding the treatment of pancreatitis are suboptimal.In chronic pancreatitis,conservative management strategies include lifestyle modifications and dietary changes followed by analgesics and pancreatic enzyme supplementation.Recently,attention has been focused on phytoceuticals or antioxidants as agents that could surpass the limitations associated with currently available therapies.Because oxidative stress has been shown to play an important role in the pathogenesis of pancreatitis,antioxidants alone or combined with conventional therapy may improve oxidativestress-induced organ damage.Interest in phytoceuticals stems from their potential use as simple,accurate tools for pancreatitis prognostication that could replace older and more tedious methods.Therefore,the use of antioxidative nutrition or phytoceuticals may represent a new direction for clinical research in pancreatitis.In this review article,recent advances in the understanding of the pathogenesis of pancreatitis are discussed and the paradigm shift underway to develop phytoceutica

关键词： Acute pancreatitis Chronic pancreatitis Se-vere ac

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Predictive proteomic biomarkers for inflammatory bowel disease-associated cancer:Where are we now in the era of the next generation proteomics?

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World Journal of Gastroenterology 2014年第37期20卷 13466-13476页

作者： Jong-Min Park Na Young Han Young-Min Han Mi Kyung Chung Hoo Keun Lee Kwang Hyun Ko Eun-Hee kim ki baik hahm CHA Cancer Prevention Research Center CHA University Gachon University College of Pharmacy Digestive Disease Center CHA University Bundang Medical Center

Recent advances in genomic medicine have opened up the possibility of tailored medicine that may eventually replace traditional "one-size-fits all" approaches to the treatment of inflammatory bowel disease(IBD). In addition to exploring the interactions between hosts and microbes, referred to as the microbiome, a variety of strategies that can be tailored to an individual in the coming era of personalized medicine in the treatment of IBD are being investigated. These include prompt genomic screening of patients at risk of developing IBD, the utility of molecular discrimination of IBD subtypesamong patients diagnosed with IBD, and the discovery of proteome biomarkers to diagnose or predict cancer risks. Host genetic factors influence the etiology of IBD, as do microbial ecosystems in the human bowel, which are not uniform, but instead represent many different microhabitats that can be influenced by diet and might affect processes essential to bowel metabolism. Further advances in basic research regarding intestinal inflammation may reveal new insights into the role of inflammatory mediators, referred to as the inflammasome, and the macromolecular complex of metabolites formed by intestinal bacteria. Collectively, knowledge of the inflammasome and metagenomics will lead to the development of biomarkers for IBD that target specific pathogenic mechanisms involved in the spontaneous progress of IBD. In this review article, our recent results regarding the discovery of potential proteomic biomarkers using a label-free quantification technique are introduced and on-going projects contributing to either the discrimination of IBD subtypes or to the prediction of cancer risks are accompanied by updated information from IBD biomarker research.

关键词： Inflammatory bowel disease Biomarker Proteomics Ta

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Efficacy and safety of ecabet sodium on functional dyspepsia:A prospective,double-blinded,randomized,multi-center controlled trial

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World Journal of Gastroenterology 2006年第17期12卷 2756-2761页

作者： Jun Haeng Lee Jae J kim ki-baik hahm Dong Ho Lee Nayoung kim Sung Kook kim Jong Jae Park Seok Reyol Choi Jong Hun Lee Soo Teik Lee Eun Hyun Lee Jong Chul Rhee Department of Medicine Sungkyunkwan University School of Medicine SeoulKorea Department of Gastroenterology Ajou University School of Medicine SuwonKorea Department of Internal Medicine Seoul National University Bundang Hospital SeoungnamGyeonggi-doKorea Department of Internal Medicine Kyungpook National University College of Medicine DaeguKorea Department of Internal Medicine Korea University Guro Hospital SeoulKorea Department of Internal Medicine Dong-A University BusanKorea Department of Internal Medicine Chonbuk National University College of Medicine ChonjuKorea Department of Preventive Medicine Graduate School of Public Health Ajou UniversitySuwonKorea

瞄准：在减轻机能性消化不良的症状比较 ecabet 钠和 cimetidine。方法：我们执行了一个多中心，未来，使随机化，双 blinded 控制了试用在病人把 ecabet 钠和 cimetidine 的临床的功效与机能性消化不良作比较。二 -- 有完成 Rome-II ... 详细信息

瞄准：在减轻机能性消化不良的症状比较 ecabet 钠和 cimetidine。方法：我们执行了一个多中心，未来，使随机化，双 blinded 控制了试用在病人把 ecabet 钠和 cimetidine 的临床的功效与机能性消化不良作比较。二 -- 有完成 Rome-II 标准的消化不良的症状的 172 个病人从 7 个中心被注册。在学习组(115 个病人) ， 1.5 g ecabet 钠一天被给两次。在控制组(121 个病人) ， 400 mg cimetidine 一天被给两次。生命的质量的症状和参数在基线被分析，在开始治疗以后的 3， 14，和 28 d。结果：二 -- 136 个病人完成了临床的试用。在治疗的 4 wk 以后，在有消化不良的症状的病人的改进的率不在二个组之间是不同的(77.4% 在 ecabet 组织，分别地， 79.3% 在 cimetidine 组织 P > 0.05 ) 。同样，征兆的改进的率不在 3 d 和 14 d 是不同的。生命的质量的参数没在两个组在学习时期期间显著地变化。在两个组没有临床上重要的不利事件。结论：在有机能性消化不良的病人， ecabet 钠与 cimetidine 有类似的临床的功效。

关键词：钠元素功能性消化不良甲氰咪胍抗消化性溃疡药

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Quality of healing of gastric ulcers: Natural products beyond acid suppression

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World Journal of Gastrointestinal Pathophysiology 2014年第1期5卷 40-47页

作者： Napapan Kangwan Jong-Min Park Eun-Hee kim ki baik hahm CHA Cancer Prevention Research Center CHA Cancer InstituteCHA University College of Pharmacy CHA University Department of Gastroenterology CHA University Bundang Medical Center

Gastric ulcer is a chronic disease featured with unexpected complications, including bleeding, stenosis and perforation, as well as a high incidence of recurrence. Clinical treatments for gastric ulcer have allowed the rapid development of potent anti-ulcer drugs during the last several decades. Gastric ulcer healing is successful with conventional treatments including H2-receptor antagonists, and proton pump inhibitors(PPIs) have been essential for ulcer healing and prevention of complications. Additionally, Helicobacter pylori eradication therapy is effective in reducing ulcer recurrence and leads to physiological changes in the gastric mucosa which affect the ulcer healing process. However, in spite of these advancements, some patients have suf-fered from recurrence or intractability in spite of continuous anti-ulcer therapy. A new concept of the quality of ulcer healing(QOUH) was initiated that considers the reconstruction of the mucosal structure and its function for preventing ulcer recurrence. Although several gastroprotection provided these achievements of the QOUH, which PPI or other acid suppressants did not accomplish, we found that gastroprotection that originated from natural products, such as a newer formulation from either Artemisia or S-allyl cysteine from garlic, were very effective in the QOUH, as well as improving clinical symptoms with fewer side effects. In this review, we will introduce the importance of the QOUH in ulcer healing and the achievements from natural products.

关键词： Quality of ulcer healing Natural products Gastric ulcers Acid suppression S-allyl cysteine Artemisia isopropanol extract

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