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Fox M. Update Motility Disorders: Gastro-Oesophageal Reflux Disease - Diagnostic and Conservative Approach. Visc Med 2024; 40:299-309. [PMID: 39664098 PMCID: PMC11631173 DOI: 10.1159/000541358] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 09/06/2024] [Indexed: 12/13/2024] Open
Abstract
Background Gastro-oesophageal reflux disease (GORD) is extremely common, with at least 1 in 10 people in the general population reporting heartburn and acid regurgitation on a weekly basis. GORD can also be associated with a variety of atypical symptoms, including chest pain, chronic cough, and laryngopharyngeal symptoms. The causes of GORD are multifactorial, and the severity of symptoms is influenced by peripheral and central factors, including psychosocial stress and anxiety. Therefore, for a variety of reasons, no single investigation provides a definitive diagnosis, and standard treatment with acid suppressants is not always effective. Summary This review introduces the Lyon Consensus, now in its second iteration, a classification system that provides a "conclusive" positive or negative diagnosis of GORD by integrating the results of endoscopy, ambulatory reflux monitoring, and high-resolution manometry. Different algorithms are applied to patients with high and low pre-test probability of a causal relationship between reflux episodes and patient symptoms. The results of these studies identify patients with "actionable" results that require escalation, revision, or discontinuation of GORD treatment. Guidance is provided on the range of conservative treatments available for GORD, including dietary and lifestyle advice, antacids and alginates, and drugs that suppress acid secretion. Key Messages GORD is a common disorder; however, the causes of reflux and symptoms can be complex. As a result, the diagnosis can be missed, and management is sometimes challenging, especially for patients with atypical symptoms. The Lyon classification establishes a conclusive diagnosis of GORD, based on results of endoscopic and physiological investigation. Typical symptoms usually respond to empiric use of alginate-antacid preparations and acid suppression; however, the management of treatment refractory symptoms is tailored to the individual.
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Affiliation(s)
- Mark Fox
- Digestive Function: Basel, Laboratory and Clinic for Motility Disorders and Functional Digestive Diseases, Centre for Integrative Gastroenterology, Klinik Arlesheim, Arlesheim, Switzerland
- Department of Gastroenterology and Hepatology, University Zürich, Zurich, Switzerland
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2
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Wu G, Liu Y, Ning D, Zhao M, Li X, Chang L, Hu Q, Li Y, Cheng L, Huang Y. Unraveling the causality between gastroesophageal reflux disease and increased cancer risk: evidence from the UK Biobank and GWAS consortia. BMC Med 2024; 22:323. [PMID: 39113061 PMCID: PMC11304656 DOI: 10.1186/s12916-024-03526-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 07/10/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Gastroesophageal reflux disease (GERD) is a common condition characterized by the reflux of stomach contents into the esophagus. Despite its widespread prevalence worldwide, the causal link between GERD and various cancer risks has not been fully established, and past medical research has often underestimated or overlooked this relationship. METHODS This study performed Mendelian randomization (MR) to investigate the causal relationship between GERD and 19 different cancers. We leveraged data from 129,080 GERD patients and 473,524 controls, along with cancer-related data, obtained from the UK Biobank and various Genome-Wide Association Studies (GWAS) consortia. Single nucleotide polymorphisms (SNPs) associated with GERD were used as instrumental variables, utilizing methods such as inverse variance weighting, weighted median, and MR-Egger to address potential pleiotropy and confounding factors. RESULTS GERD was significantly associated with higher risks of nine types of cancer. Even after adjusting for all known risk factors-including smoking, alcohol consumption, major depression, and body mass index (BMI)-these associations remained significant, with higher risks for most cancers. For example, the adjusted risk for overall lung cancer was (OR, 1.23; 95% CI: 1.14-1.33), for lung adenocarcinoma was (OR, 1.18; 95% CI: 1.03-1.36), for lung squamous cell carcinoma was (OR, 1.35; 95% CI: 1.19-1.53), and for oral cavity and pharyngeal cancer was (OR, 1.73; 95% CI: 1.22-2.44). Especially noteworthy, the risk for esophageal cancer increased to (OR, 2.57; 95% CI: 1.23-5.37). Mediation analyses further highlighted GERD as a significant mediator in the relationships between BMI, smoking, major depression, and cancer risks. CONCLUSIONS This study identifies a significant causal relationship between GERD and increased cancer risk, highlighting its role in cancer development and underscoring the necessity of incorporating GERD management into cancer prevention strategies.
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Affiliation(s)
- Gujie Wu
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yaqiong Liu
- Regenerative Medicine Institute, School of Medicine, National University of Ireland (NUI), Galway, Ireland
| | - Dong Ning
- Department of Physiology, School of Medicine, National University of Ireland (NUI), Galway, Ireland
| | - Mengnan Zhao
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xiaoqing Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lu Chang
- Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Qili Hu
- Department of Radiology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
| | - Yao Li
- Department of Radiology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China
| | - Lin Cheng
- Regenerative Medicine Institute, School of Medicine, National University of Ireland (NUI), Galway, Ireland.
| | - Yiwei Huang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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3
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Iijima K. Etiologic factors for Barrett's esophagus: toward countermeasures in Asia. Expert Rev Gastroenterol Hepatol 2024; 18:407-420. [PMID: 39072626 DOI: 10.1080/17474124.2024.2386367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 07/26/2024] [Indexed: 07/30/2024]
Abstract
INTRODUCTION Over the past several decades, Europe and the United States have experienced a rapid increase in esophageal adenocarcinoma. Research and countermeasures against Barrett's esophagus, its precancerous lesion, are progressing. Because esophageal adenocarcinoma has an extremely poor prognosis when diagnosed in an advanced stage, recommendations for early cancer detection have been made based on the various proven etiological factors of Barrett's esophagus and the actual cancer risk of Barrett's esophagus. In recent years, there have been indications of an increase in esophageal adenocarcinoma in Japan, and a similar trend of cancer will occur shortly in other Asian countries. Consequently, Asian countries must implement similar countermeasures against Barrett's esophagus and esophageal adenocarcinoma, referencing the knowledge gained thus far in Europe and the United States. AREAS COVERED This review summarizes the latest findings on the etiologic factors of Barrett's esophagus and discusses the differences between Westerners and Asians. The current status of Barrett's esophagus in Japan and other Asian countries is also summarized. EXPERT OPINION The etiological factors and cancer incidence of Barrett's esophagus in Asia diverge somewhat from those observed in Europe and America. Therefore, it is imperative to implement measures that are tailored to the actual circumstances of Asian people.
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Affiliation(s)
- Katsunori Iijima
- Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan
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4
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Genetic and epigenetic instability induced by betel quid associated chemicals. Toxicol Rep 2023; 10:223-234. [PMID: 36845258 PMCID: PMC9945799 DOI: 10.1016/j.toxrep.2023.02.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 02/03/2023] [Indexed: 02/06/2023] Open
Abstract
Over the years, betel quid chewing and tobacco use have attracted considerable interest as they are implicated as the most likely causative risk factors of oral and esophageal cancers. Although areca nut use and betel quid chewing may lead to apoptosis, chronic exposure to areca nut and slaked lime may promote pre-malignant and malignant transformation of oral cells. The putative mutagenic and carcinogenic mechanisms may involve endogenous nitrosation of areca and tobacco alkaloids as well as the presence of direct alkylating agents in betel quid and smokeless tobacco. Metabolic activation of carcinogenic N-nitrosamines by phase-I enzymes is required not only to elicit the genotoxicity via the reactive intermediates but also to potentiate the mutagenicity with the sporadic alkylations of nucleotide bases, resulting in the formation of diverse DNA adducts. Persistent DNA adducts provides the impetus for genetic and epigenetic lesions. The genetic and epigenetic factors cumulatively influence the development and progression of disorders such as cancer. Accumulation of numerous genetic and epigenetic aberrations due to long-term betel quid (with or without tobacco) chewing and tobacco use culminates into the development of head and neck cancers. We review recent evidence that supports putative mechanisms for mutagenicity and carcinogenicity of betel quid chewing along with tobacco (smoking and smokeless) use. The detailed molecular mechanisms of the extent of accumulation and patterns of genetic alterations, indicative of the prior exposure to carcinogens and alkylating agents because of BQ chewing and tobacco use, have not yet been elucidated.
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Fox M, Gyawali CP. Dietary factors involved in GERD management. Best Pract Res Clin Gastroenterol 2023; 62-63:101826. [PMID: 37094911 DOI: 10.1016/j.bpg.2023.101826] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/10/2023] [Accepted: 02/15/2023] [Indexed: 04/26/2023]
Abstract
Gastroesophageal reflux disease (GERD) is extremely common, and even modest weight gain has been associated with higher symptom burden as well as objective evidence of reflux on endoscopy and physiological measurement. Certain trigger foods, especially citrus, coffee, chocolate, fried food, spicy food and red sauces are frequently reported to worsen reflux symptoms, although hard evidence linking these items to objective GERD is lacking. There is better evidence that large meal volume and high calorie content can increase esophageal reflux burden. Conversely, sleeping with the head end of the bed raised, avoiding lying down close to meals, sleeping on the left side and weight loss can improve reflux symptoms and objective reflux evidence, especially when the esophagogastric junction 'reflux barrier' is compromised (e.g., in the presence of a hiatus hernia). Consequently, attention to diet and weight loss are both important elements of management of GERD, and need to be incorporated into management plans.
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Affiliation(s)
- Mark Fox
- Digestive Function: Basel, Laboratory and Clinic for Motility Disorders and Functional Digestive Diseases, Centre for Integrative Gastroenterology, Klinik Arlesheim, Arlesheim, Switzerland; Department of Gastroenterology and Hepatology, University Hospital, Zürich, Switzerland
| | - C Prakash Gyawali
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, USA.
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6
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Sugano K, Spechler SJ, El-Omar EM, McColl KEL, Takubo K, Gotoda T, Fujishiro M, Iijima K, Inoue H, Kawai T, Kinoshita Y, Miwa H, Mukaisho KI, Murakami K, Seto Y, Tajiri H, Bhatia S, Choi MG, Fitzgerald RC, Fock KM, Goh KL, Ho KY, Mahachai V, O'Donovan M, Odze R, Peek R, Rugge M, Sharma P, Sollano JD, Vieth M, Wu J, Wu MS, Zou D, Kaminishi M, Malfertheiner P. Kyoto international consensus report on anatomy, pathophysiology and clinical significance of the gastro-oesophageal junction. Gut 2022; 71:1488-1514. [PMID: 35725291 PMCID: PMC9279854 DOI: 10.1136/gutjnl-2022-327281] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 05/03/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVE An international meeting was organised to develop consensus on (1) the landmarks to define the gastro-oesophageal junction (GOJ), (2) the occurrence and pathophysiological significance of the cardiac gland, (3) the definition of the gastro-oesophageal junctional zone (GOJZ) and (4) the causes of inflammation, metaplasia and neoplasia occurring in the GOJZ. DESIGN Clinical questions relevant to the afore-mentioned major issues were drafted for which expert panels formulated relevant statements and textural explanations.A Delphi method using an anonymous system was employed to develop the consensus, the level of which was predefined as ≥80% of agreement. Two rounds of voting and amendments were completed before the meeting at which clinical questions and consensus were finalised. RESULTS Twenty eight clinical questions and statements were finalised after extensive amendments. Critical consensus was achieved: (1) definition for the GOJ, (2) definition of the GOJZ spanning 1 cm proximal and distal to the GOJ as defined by the end of palisade vessels was accepted based on the anatomical distribution of cardiac type gland, (3) chemical and bacterial (Helicobacter pylori) factors as the primary causes of inflammation, metaplasia and neoplasia occurring in the GOJZ, (4) a new definition of Barrett's oesophagus (BO). CONCLUSIONS This international consensus on the new definitions of BO, GOJ and the GOJZ will be instrumental in future studies aiming to resolve many issues on this important anatomic area and hopefully will lead to better classification and management of the diseases surrounding the GOJ.
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Affiliation(s)
- Kentaro Sugano
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Stuart Jon Spechler
- Division of Gastroenterology, Center for Esophageal Diseases, Baylor University Medical Center, Dallas, Texas, USA
| | - Emad M El-Omar
- Microbiome Research Centre, St George & Sutherland Clinical Campuses, School of Clinical Medicine, Faculty of Medicine & Health, Sydney, New South Wales, Australia
| | - Kenneth E L McColl
- Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - Kaiyo Takubo
- Research Team for Geriatric Pathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
| | - Takuji Gotoda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Katsunori Iijima
- Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan
| | - Haruhiro Inoue
- Digestive Disease Center, Showa University Koto Toyosu Hospital, Tokyo, Japan
| | - Takashi Kawai
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
| | | | - Hiroto Miwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine, Kobe, Japan
| | - Ken-Ichi Mukaisho
- Education Center for Medicine and Nursing, Shiga University of Medical Science, Otsu, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Oita University Faculty of Medicine, Yuhu, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hisao Tajiri
- Jikei University School of Medicine, Minato-ku, Tokyo, Japan
| | | | - Myung-Gyu Choi
- Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, The Republic of Korea
| | - Rebecca C Fitzgerald
- Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK
| | - Kwong Ming Fock
- Department of Gastroenterology and Hepatology, Duke NUS School of Medicine, National University of Singapore, Singapore
| | | | - Khek Yu Ho
- Department of Medicine, National University of Singapore, Singapore
| | - Varocha Mahachai
- Center of Excellence in Digestive Diseases, Thammasat University and Science Resarch and Innovation, Bangkok, Thailand
| | - Maria O'Donovan
- Department of Histopathology, Cambridge University Hospital NHS Trust UK, Cambridge, UK
| | - Robert Odze
- Department of Pathology, Tuft University School of Medicine, Boston, Massachusetts, USA
| | - Richard Peek
- Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Massimo Rugge
- Department of Medicine DIMED, Surgical Pathology and Cytopathology Unit, University of Padova, Padova, Italy
| | - Prateek Sharma
- Department of Gastroenterology and Hepatology, University of Kansas School of Medicine, Kansas City, Kansas, USA
| | - Jose D Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Michael Vieth
- Institute of Pathology, Klinikum Bayreuth, Friedrich-Alexander University Erlangen, Nurenberg, Germany
| | - Justin Wu
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Duowu Zou
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | | | - Peter Malfertheiner
- Medizinixhe Klinik und Poliklinik II, Ludwig Maximillian University Klinikum, Munich, Germany
- Klinik und Poliklinik für Radiologie, Ludwig Maximillian University Klinikum, Munich, Germany
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7
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Salivary Trefoil Factor Family (TFF) Peptides and Their Roles in Oral and Esophageal Protection: Therapeutic Potential. Int J Mol Sci 2021; 22:ijms222212221. [PMID: 34830103 PMCID: PMC8624312 DOI: 10.3390/ijms222212221] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 11/16/2022] Open
Abstract
Human saliva is a complex body fluid with more than 3000 different identified proteins. Besides rheological and lubricating properties, saliva supports wound healing and acts as an antimicrobial barrier. TFF peptides are secreted from the mucous acini of the major and minor salivary glands and are typical constituents of normal saliva; TFF3 being the predominant peptide compared with TFF1 and TFF2. Only TFF3 is easily detectable by Western blotting. It occurs in two forms, a disulfide-linked homodimer (Mr: 13k) and a high-molecular-mass heterodimer with IgG Fc binding protein (FCGBP). TFF peptides are secretory lectins known for their protective effects in mucous epithelia; the TFF3 dimer probably has wound-healing properties due to its weak motogenic effect. There are multiple indications that FCGBP and TFF3-FCGBP play a key role in the innate immune defense of mucous epithelia. In addition, homodimeric TFF3 interacts in vitro with the salivary agglutinin DMBT1gp340. Here, the protective roles of TFF peptides, FCGBP, and DMBT1gp340 in saliva are discussed. TFF peptides are also used to reduce radiotherapy- or chemotherapy-induced oral mucositis. Thus, TFF peptides, FCGBP, and DMBT1gp340 are promising candidates for better formulations of artificial saliva, particularly improving wound healing and antimicrobial effects even in the esophagus.
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Wang SM, Freedman ND, Katki HA, Matthews C, Graubard BI, Kahle LL, Abnet CC. Gastroesophageal reflux disease: A risk factor for laryngeal squamous cell carcinoma and esophageal squamous cell carcinoma in the NIH-AARP Diet and Health Study cohort. Cancer 2021; 127:1871-1879. [PMID: 33615447 PMCID: PMC8406665 DOI: 10.1002/cncr.33427] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/30/2020] [Accepted: 12/16/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND Prior studies have suggested that gastroesophageal reflux disease (GERD) may be associated with risk of squamous cancers of the larynx and esophagus; however, most of these studies have had methodological limitations or insufficient control for potential confounders. METHODS We prospectively examined the association between GERD and esophageal adenocarcinoma (EADC), esophageal squamous cell carcinoma (ESCC), and laryngeal squamous cell carcinoma (LSCC) in 490,605 participants of the NIH-AARP Diet and Health Study cohort who were 50-71 years of age at baseline. Exposure to risk factors were obtained from the baseline questionnaire. GERD diagnosis was extracted among eligible participants via linkage to Medicare diagnoses codes and then multiply imputed for non-Medicare-eligible participants. Hazard ratios (HRs) and 95% CIs of GERD were computed using Cox regression. RESULTS From 1995 to 2011, we accrued 931 cases of EADC, 876 cases of LSCC, and 301 cases of ESCC in this cohort and estimated multivariable-adjusted HRs of 2.23 (95% CI, 1.72-2.90), 1.91 (95% CI, 1.24-2.94), and 1.99 (95% CI, 1.39-2.84) for EADC, LSCC, and ESCC, respectively. The associations were independent of sex, smoking status, alcohol intake, and follow-up time periods. We estimated that among the general population in the United States, 22.04% of people aged 50-71 years suffered from GERD. Using risk factor distributions for the United States from national survey data, 16.92% of LSCC cases and 17.32% of ESCC cases among individuals aged 50-71 years were estimated to be associated with GERD. CONCLUSION GERD is a common gastrointestinal disorder, but future prospective studies are needed to replicate our findings. If replicated, they may inform clinical surveillance of GERD patients and suggest new avenues for prevention of these malignancies.
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Affiliation(s)
- Shao-Ming Wang
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
| | - Neal D Freedman
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
| | - Hormuzd A Katki
- Biostatistics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Charles Matthews
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
| | - Barry I Graubard
- Biostatistics Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Lisa L Kahle
- Information Management Services Inc, Calverton, Maryland
| | - Christian C Abnet
- Metabolic Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland
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Zhao C, Lu Q, Gu Y, Pan E, Sun Z, Zhang H, Zhou J, Du Y, Zhang Y, Feng Y, Liu R, Pu Y, Yin L. Distribution of N-nitrosamines in drinking water and human urinary excretions in high incidence area of esophageal cancer in Huai'an, China. CHEMOSPHERE 2019; 235:288-296. [PMID: 31260869 DOI: 10.1016/j.chemosphere.2019.06.124] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 06/13/2019] [Accepted: 06/16/2019] [Indexed: 05/22/2023]
Abstract
The Huai'an area in Jiangsu Province of East China is an endemic region of esophageal cancer (EC). The regional heterogeneity of EC suggests that the levels of potential carcinogens might vary throughout the environment. It has been suggested that the most likely carcinogens related to EC are a group known as the N-nitrosamines. In this study, we measured the concentrations of nine nitrosamines in drinking water and human urine in two areas in China, one with a high incidence of EC (Huai'an) and one with a low incidence (Nanjing). Among the nine target analytes, N-nitrosodi-n-propylamine (NDPA), N-nitrosodibutylamine (NDBA), N-nitrosopyrrolidine (NPyr), N-nitrosodiethylamine (NDEA) and N-nitrosomorpholine (NMor) occurred at higher concentrations in drinking water in the high incidence area. Inhabitants from the high incidence area also had urinary excretions with significantly higher concentrations of NDEA, NDBA, N-nitrosopiperidine (NPip) and N-nitrosodiphenylamine (NDPhA). These findings indicated that people in the high EC incidence area were exposed to higher levels of nitrosamines. However, the association between the incidence of EC and nitrosamines exposure will need to be evaluated in more detail.
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Affiliation(s)
- Chao Zhao
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Qiang Lu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yun Gu
- Departments of Thoracic Surgery, People's Hospital of Lianshui, Lianshui, 223400, Jiangsu, China
| | - Enchun Pan
- Huai'an Center for Disease Control and Prevention, Huai'an, 223001, Jiangsu, China
| | - Zhongming Sun
- Huai'an Center for Disease Control and Prevention, Huai'an, 223001, Jiangsu, China
| | - Hu Zhang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Jingjing Zhou
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Ying Du
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Ying Zhang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yuanmei Feng
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Ran Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Yuepu Pu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China
| | - Lihong Yin
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education of China, School of Public Health, Southeast University, Nanjing, 210009, Jiangsu, China.
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Ashworth A, Cutler C, Farnham G, Liddle L, Burleigh M, Rodiles A, Sillitti C, Kiernan M, Moore M, Hickson M, Easton C, Bescos R. Dietary intake of inorganic nitrate in vegetarians and omnivores and its impact on blood pressure, resting metabolic rate and the oral microbiome. Free Radic Biol Med 2019; 138:63-72. [PMID: 31082507 DOI: 10.1016/j.freeradbiomed.2019.05.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Revised: 04/30/2019] [Accepted: 05/07/2019] [Indexed: 12/13/2022]
Abstract
Vegetarian diets are commonly associated with lower blood pressure levels. This has been related to greater consumption of inorganic nitrate, since vegetables are the main source of this anion. Dietary nitrate is reduced to nitrite by commensal bacteria in the mouth, which in turn leads to increased circulatory nitrite availability. Nitrite can form nitric oxide by several pathways promoting a reduction in the vascular tone and lower blood pressure. This study tested whether vegetarians have higher concentrations of nitrite in saliva and plasma, and lower blood pressure and resting metabolic rate (RMR), due to higher intakes of nitrate, compared to omnivores. Following a non-randomized, cross-over and single-blinded design we measured dietary nitrate intake, blood pressure and RMR in young and healthy vegetarians (n = 22) and omnivores (n = 19) with similar characteristics after using placebo or antibacterial mouthwash for a week to inhibit oral bacteria. Additionally, we analyzed salivary and plasma nitrate and nitrite concentrations, as well as the oral nitrate-reduction rate and oral microbiome in both groups. Dietary nitrate intake in vegetarians (97 ± 79 mg/day) was not statistically different (P > 0.05) to omnivores (78 ± 47 mg/day). Salivary and plasma nitrate and nitrite concentrations were similar after placebo mouthwash in both groups (P > 0.05). The oral nitrate-reducing capacity, abundance of oral bacterial species, blood pressure and RMR were also similar between vegetarians and omnivores (P > 0.05). Antibacterial mouthwash significantly decreased abundance of oral nitrate-reducing bacterial species in vegetarians (_16.9%; P < 0.001) and omnivores (_17.4%; P < 0.001), which in turn led to a significant reduction of the oral nitrate-reducing capacity in vegetarians (-78%; P < 0.001) and omnivores (-85%; P < 0.001). However, this did not lead to a significant increase in blood pressure and RMR in either groups (P > 0.05). These findings suggest that vegetarian diets may not alter nitrate and nitrite homeostasis, or the oral microbiome, compared to an omnivore diet. Additionally, inhibition of oral nitrite synthesis for a week with antibacterial mouthwash did not cause a significant raise in blood pressure and RMR in healthy, young individuals independent of diet.
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Affiliation(s)
- Ann Ashworth
- Institute of Health & Community, University of Plymouth, Plymouth, PL4 8AA, UK
| | - Craig Cutler
- Institute of Health & Community, University of Plymouth, Plymouth, PL4 8AA, UK
| | - Garry Farnham
- Peninsula Medical School, University of Plymouth, Plymouth, PL4 8AA, UK
| | - Luke Liddle
- School of Social Sciences, Bishop Grosseteste University, Lincolnshire, LN1 3DY, UK; Institute for Clinical Exercise and Health Science, University of the West of Scotland, South Lanarkshire, G72 0LH, UK
| | - Mia Burleigh
- Institute for Clinical Exercise and Health Science, University of the West of Scotland, South Lanarkshire, G72 0LH, UK
| | - Ana Rodiles
- School of Biological and Marine Sciences, University of Plymouth, Plymouth, PL4 8AA, UK
| | - Carla Sillitti
- CNR-Institute for Agricultural and Forest Systems in the Mediterranean, Catania, 95128, Italy
| | - Michele Kiernan
- Peninsula Medical School, University of Plymouth, Plymouth, PL4 8AA, UK
| | - Melanie Moore
- Institute of Health & Community, University of Plymouth, Plymouth, PL4 8AA, UK
| | - Mary Hickson
- Institute of Health & Community, University of Plymouth, Plymouth, PL4 8AA, UK
| | - Chris Easton
- Institute for Clinical Exercise and Health Science, University of the West of Scotland, South Lanarkshire, G72 0LH, UK
| | - Raul Bescos
- Institute of Health & Community, University of Plymouth, Plymouth, PL4 8AA, UK.
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Mignogna MD, Leuci S. Interface Between Oral and Systemic Disease. CONTEMPORARY ORAL MEDICINE 2019:67-136. [DOI: 10.1007/978-3-319-72303-7_9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Ahada CPS, Suthar S. Groundwater nitrate contamination and associated human health risk assessment in southern districts of Punjab, India. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2018; 25:25336-25347. [PMID: 29946843 DOI: 10.1007/s11356-018-2581-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 06/18/2018] [Indexed: 05/25/2023]
Abstract
Consumption of high NO3 containing water may pose serious health hazard especially in children (< 5 years). The source of NO3 in groundwater includes surface leaching from wastewater and waste dump sites, animal excreta disposal, industrial effluents, and N-based fertilizers, etc. This study aimed to investigate the concentration of NO3 in groundwater of 14 intensively cultivated districts of Malwa Punjab, India, and its possible health hazards in local residents. The sampling of 76 sites revealed the concentration of NO3 in ranges of 38.45-198.05 mgL-1, and over 92% sites showed the high level of it than the safe limits as decided by the Bureau of Indian standards (45 mg L-1) and World Health Organization (50 mg L-1). The possible health hazards of high NO3 intake was estimated using USEPA human health risk assessment (HHRA) model for both adult and children. Results of this study suggested the chronic daily intake (CDI) in the ranges of 1.09-5.65 and 2.56-13.20 in adult and children population of this region, respectively. The hazard quotient (HQnitrate) value was > 1 in most sampling locations ranging 1.09-5.65 for the adult and 2.56-13.20 for children population of Malwa. This study indicates that 93.42% adult and 100% young population of the Malwa are at higher risk of chronic toxicity by excess NO3 intake. The HHRA results suggested a high vulnerability of a local community to NO3 toxicity in this region; therefore, there is an instant need to take preventive measures to safeguard the health of local residents.
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Affiliation(s)
- Chetan P S Ahada
- School of Environment and Natural Resources, Doon University, Dehradun, Uttarakhand, 248001, India
| | - Surindra Suthar
- School of Environment and Natural Resources, Doon University, Dehradun, Uttarakhand, 248001, India.
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Adam, Eve and the reflux enigma: age and sex differences across the gastro-oesophageal reflux spectrum. Eur J Gastroenterol Hepatol 2017; 29:634-639. [PMID: 28151751 DOI: 10.1097/meg.0000000000000845] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
INTRODUCTION We present demographic differences across the gastro-oesophageal reflux disease (GORD) spectrum in a UK District General Hospital. PATIENTS AND METHODS Data were prospectively collected over 37 years. At endoscopy patients were categorized as: erosive oesophagitis (EO), Barrett's oesophagus (BO) or nonerosive reflux disease (NER). Analysis 1: comparison of EO, BO and NER 1977-2001 when the database for GORD without BO closed. Analysis 2: demographic differences in oesophageal adenocarcinoma (OAC) in total BO population diagnosed 1977-2011. RESULTS GORD 1977-2001 (n=11 944): sex, male predominance in EO and BO but not NER; male : female ratios, 1.81, 1.65, 0.87, respectively (P<0.0001); mean age at presentation, EO 54 years, BO 62 years, NER 50 years; women were older than men by 10, 7 and 6 years, respectively.BO 1977-2011: prevalent OAC, 87/1468 (6%); male : female ratio, 4.1 (P<0.0001); incident OAC, 54/1381 (3.9%); male : female ratio, 3.5 (P<0.0001). Among all BO, more men developed OAC (3 vs. 0.9%). Within each sex, proportion of OAC higher among men (4.9 vs. 2.3%); at OAC diagnosis women were slightly but not significantly older (69.9 vs. 72.3 years, P=0.322). CONCLUSION Two views may explain our findings. First, women have either milder reflux, or reduced mucosal sensitivity hence reflux remains silent for longer. Alternatively, women genuinely develop reflux later, that is, are more protected and for longer from developing GORD and its complications. Early evidence is emerging that female sex hormones may indeed have a protective role in GORD during the reproductive period. We suggest reflux and its consequences may be an example of 'protection' conferred on Eve.
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Honda J, Iijima K, Asanuma K, Ara N, Shiroki T, Kondo Y, Hatta W, Uno K, Asano N, Koike T, Shimosegawa T. Estrogen Enhances Esophageal Barrier Function by Potentiating Occludin Expression. Dig Dis Sci 2016; 61:1028-38. [PMID: 26660903 DOI: 10.1007/s10620-015-3980-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Accepted: 11/24/2015] [Indexed: 12/21/2022]
Abstract
BACKGROUND We recently demonstrated that a female sex hormone, estrogen, suppressed esophageal epithelial injury in a reflux esophagitis model of rat, suggesting that estrogen may play an important role in controlling the progress of the gastro-esophageal reflux disease spectrum. However, the precise mechanism of the action is unclear. AIM To investigate the potential role of estrogen in the esophageal barrier function. METHODS Male rabbits were pretreated with either continuous release 17β-estradiol or placebo, and the excised esophageal mucosa was subjected to Ussing chamber experiments after the 2-week pre-treatment. The mucosal side of the chamber was perfused with luminal irritants (HCl or acidified sodium nitrite), while the basal side was perfused by modified Krebs buffer. The epithelial barrier function was evaluated by the transmembrane resistance and the epithelial permeability. The intercellular space of the epithelium was investigated with transmission electron microscopy and the expression of tight junction protein, occludin, claudin-1, and claudin-4, with immunoblotting. RESULTS Estrogen pre-treatment significantly attenuated the decrease in the transmembrane resistance and the increase in the epithelial permeability induced by luminal irritants. Furthermore, the dilation of the intercellular space induced by luminal HCl was significantly alleviated by 17β-estradiol administration. The baseline occludin expression was significantly potentiated by 17β-estradiol administration. CONCLUSIONS This is the first study showing an enhancement of the esophageal barrier function by 17β-estradiol administration. The lack of the protective effect of estrogen could be responsible for the male predominance of erosive reflux esophagitis.
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Affiliation(s)
- Junya Honda
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Katsunori Iijima
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan.
| | - Kiyotaka Asanuma
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Nobuyuki Ara
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Takeharu Shiroki
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Yutaka Kondo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Waku Hatta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Kaname Uno
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Naoki Asano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Tomoyuki Koike
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aobaku, Sendai, 980-8574, Japan
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Kusaka G, Uno K, Iijima K, Shimosegawa T. Role of nitric oxide in the pathogenesis of Barrett’s-associated carcinogenesis. World J Gastrointest Pathophysiol 2016; 7:131-137. [PMID: 26909236 PMCID: PMC4753179 DOI: 10.4291/wjgp.v7.i1.131] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 09/01/2015] [Accepted: 11/11/2015] [Indexed: 02/06/2023] Open
Abstract
Barrett’s esophagus (BE), a premalignant condition to Barrett’s adenocarcinoma (BAC), is closely associated with chronic inflammation due to gastro-esophageal reflux. Caudal type homeobox 2 (CDX2), a representative marker of BE, is increased during the metaplastic and neoplastic transformation of BE. Nitric oxide (NO) has been proposed to be a crucial mediator of Barrett’s carcinogenesis. We previously demonstrated that CDX2 might be induced directly under stimulation of large amounts of NO generated around the gastro-esophageal junction (GEJ) by activating epithelial growth factor receptor in a ligand-independent manner. Thus, we reviewed recent developments on the role of NO in Barrett’s carcinogenesis. Notably, recent studies have reported that microbial communities in the distal esophagus are significantly different among groups with a normal esophagus, reflux esophagitis, BE or BAC, despite there being no difference in the bacterial quantity. Considering that microorganism components can be one of the major sources of large amounts of NO, these studies suggest that the bacterial composition in the distal esophagus might play an important role in regulating NO production during the carcinogenic process. Controlling an inflammatory reaction due to gastro-esophageal reflux or bacterial composition around the GEJ might help prevent the progression of Barrett’s carcinogenesis by inhibiting NO production.
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Iijima K, Shimosegawa T. Involvement of luminal nitric oxide in the pathogenesis of the gastroesophageal reflux disease spectrum. J Gastroenterol Hepatol 2014; 29:898-905. [PMID: 24863184 DOI: 10.1111/jgh.12548] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/29/2014] [Indexed: 12/16/2022]
Abstract
Over the last 3 decades, the incidence of esophageal adenocarcinoma has dramatically increased in Western countries; a similar increase may be observed in Asian countries in the near future. Esophageal adenocarcinoma arises from a sequential gastroesophageal reflux disease (GERD) spectrum from reflux erosive esophagitis, to Barrett's esophagus, and finally to esophageal adenocarcinoma. At present, gastric acid and bile are assumed to be primarily involved in the etiology of the GERD spectrum. We reported in 2002 that, at the gastroesophageal junction in humans, abundant amounts of nitric oxide (NO) are generated luminally through the entero-salivary re-circulation of dietary nitrate. Since then, we have carried out a series of experiments to demonstrate that NO diffuses into the adjacent epithelium at cytotoxic levels. This diffusion results in disruption of the epithelial barrier function, exacerbation of inflammation, acceleration of columnar transformation in the esophagus (Barrett's esophagus) via the induction of caudal-type homeobox 2, and the shifting of carcinogenic N-nitroso compound formation from the luminal to epithelial compartment. These results suggest that, in addition to conventionally recognized causative factors, luminal NO could also be involved in the pathogenesis of the GERD spectrum. In addition, we recently showed that there is a prominent gender-related difference in NO-related cytotoxicity in the esophagus and that estrogen attenuated the esophageal tissue damage via the estrogen receptor in female rats. The role of estrogen in attenuating the esophageal tissue damage in NO-related esophageal damage could explain the well-recognized male predominance in the GERD spectrum in humans.
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Affiliation(s)
- Katsunori Iijima
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Knezevich A, Muzic J, Hatsukami DK, Hecht SS, Stepanov I. Nornicotine nitrosation in saliva and its relation to endogenous synthesis of N'-nitrosonornicotine in humans. Nicotine Tob Res 2013; 15:591-5. [PMID: 22923602 PMCID: PMC3611998 DOI: 10.1093/ntr/nts172] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2012] [Accepted: 06/18/2012] [Indexed: 12/30/2022]
Abstract
INTRODUCTION We recently reported that certain amounts of the carcinogen N'-nitrosonornicotine (NNN) can be formed endogenously from nicotine and/or nornicotine in some users of oral nicotine replacement therapy products. Although the acidic environment of the stomach creates the most favorable conditions for nitrosation, this reaction could also occur in the oral cavity in the presence of bacteria that catalyze nitrosation at neutral pH. METHODS To test the hypothesis that endogenous formation of NNN could occur in the oral cavity, we investigated nitrosation of nicotine and nornicotine in human saliva. To specifically identify NNN as derived from precursors added to saliva, we incubated saliva samples with [pyridine-D(4)]nicotine and [pyridine-D(4)]nornicotine, with and without the addition of nitrite, and subsequently analyzed [pyridine-D(4)]NNN by liquid chromatography-tandem mass spectrometry. RESULTS Consistent with kinetic studies on nicotine and nornicotine nitrosation, incubation of saliva with [pyridine-D(4)]nornicotine alone produced detectable amounts of [pyridine-D(4)]NNN, whereas only traces of [pyridine-D(4)]NNN were found in samples incubated with [pyridine-D(4)]nicotine and sodium nitrite. Incubation of saliva samples from 10 nonsmoking volunteers with [pyridine-D(4)]nornicotine resulted in the formation of [pyridine-D(4)]NNN in 8 samples, with yields ranging from 0.003% to 0.051% of the added alkaloid. CONCLUSION Our results demonstrate that NNN can be formed from nornicotine in human saliva without deliberate addition of any other substance. Therefore, nornicotine, as present in tobacco or in nicotine replacement products, is a carcinogen precursor.
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Affiliation(s)
| | - John Muzic
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Dorothy K. Hatsukami
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN
- Tobacco Research Programs, University of Minnesota, Minneapolis, MN
| | - Stephen S. Hecht
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN
- Tobacco Research Programs, University of Minnesota, Minneapolis, MN
| | - Irina Stepanov
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN
- Division of Environmental Health Sciences, University of Minnesota, Minneapolis, MN
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Kusaka G, Uno K, Iijima K, Endo H, Asano N, Koike T, Imatani A, Shimosegawa T. The role of nitric oxide in the induction of caudal-type homeobox 2 through epidermal growth factor receptor in the development of Barrett's esophagus. Scand J Gastroenterol 2012; 47:1148-58. [PMID: 22834965 DOI: 10.3109/00365521.2012.703232] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The high concentration of nitric oxide (NO) around the gastro-esophageal junction (GEJ) might play an important role in the development of Barrett's esophagus (BE), a precursor of Barrett's adenocarcimona. Although previous studies revealed that the expression of caudal-type homeobox 2 (CDX2), an important marker of BE, might be induced through Epidermal Growth Factor Receptor (EGFR), the roles of NO in this signal transduction remain unclear. MATERIAL AND METHODS First, we investigated the expressions of EGFR, CDX2 and nitrotyrosine by immunohistochemical study for BE and squamous epithelium of human specimens. Second, we studied the effect of peroxynitrite, peroxynitrite stimulator, SIN-1, or NO donor, NOC7, on the expression of phosphorylated EGFR and CDX2 in KYSE30, an EGFR-rich human esophageal squamous cell carcinoma cell-line. Specific inhibitors for EGFR, AG1478 and small interfering RNA for EGFR (EGFR-siRNA) were employed to elucidate the role of EGFR in the induction of CDX2. RESULTS The immunohistochemical study revealed that the expressions of EGFR, CDX2 and nitrotyrosine in BE were stronger than those in squamous epithelium with positive correlations. Exposure to peroxynitrite, SIN-1 or NOC7 induced EGFR phosphorylation and CDX2 expression in dose- and time-dependent manners. Both EGFR phosphorylation and CDX2 induction were significantly diminished by AG 1478 and EGFR-siRNA. CONCLUSIONS We revealed for the first time that extrinsic NO might directly induce CDX2 expression through EGFR phosphorylation. We suggested that NO had an important role in the development of BE from squamous epithelium around GEJ.
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Affiliation(s)
- Gen Kusaka
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1Seiryo-machi, Aoba-ku, Sendai, Miyagi, Japan
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McAdam E, Haboubi HN, Forrester G, Eltahir Z, Spencer-Harty S, Davies C, Griffiths AP, Baxter JN, Jenkins GJS. Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) are important mediators of reflux-induced cell signalling in esophageal cells. Carcinogenesis 2012; 33:2035-43. [PMID: 22826608 DOI: 10.1093/carcin/bgs241] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) has been implicated in both DNA damage induction and aberrant cell signalling in various tissue and cell backgrounds. We investigated here the role of iNOS and NO in DNA damage induction and nuclear factor-kappa B (NF-κB) signalling in esophageal cells in vitro. As esophageal adenocarcinoma develops in a background of Barrett's esophagus secondary to reflux disease, it is possible that inflammatory mediators like NO may be important in esophageal cancer development. We show that reflux components like stomach acid and bile acids [deoxycholic acid (DCA)] can induce iNOS gene and protein expression and produce NO generation in esophageal cells, using real-time PCR, western blotting and NO sensitive fluorescent probes, respectively. This up-regulation of iNOS expression was not dependent on NF-κB activity. DCA-induced DNA damage was independent of NF-κB and only partially dependent on iNOS and NO, as measured by the micronucleus assay. These same reflux constituents also activated the oncogenic transcription factor NF-κB, as measured by transcription factor enzyme-linked immunosorbent assay and gene expression studies with NF-κB linked genes (e.g. interleukin-8). Importantly, we show here for the first time that basal levels of NF-κB activity (and possibly acid and DCA-induced NF-κB) are dependent on iNOS/NO and this may lead to a positive feedback loop whereby induced iNOS is upstream of NF-κB, hence prolonging and potentially amplifying this signalling, presumably through NO activation of NF-κB. Furthermore, we confirm increased protein levels of iNOS in esophageal adenocarcinoma and, therefore, in neoplastic development in the esophagus.
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Affiliation(s)
- E McAdam
- Institute of Life Science, School of Medicine, Swansea University Swansea, SA28PP, UK
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Takata Y, Kristal AR, Santella RM, King IB, Duggan DJ, Lampe JW, Rayman MP, Blount PL, Reid BJ, Vaughan TL, Peters U. Selenium, selenoenzymes, oxidative stress and risk of neoplastic progression from Barrett's esophagus: results from biomarkers and genetic variants. PLoS One 2012; 7:e38612. [PMID: 22715394 PMCID: PMC3371043 DOI: 10.1371/journal.pone.0038612] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2012] [Accepted: 05/07/2012] [Indexed: 11/19/2022] Open
Abstract
Clinical trials have suggested a protective effect of selenium supplementation on the risk of esophageal cancer, which may be mediated through the antioxidant activity of selenoenzymes. We investigated whether serum selenium concentrations, selenoenzyme activity, oxidative stress and genetic variation in selenoenzymes were associated with the risk of neoplastic progression to esophageal adenocarcinoma (EA) and two intermediate endpoints, aneuploidy and tetraploidy. In this prospective cohort study, during an average follow-up of 7.3 years, 47 EA cases, 41 aneuploidy cases and 51 tetraploidy cases accrued among 361 participants from the Seattle Barrett's Esophagus Research Study who were free of EA at the time of blood draw and had at least one follow-up visit. Development to EA was assessed histologically and aneuploidy and tetraploidy by DNA content flow cytometry. Serum selenium concentrations were measured using atomic absorption spectrometry, activity of glutathione peroxidase (GPX) 1 and GPX3 by substrate-specific coupled test procedures, selenoprotein P (SEPP1) concentrations and protein carbonyl content by ELISA method and malondialdehyde concentrations by HPLC. Genetic variants in GPX1-4 and SEPP1 were genotyped. Serum selenium was not associated with the risk of neoplastic progression to EA, aneuploidy or tetraploidy (P for trend = 0.25 to 0.85). SEPP1 concentrations were positively associated with the risk of EA [hazard ratio (HR) = 3.95, 95% confidence intervals (CI) = 1.42-10.97 comparing the third tertile with the first] and with aneuploidy (HR = 6.53, 95% CI = 1.31-32.58), but not selenoenzyme activity or oxidative stress markers. No genetic variants, overall, were associated with the risk of neoplastic progression to EA (global p = 0.12-0.69). Our results do not support a protective effect of selenium on risk of neoplastic progression to EA. Our study is the first to report positive associations of plasma SEPP1 concentrations with the risk of EA and aneuploidy, which warrants further investigation.
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Affiliation(s)
- Yumie Takata
- Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Alan R. Kristal
- Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Regina M. Santella
- Department of Environmental Health Sciences, Columbia University, New York, New York, United States of America
| | - Irena B. King
- Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Department of Internal Medicine, University of New Mexico, Albuquerque, New Mexico, United States of America
| | - David J. Duggan
- Division of Genetic Basis of Human Disease, Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Johanna W. Lampe
- Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Margaret P. Rayman
- Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom
| | - Patricia L. Blount
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Brian J. Reid
- Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Thomas L. Vaughan
- Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Ulrike Peters
- Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- * E-mail:
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Nasseri-Moghaddam S, Nokhbeh-Zaeem H, Saniee P, Pedramnia S, Sotoudeh M, Malekzadeh R. Oral nitrate reductase activity and erosive gastro-esophageal reflux disease: a nitrate hypothesis for GERD pathogenesis. Dig Dis Sci 2012; 57:413-8. [PMID: 21881975 DOI: 10.1007/s10620-011-1865-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2011] [Accepted: 08/08/2011] [Indexed: 01/10/2023]
Abstract
BACKGROUND Despite the rich literature on GERD, its cause and reason for increased prevalence remain obscure. Currently accepted mechanisms leave many questions unanswered. Nitrite chemistry at the GEJ is well described for carcinogenesis. Recent epidemiological and animal data have linked nitrates to GERD. "Nitrate reductase" of oral bacteria converts nitrates to nitrites. We hypothesized that nitrate reductase activity is higher in patients with erosive GERD, delivering more nitrite at the gastroesophageal-junction for a given nitrate intake. AIM To compare oral nitrate reductase activity of erosive GERD patients with controls. METHODS Patients with erosive GERD and controls without GERD were enrolled. After overnight fasting, nitrite of oral cavity contents was measured at 1-min intervals for 3 min while incubating a 10-mg nitrate-N/L solution in the mouth. Nitrate reductase activity was calculated and compared between groups. RESULTS Eleven cases (ten males, mean age: 42.6 ± 11.7 year) and ten controls (eight males, mean age: 37.6 ± 9.2 year) were enrolled. Mean nitrate reductase activity was 3.23 ± 0.99 vs. 2.30 ± 0.83 "μg nitrite-N formed/person/minute" in cases and controls, respectively (p = 0.03). CONCLUSIONS Oral nitrate reductase activity in erosive GERD patients is higher than controls. Therefore, any dietary nitrate load generates more nitrite in these patients. This excess nitrite at the gastroesophageal junction, may potentially contribute to the development of GERD. This is the first report linking oral nitrite production to erosive GERD in man. We suggest that a "nitrate hypothesis" may answer yet unanswered questions about GERD pathogenesis. If confirmed, it may change our understanding of mechanisms of GERD and provide novel therapeutic targets.
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Abstract
INTRODUCTION Incidence of oesophageal adenocarcinoma (OAC) is increasing rapidly. OAC arises in columnar-lined oesophagus (CLO), a metaplastic change affecting some patients with gastro-oesophageal reflux disease (GORD). As yet there is no reliable method of identifying those at highest risk. Our earlier observation of an association between OAC and blood group O Rhesus negative, if confirmed, may help identify those at greatest risk. AIM AND METHODS To assess the distribution of blood group and Rhesus D (RhD) factor in patients with GORD compared with the blood donating general population. GORD was categorized as nonerosive reflux (NER), erosive oesophagitis, CLO and OAC. The Rotherham Hospital database holds details of all GORD, CLO and OAC patients seen in the Gastroenterology Unit. Blood group information for patients with GORD was obtained from patients' records and the hospital's blood transfusion service. The blood group distribution in the general population was obtained from the National Blood Transfusion Service. The number of expected to observed patients in each blood group for each subtype was compared. RESULTS Two thousand six hundred and ten NER, 2813 erosive oesophagitis, 568 CLO and 73 OAC patients had a recorded blood group. For RhD positive patients observed proportions in each blood group were similar to expected. The most striking difference was the marked excess of OAC in blood group O, Rhesus negative (P=0.002). CONCLUSION CLO patients with blood group O, RhD negative carry a disproportionately higher risk of developing OAC. The mechanism is unknown but the finding has practical application in guiding risk stratification and intensity of surveillance.
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De Ceglie A, Fisher DA, Filiberti R, Blanchi S, Conio M. Barrett's esophagus, esophageal and esophagogastric junction adenocarcinomas: the role of diet. Clin Res Hepatol Gastroenterol 2011; 35:7-16. [PMID: 20970272 DOI: 10.1016/j.gcb.2010.08.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2010] [Revised: 08/20/2010] [Accepted: 08/27/2010] [Indexed: 02/04/2023]
Abstract
Identification of modifiable risk factors is an attractive approach to primary prevention of esophageal adenocarcinoma (EAC) and esophagogastric junction adenocarcinoma (EGJAC). We conducted a review of the literature to investigate the association between specific dietary components and the risk of Barrett’s esophagus (BE), EAC and EGJAC, supposing diet might be a risk factor for these tumors. Consumption of meat and high-fat meals has been found positively associated with EAC and EGJAC. An inverse association with increased intake of fruit, vegetables and antioxidants has been reported but this association was not consistent across all studies reviewed. Few studies have examined the association between diet and BE. Additional research is needed to confirm the aforementioned association and clarify the mechanisms by which dietary components affect the risk of developing EAC and EGJAC. Future studies could advance our knowledge by emphasizing prospective designs to reduce recall bias, by using validated dietary intake questionnaires and biological measures and by considering important confounders such as gastro-esophageal reflux disease (GERD) symptoms, tobacco and alcohol use, biometrics, physical activity, and socioeconomic factors.
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Affiliation(s)
- A De Ceglie
- Department of Gastroenterology and Digestive Endoscopy, Cancer Institute Giovanni Paolo II, Bari, Italy
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The pathogenesis of Barrett's metaplasia and the progression to esophageal adenocarcinoma. Recent Results Cancer Res 2010; 182:39-63. [PMID: 20676870 DOI: 10.1007/978-3-540-70579-6_4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The most important risk factor for the development of Barrett's esophagus is the reflux of both gastric and duodenal contents into the esophagus. The reason why Barrett's metaplasia develops only in a minority of patients suffering from gastroesophageal reflux disease remains unknown.The exact mechanism behind the transition of normal squamous epithelium into specialized columnar epithelium is also unclear. It is likely that stem cells are involved in this metaplastic change, as they are the only permanent residents of the epithelium. Several tumorigenic steps that lead to the underlying genetic instability, which is indispensable in the progression from columnar metaplasia to esophageal adenocarcinoma have been described. This review outlines the process of pathogenesis of Barrett's metaplasia and its progression to esophageal adenocarcinoma.
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Endo H, Iijima K, Asanuma K, Ara N, Ito H, Asano N, Uno K, Koike T, Imatani A, Shimosegawa T. Exogenous luminal nitric oxide exposure accelerates columnar transformation of rat esophagus. Int J Cancer 2010; 127:2009-19. [PMID: 20131319 DOI: 10.1002/ijc.25227] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Exposure of the esophageal mucosa to refluxed gastroduodenal contents is recognized to be an important risk factor for Barrett's esophagus (BE). At the human gastroesophageal junction, nitric oxide is generated luminally through the enterosalivary recirculation of dietary nitrate, and in cases with gastroesophageal reflux, the site of luminal nitric oxide generation could shift to the distal esophagus. The aim of this study is to investigate whether exogenous luminal nitric oxide could promote the development of BE in rats. Sodium nitrite plus ascorbic acid were administered to a rat surgical model of BE, in which the gastroduodenal contents were refluxed into the esophagus to generate exogenous luminal nitric oxide in the esophagus by the acid-catalyzed chemical reaction between the 2 reagents. The emergence of BE was evaluated histologically in the early phase (several weeks) after the surgery with or without exogenous nitric oxide administration. To elucidate the histogenesis of BE, CDX2, MUC2 and MUC6 expressions were investigated immunohistochemically. Coadministration of sodium nitrite plus ascorbic acid significantly accelerated the timing of emergence and increased the area of BE compared with controls. Administration of either reagent alone did not show any promotive effects on BE formation. Immunohistochemically, the columnar epithelium thus induced was similar to the specialized intestinal metaplasia in human BE. The results of this animal model study suggest that exogenous luminal nitric oxide could be involved in the pathogenesis of the columnar transformation of the esophagus. Further studies in human are warranted.
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Affiliation(s)
- Hiroyuki Endo
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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Clemons NJ, Shannon NB, Abeyratne LR, Walker CE, Saadi A, O'Donovan ML, Lao-Sirieix PP, Fitzgerald RC. Nitric oxide-mediated invasion in Barrett's high-grade dysplasia and adenocarcinoma. Carcinogenesis 2010; 31:1669-75. [PMID: 20584750 DOI: 10.1093/carcin/bgq130] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Nitric oxide (NO) has been shown to induce double strand DNA breaks in Barrett's oesophagus (BO) and in other cancers has a role in invasion. The specific aims of this study were to investigate whether NO can induce invasion in cells representative of different stages of Barrett's progression and to determine possible underlying mechanisms. Physiological concentrations of NO that mimic luminal production of NO from dietary sources enhanced invasion in cell lines from high-grade dysplasia (GihTERT) and oesophageal adenocarcinoma (FLO) but not a non-dysplastic Barrett's cell line (QhTERT). Real-time reverse transcription-polymerase chain reaction revealed that NO induced expression of matrix metalloproteinase (MMP)-1, -3, -7, -9 and -10 and tissue inhibitor of metalloproteinase (TIMP)-1, -2 and -3 in these cell lines. Furthermore, ex vivo treatment of Barrett's biopsy samples with NO induced increases in MMP-1 and TIMP-1 expression, suggesting that NO enhances invasion through deregulating MMP and TIMP expression in epithelial cells. In keeping with these findings, microarray analysis and immunohistochemistry performed on biopsy samples showed enhanced expression of MMP-1, -3, -7 and -10 and TIMP-1 in the progression from non-dysplastic BO to adenocarcinoma, although this could not be directly attributed to the effect of NO. Thus, NO may play a role in Barrett's carcinogenesis through deregulating MMP and TIMP expression to enhance invasive potential.
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Affiliation(s)
- Nicholas J Clemons
- Medical Research Council Cancer Cell Unit, Hutchison/Medical Research Council Centre, Hills Road, Cambridge, CB2 0XZ, UK
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Ito H, Iijima K, Ara N, Asanuma K, Endo H, Asano N, Koike T, Abe Y, Imatani A, Shimosegawa T. Reactive nitrogen oxide species induce dilatation of the intercellular space of rat esophagus. Scand J Gastroenterol 2010; 45:282-91. [PMID: 20001645 DOI: 10.3109/00365520903469956] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Dilatation of the intercellular space (DIS) of the esophageal epithelium is recognized as one of the earliest histological changes in gastroesophageal reflux disease patients. At the human gastroesophageal junction, reactive nitrogen oxide species (RNOS) are generated luminally through the entero-salivary re-circulation of dietary nitrate. In cases with gastroesophageal reflux, the site of luminal RNOS generation may shift to the distal esophagus. The aim of this study was to investigate whether luminal RNOS exposure could be involved in the pathogenesis of DIS. MATERIAL AND METHODS Rat esophageal mucosa was studied with an Ussing chamber model. On the luminal side of the chamber, RNOS were generated by the acidification of physiologic concentrations of sodium nitrite (1.0 or 5.0 mM). Esophageal barrier function was assessed by means of electrophysiological transmembrane resistance and membrane permeability by means of (3)H-mannitol flux. The dimensions of the intercellular spaces were assessed by using transmission electron microscopy. RESULTS Administration of acid plus sodium nitrite induced DIS of the esophageal epithelium, and this ultrastructural morphological change was accompanied by a concomitant decrease in the transmembrane resistance and an increase in the epithelial permeability. The DIS induced by luminal RNOS was also confirmed in an in vivo exposure model. CONCLUSIONS The present animal study indicates that the RNOS generated by the acidification of salivary nitrite in the presence of refluxed gastric acid in the esophagus could be a luminal factor that is responsible for the induction of DIS. Further studies are warranted to investigate the clinical relevance of the present findings to the human situation.
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Affiliation(s)
- H Ito
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Aobaku, Sendai, Japan
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Islami F, Kamangar F, Nasrollahzadeh D, Møller H, Boffetta P, Malekzadeh R. Oesophageal cancer in Golestan Province, a high-incidence area in northern Iran - a review. Eur J Cancer 2009; 45:3156-65. [PMID: 19800783 DOI: 10.1016/j.ejca.2009.09.018] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2009] [Revised: 09/11/2009] [Accepted: 09/15/2009] [Indexed: 12/20/2022]
Abstract
Golestan Province, located in the south-east littoral of the Caspian Sea in northern Iran, has one of the highest rates of oesophageal cancer (OC) in the world. We review the epidemiologic studies that have investigated the epidemiologic patterns and causes of OC in this area and provide some suggestions for further studies. Oesophageal squamous cell carcinoma (OSCC) constitutes over 90% of all OC cases in Golestan. In retrospective studies, cigarettes and hookah smoking, nass use (a chewing tobacco product), opium consumption, hot tea drinking, poor oral health, low intake of fresh fruit and vegetables, and low socioeconomic status have been associated with higher risk of OSCC in Golestan. However, the association of tobacco with OSCC in this area is not as strong as that seen in Western countries. Alcohol is consumed by a very small percentage of the population and is not a risk factor for OSCC in this area. Other factors, such as polycyclic aromatic hydrocarbons, N-nitroso compounds, drinking water contaminants, infections, food contamination with mycotoxins, and genetic factors merit further investigation as risk factors for OSCC in Golestan. An ongoing cohort study in this area is an important resource for studying some of these factors and also for confirming the previously found associations.
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Affiliation(s)
- Farhad Islami
- Digestive Disease Research Center, Shariati Hospital, Tehran University of Medical Sciences, 14117 Tehran, Iran
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Takahama U, Tanaka M, Hirota S, Yamauchi R. Formation of an oxathiolone compound from rutin in acidic mixture of saliva and buckwheat dough: Possibility of its occurrence in the stomach. Food Chem 2009. [DOI: 10.1016/j.foodchem.2009.02.036] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Ishiyama F, Iijima K, Asanuma K, Ara N, Yoshitake J, Abe Y, Koike T, Imatani A, Ohara S, Shimosegawa T. Exogenous luminal nitric oxide exacerbates esophagus tissue damage in a reflux esophagitis model of rats. Scand J Gastroenterol 2009; 44:527-37. [PMID: 19172433 DOI: 10.1080/00365520802699260] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Cytotoxic concentrations of nitric oxide are generated luminally at the gastroesophageal junction through the entero-salivary recirculation of dietary nitrate in humans. The site of luminal nitric oxide generation shifts to the lower esophagus when gastric acid is refluxed into the esophagus. The aim of this study was to investigate the influence of persistent administration of exogenous nitric oxide on esophageal damage. MATERIAL AND METHODS 0.1% sodium nitrite and/or 1% ascorbic acid was administered in an established rat acid-refluxed esophagitis model. Co-administration of both reactants in this model is thought to induce high concentrations of nitric oxide luminally in the esophagus by an acid-catalyzed chemical reaction when refluxed gastric acid is present. The tissue damage was evaluated by a macroscopic lesion index and myeloperoxidase activity. Nitrotyrosin was assessed immunohistochemically as a footprint of peroxynitrite formation. RESULTS Co-administration of sodium nitrite and ascorbic acid induced a 4- to 5-fold increase in the esophageal damage compared with baseline reflux esophagitis, while the damage was unchanged when either of the reagents alone was given. Nitrotyrosine was strongly stained in the tissue from the co-administration. Treatment of superoxide scavengers efficiently prevented the exacerbation of esophageal damage by exogenous nitric oxide exposure, suggesting an essential role of superoxide in esophageal damage. CONCLUSIONS Exogenous luminal nitric oxide greatly exacerbated the tissue damage of reflux esophagitis. Diffusion of the luminal nitric oxide into the adjacent superoxide-enriched inflamed tissue of the esophagus could lead to the production of the highly toxic agent peroxynitrite, thus causing exacerbation of the esophageal damage.
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Affiliation(s)
- Fumitake Ishiyama
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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Takahama U, Tanaka M, Oniki T, Hirota S. Reactions of thiocyanate in the mixture of nitrite and hydrogen peroxide under acidic conditions: Investigation of the reactions simulating the mixture of saliva and gastric juice. Free Radic Res 2009; 41:627-37. [PMID: 17516234 DOI: 10.1080/10715760701218566] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Nitrite and SCN(-) in saliva can mixes with H(2)O(2) in the stomach. The mixing can result in the formation of ONOOH. It is not yet known how salivary SCN(-) reacts with ONOOH. An objective of the present study was to elucidate the reaction between ONOOH and SCN(-). In nitrite/H(2)O(2) systems at pH 2, SCN(-) inhibited the consumption of nitrite and the formation of O(3)(-). SCN(-) enhanced the decomposition of ONOOH and H(2)O(2) in HNO(2)/H(2)O(2) systems. Accompanying the reactions, sulfate was formed, suggesting that ONOOH oxidized SCN(-). SCN(-) inhibited the nitration of phenolics induced by HNO(2)/H(2)O(2). The inhibition is discussed taking SCN(-)-dependent reduction of ONOOH to HNO(2) into consideration. SCN(-) also inhibited H(2)O(2)-induced consumption of nitrite and nitration of phenolics in acidified saliva. The result obtained in this study suggests that salivary SCN(-) can reduce ONOOH to O(2)(-)/HNO(2) inhibiting nitrating reactions in the stomach.
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Affiliation(s)
- Umeo Takahama
- Department of Bioscience, Kyushu Dental College, Kitakyushu, Japan.
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Takahama U, Hirota S, Kawagishi S. Effects of pH on nitrite-induced formation of reactive nitrogen oxide species and their scavenging by phenolic antioxidants in human oral cavity. Free Radic Res 2009; 43:250-61. [DOI: 10.1080/10715760802691463] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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34
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Takahama U, Ryu K, Oniki T, Hirota S. Dual-function of thiocyanate on nitrite-induced formation of reactive nitrogen oxide species in human oral cavity: Inhibition under neutral and enhancement under acidic conditions. Free Radic Res 2009; 41:1289-300. [DOI: 10.1080/10715760701710885] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Walz A, Odenbreit S, Stühler K, Wattenberg A, Meyer HE, Mahdavi J, Borén T, Ruhl S. Identification of glycoprotein receptors within the human salivary proteome for the lectin-like BabA and SabA adhesins of Helicobacter pylori by fluorescence-based 2-D bacterial overlay. Proteomics 2009; 9:1582-92. [PMID: 19253298 DOI: 10.1002/pmic.200700808] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Because gastric infection by Helicobacter pylori takes place via the oral route, possible interactions of this bacterium with human salivary proteins could occur. By using modified 1- and 2-D bacterial overlay, binding of H. pylori adhesins BabA and SabA to the whole range of salivary proteins was explored. Bound salivary receptor molecules were identified by MALDI-MS and by comparison to previously established proteome maps of whole and glandular salivas. By use of adhesin-deficient mutants, binding of H. pylori to MUC7 and gp-340 could be linked to the SabA and BabA adhesins, respectively, whereas binding to MUC5B was associated with both adhesins. Binding of H. pylori to the proline-rich glycoprotein was newly detected and assigned to BabA adhesin whereas the SabA adhesin was found to mediate binding to newly detected receptor molecules, including carbonic anhydrase VI, secretory component, heavy chain of secretory IgA1, parotid secretory protein and zinc-alpha(2)-glycoprotein. Some of these salivary glycoproteins are known to act as scavenger molecules or are involved in innate immunity whereas others might come to modify the pathogenetic properties of this organism. In general, this 2-D bacterial overlay technique represents a useful supplement in adhesion studies of bacteria with complex protein mixtures.
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Affiliation(s)
- Anke Walz
- Department of Operative Dentistry and Periodontology, Dental School, University of Regensburg, Regensburg, Germany
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Yin M, Tan D, Wei Q. Genetic variants of the XRCC1 gene and susceptibility to esophageal cancer: a meta-analysis. Int J Clin Exp Med 2009; 2:26-35. [PMID: 19436829 PMCID: PMC2680054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2008] [Accepted: 01/12/2009] [Indexed: 05/27/2023]
Abstract
To summarize published data on the role of common genetic variants of the X-ray repair cross-complementing group 1 (XRCC1) gene in susceptibility to esophageal cancer (EC), we performed a meta-analysis including 11 eligible publications with 3,306 patients and 6,852 controls for Arg(399)Gln and 832 patients and 1,418 controls for Arg(194)Trp. Overall, the variant Gln(399) allele was not associated with EC risk, compared with the Arg(399) allele in the populations included in the analysis. However, stratified analysis revealed that Gln(399) allele was associated with an increased EC risk among Chinese populations in a recessive model (OR, 1.33; 95% CI 1.01-1.76; fixed effects) and by homozygote contrast (OR, 1.35; 95% CI 1.01-1.81), particularly for the tumor histology of squamous cell carcinoma (OR, 1.34; 95% CI 1.03-1.73 for the recessive model) and (OR, 1.34; 95% CI 1.02-1.76 for the homozygote contrast). There was no apparent effect of the Trp(194) allele, compared to the Arg(194) allele, on the EC risk in all analyses. These results suggest that the XRCC1 Arg(399)Gln polymorphism may be a potential biomarker of EC susceptibility in Chinese populations, particularly for squamous cell carcinoma. Further larger studies with multi-ethnic populations are required to further assess the association between XRCC1 polymorphisms and EC risk.
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Affiliation(s)
- Ming Yin
- Department of Epidemiology, The University of Texas, M. D. Anderson Cancer Center1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Dongfeng Tan
- Department of Pathology, The University of Texas, M. D. Anderson Cancer Center1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Qingyi Wei
- Department of Epidemiology, The University of Texas, M. D. Anderson Cancer Center1515 Holcombe Blvd, Houston, TX 77030, USA
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Takahama U, Tanaka M, Hirota S. Interaction between ascorbic acid and chlorogenic acid during the formation of nitric oxide in acidified saliva. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2008; 56:10406-10413. [PMID: 18922016 DOI: 10.1021/jf8018535] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2023]
Abstract
When saliva and gastric juice are mixed, salivary nitrite is transformed to nitrous acid to produce nitric oxide (NO). The NO formation in acidified saliva was enhanced by ascorbic acid and chlorogenic acid. Thiocyanate ion (SCN(-)) also enhanced the transformation of nitrous acid to NO. During the NO formation in the presence of both ascorbic acid and chlorogenic acid, ascorbic acid was preferentially oxidized. Chlorogenic acid was oxidized after ascorbic acid had been oxidized. Ascorbyl radical was detected during the oxidation of ascorbic acid, and the radical intensity was decreased by chlorogenic acid. The decrease is discussed to be due to the reduction of the oxidation intermediate or product of chlorogenic acid by ascorbyl radical. The result obtained in this study suggests that ascorbic acid was preferentially oxidized and that not only ascorbic acid but also ascorbyl radical could interact with the oxidation intermediate or product of chlorogenic acid when chlorogenic acid was added to the mixture of saliva and gastric juice that contained ascorbic acid.
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Affiliation(s)
- Umeo Takahama
- Department of Bioscience, Kyushu Dental College, Kitakyushu 803-8580, Japan.
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Rubio CA, Dick EJ, Forssell L, Hubbard GB. The frequency of histological features mimicking reflux esophagitis: a study in non-human primates. In Vivo 2008; 22:721-4. [PMID: 19180997 PMCID: PMC3468915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
BACKGROUND The frequency of histological changes mimicking those described for reflux esophagitis in humans was assessed in a cohort of non-human primates (NHP). MATERIALS AND METHODS A total of 121 consecutive esophagi (from 103 baboons and 18 macaques) were classified according to Ismail-Beiji for reflux esophagitis in humans into grade 1, grade 2 and grade 3 esophagitis. RESULTS Histological features compatible with reflux esophagitis were found in 28.2% of the baboons and in 22.2% of the macaques. Esophagitis grade 1 was more common in baboons (24%) than in macaques (6%), while esophagitis grade 2 was more common in macaques (17%) than in baboons (2%). CONCLUSION Although the prevalence of reflux esophagitis in man is at least 2%, only a fraction of patients demonstrate histological features consistent with grades 1, 2 or 3 esophagitis. Hence, the finding that 27% of a cohort of consecutive, unselected NHP had grades 1, 2 or 3 esophagitis at histology is remarkable. The possible causes for the difference between species, such as the oblique position often adopted by NHP during the gastric phase of digestion, the diet, regurgitation and subsequent re-ingestion, as well as the stress of NHP when kept in captivity, are reviewed.
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Affiliation(s)
- Carlos A Rubio
- Southwest National Primate Research Center, Southwest Foundation for Biomedical Research, San Antonio, TX 78245-0549, USA.
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Shibata A, Matsuda T, Ajiki W, Sobue T. Trend in incidence of adenocarcinoma of the esophagus in Japan, 1993-2001. Jpn J Clin Oncol 2008; 38:464-8. [PMID: 18664481 DOI: 10.1093/jjco/hyn064] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Several studies with population-based cancer registry data have suggested that incidence of adenocarcinoma of the esophagus has been increasing since 1970 in some European and North American countries and Australia. However, data from Asian countries with regard to the incidence of esophageal cancer by histological type based on the population-based cancer registry are lacking. The aim of this study was to describe the incidence of esophageal cancer by histological type in a Japanese population. METHODS Cancer incidence data for 1993-2001 from 15 population-based cancer registries were collected by the Japan Cancer Surveillance Research Group in 2005. We used data from eight registries corresponding to inclusion criteria for data quality. RESULTS Squamous cell carcinoma remains the predominant type in all esophageal cancers in Japan. The ratio of squamous cell carcinoma to adenocarcinoma is 26:1. For adenocarcinoma, estimated average annual percentage change was 4.7% (95% confidence interval: 0.7, 8.9) in men and 6.0% (2.4, 9.8) in women. Age-adjusted incidence rate (the world standard population) per 100 000 for 2001 was 0.3 in men and 0.05 in women. Incidence of squamous cell carcinoma was increasing slightly in men and nearly constant in women. Age-adjusted incidence rate for 2001 was 8.2 in men and 1.0 in women. CONCLUSION No dramatic increase in adenocarcinoma has occurred, and absolute incidence remains low in Japan.
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Affiliation(s)
- Akiko Shibata
- Yamagata Prefectural Medical Center for Cancer and Life-style Related Disease, 1800 Aoyagi Yamagata, 990-2292 Yamagata, Japan.
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Abstract
Early gastric cancer is a curable disease regardless of its location, histologic type, genetic changes, or the ethnicity of the patient. To improve the detection rate of early gastric cancer, intensive training of endoscopists and the use of novel endoscopic techniques have been introduced into routine examinations in Japan. In the United States, where most gastric cancer is found in advanced stages, a similar approach should be advocated. Endoscopic resection of high-grade dysplasia is also encouraged in the United States not only for proper diagnosis but also for achieving cure without surgical intervention.
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Affiliation(s)
- Kentaro Sugano
- Department of Medicine, Jichi Medical University, Yakushiji 3311-1, Shimotsuke-City, Tochigi, Japan.
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Doecke J, Zhao ZZ, Pandeya N, Sadeghi S, Stark M, Green AC, Hayward NK, Webb PM, Whiteman DC. Polymorphisms in MGMT and DNA repair genes and the risk of esophageal adenocarcinoma. Int J Cancer 2008; 123:174-80. [PMID: 18386788 DOI: 10.1002/ijc.23410] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Rates of adenocarcinoma of the esophagus (EAC) and esophago-gastric junction (EGJAC) have increased rapidly in recent decades. The primary risk factors, gastro-esophageal acid reflux and smoking, are potentially genotoxic through the generation of N-nitroso compounds. The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is the major cellular defense against alkylating DNA damage. We compared patients with EAC (n = 263) or EGJAC (n = 303) with matched population controls (n = 1,337) for the frequency of 5 MGMT single nucleotide polymorphisms (SNPs) (rs12269324, rs12268840, L84F, I143V, K178R), as well as SNPs in DNA repair genes ERCC1 (N118N), XRCC1 (Q399R) and XPD (K751Q). Relative risks were estimated using multivariable logistic regression. Potential biological interaction was assessed through the synergy index S. Each MGMT SNP conferred increased risks of EAC but not EGJAC; strongest associations were found for the 2 variant MGMT alleles rs12268840 and I143V (p = 0.005 and p < 0.001, respectively). Homozygous carriers of MGMT rs12268840 with frequent acid reflux had significantly higher risks of EAC (OR 15.5, 95% CI 5.8-42) than expected under an additive model, consistent with biological interaction (S = 3.3, 95% CI 1.1-10). Modest, nonsignificant interactions with smoking were also observed. Homozygous variant ERCC1 genotype was associated with reduced risks of EAC (OR 0.6, 95% CI 0.4-1.1), while the homozygous variant XRCC1 genotype conferred higher risks of EGJAC (OR 1.6, 95% CI 1.1-2.4). No associations with EAC or EGJAC were observed with XPD (rs13181). In summary, MGMT SNPs are associated with increased risks of EAC. Exposure to acid reflux, and possibly smoking, confer markedly higher risks among homozygous variant genotype carriers.
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Affiliation(s)
- James Doecke
- Queensland Institute of Medical Research, Brisbane, Queensland, Australia
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Abstract
BACKGROUND & AIMS Esophageal acid exposure conventionally is measured 5 cm above the lower esophageal sphincter (LES). The aim of this study was to compare pH profiles at sites within the LES, the distal esophagus, and the proximal stomach. METHODS Ten normal subjects underwent esophageal manometry followed by 24-hour esophagogastric pH monitoring using an 8-channel pH probe recording at 5 and 1.5 cm above and at 0, 1.5, 3.0, 4.5, 6.0, and 9.5 cm below the proximal LES border. During pH recording, a 4-hour gastric emptying test with an egg sandwich meal was performed. RESULTS The LES was 3.2 +/- 0.4 cm in length. There was a progressive increase in acid exposure from the esophageal to the gastric pH sensors. pH was less than 4 for 3.4% +/- 1.6%, 12.7% +/- 8.5%, 26.5% +/- 10.2%, 48.1% +/- 11.3%, 66.5% +/- 9.9%, 80.8% +/- 5.6%, 89.2% +/- 3.0%, and 96.7% +/- 1.1% of the total time for pH probes at 5 and 1.5 cm above and 0, 1.5, 3, 4.5, 6.0, and 9.5 cm below the proximal LES border, respectively. Percentage acid exposures correlated significantly with the position of the probe (r = -0.95; P < .01). Intrasphincteric acidity increased postprandially. Gastric emptying was correlated inversely with the intragastric hydrogen ion concentration (r = -0.82). CONCLUSIONS The percentage of recording time that pH was less than 4 was significantly higher in the intrasphincteric area and 1.5 cm above the proximal LES compared with the traditional site 5 cm above the proximal manometric LES border. High acid exposure in the intrasphincteric region might explain the susceptibility of the distal esophagus to erosions, strictures, and Barrett's esophagus.
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43
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Kuroiwa Y, Yamada M, Matsui K, Okamura T, Ishii Y, Masumura KI, Tasaki M, Umemura T, Mitsumori K, Nohmi T, Hirose M, Nishikawa A. Combined Ascorbic Acid and Sodium Nitrite Treatment Induces Oxidative DNA Damage-Associated Mutagenicity In Vitro, but Lacks Initiation Activity in Rat Forestomach Epithelium. Toxicol Sci 2008; 104:274-82. [DOI: 10.1093/toxsci/kfn081] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
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Rubio CA, Dick EJ, Orrego A, Hubbard GB. The frequency of lymphocytic and reflux esophagitis in non-human primates. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2008; 1:531-535. [PMID: 18787683 PMCID: PMC2480590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/26/2008] [Accepted: 02/26/2008] [Indexed: 05/26/2023]
Abstract
We previously reported in humans a novel histologic phenotype of non-gastro-esophageal reflux disease called lymphocytic esophagitis. In this work, the esophagi of 121 non-human primates (103 baboons and 18 macaques) were investigated. 45 baboons (43.7%) and 9 macaques (50%) had lymphocytic esophagitis. The lymphocytic infiltration in the squamous epithelium involved not only papillary but also inter-papillary fields. Microscopic examination around the papillae revealed a mean of 52 intraepithelial lymphocytes (IELs) per high power field. Of the remaining baboons, 29 had reflux esophagitis (GERD). Among them, 25 (24.3%) 2 (1.9%) and 2 (1.9%) had grade1, 2 and 3 esophagitis, respectively. Of the remaining macaques, 4 had GERD: 1 (5.5%) with grade 1 and 3 (16.7%) with grade 2 esophagitis. None of the macaques had grade 3 esophagitis. The IEL population in lymphocytic esophagitis was composed of T cells, a subset of natural killer cells and of helper and inflammatory T cells. This investigation in non-human primates substantiates the identity of lymphocytic esophagitis as a subset of chronic esophagitis, as well as of reflux esophagitis. The antigenic agent(s) responsible for the marked immunological reaction in lymphocytic esophagitis in non-human primates (and in humans) remains unknown.
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Affiliation(s)
- Carlos A Rubio
- Southwest National Primate Research Center, Southwest Foundation for Biomedical Research San Antonio, TX 78245-0549, USA.
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Saliva variations in gastro-oesophageal reflux disease. J Dent 2008; 36:268-71. [PMID: 18313197 DOI: 10.1016/j.jdent.2008.01.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2007] [Revised: 01/07/2008] [Accepted: 01/08/2008] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVES The protective role of saliva in the case of oesophageal exposition to gastric acid has long been studied but some contradictions still remain. The main end-point of this study was to evaluate if a qualitative and quantitative alteration in salivary secretion exists in patients affected by GERD. METHODS One hundred and twenty patients (T group) with clinically and endoscopically diagnosed GERD, and 98 healthy subjects (C group) have been evaluated; salivary tests (i.e. basal flow rate, stimulated flow rate, pH, [Na(+)] and [K(+)]) were performed, socio-demographical variables and oral GERD-related symptoms were taken into account. SPSS 10.5 software was used for statistical univariate and multivariate analyses. RESULTS GERD patients and controls were found to have a similar basal flow rate but different stimulated salivary function [T group mean value 0.989 ml/min (+/-0.48718) vs. C group 1.2197 ml/min (+/-0.6108), pH [T group mean value 8.935 (+/-0.471) vs. C group 7.879 (+/-0.526)] and a higher K(+) concentration. In GERD patients we also registered a significant association with xerostomia [69/120 (57.5%) vs. 28/98 (28.7%)] and an oral burning sensation [58/120 (48.3%) vs. 19/98 (19.3%)]. CONCLUSIONS Our findings assess that salivary secretion is altered in GERD patients and highlight the need for further investigations in order to define the role of saliva in the etiopathogenesis of GERD.
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Kuroiwa Y, Okamura T, Ishii Y, Umemura T, Tasaki M, Kanki K, Mitsumori K, Hirose M, Nishikawa A. Enhancement of esophageal carcinogenesis in acid reflux model rats treated with ascorbic acid and sodium nitrite in combination with or without initiation. Cancer Sci 2008; 99:7-13. [PMID: 17953708 PMCID: PMC11158633 DOI: 10.1111/j.1349-7006.2007.00649.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2007] [Revised: 09/12/2007] [Accepted: 09/19/2007] [Indexed: 11/29/2022] Open
Abstract
Combined treatment with sodium nitrite (NaNO2) and ascorbic acid (AsA) has already been shown to promote rat forestomach carcinogenesis, possibly due to nitric oxide generation under acidic conditions. We hypothesized that a similar effect might occur in the esophagus when the luminal pH is decreased by acid reflux. To clarify this possibility, reflux esophagitis model rats (F344 male) were coadministered 0.2% NaNO2 in the drinking water and 1% AsA in the diet. After 32 weeks of the combined treatment, a significant increase in the incidence of epithelial hyperplasias of the lower-middle and lowest parts of the esophagus were observed compared with the basal-diet group, along with exacerbation of dysplasia and extension of the lesions. Additionally, one squamous cell papilloma was found only in the combined-treatment group. Subsequently, we confirmed the enhancing effects of NaNO2 and AsA cotreatment in the rat N-bis(2-hydroxypropyl)nitrosamine-initiated esophageal tumorigenesis model. The incidence of hyperplasia was enhanced in all segments, along with the incidence and multiplicity of squamous cell papillomas in the lowest segment of the esophagus. Thus, the data demonstrate that combined treatment with NaNO2 and AsA exerts promoting effects on rat esophageal carcinogenesis under acid reflux conditions, as in the forestomach. These findings suggest that the risk of excessive intake of a combination of nitrite and antioxidants for esophageal carcinogenesis is appreciable, particularly in patients with reflux esophagitis.
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Affiliation(s)
- Yuichi Kuroiwa
- Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-Ku, Tokyo 158-8501, Japan
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Räsänen JV, Sihvo EIT, Rantanen TK, Ahotupa MO, Färkkilä MA, Harjula A, Salo JA. Gastroesophageal reflux patients' defective antioxidative capacity in the proximal esophageal mucosa before antireflux surgery and also after 4-year follow-up. Ann Med 2008; 40:74-80. [PMID: 17943478 DOI: 10.1080/07853890701668508] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
BACKGROUND Oxidative stress has a role in the pathogenesis of gastroesophageal reflux disease (GERD). AIM To investigate the redox balance in proximal esophagus before and 6 and 48 months after antireflux surgery. METHODS In 20 GERD patients and 9 controls oxidative stress by myeloperoxidase activity (MPO activity) and antioxidative capacity of esophageal mucosa by superoxide dismutase activity (SOD), and glutathione content (GSH) was measured from proximal esophageal samples. RESULTS In proximal esophagus of GERD patients compared to controls', antioxidative capacity appearing as GSH level was significantly decreased (P < 0.001) at all time points and as SOD levels preoperatively (P < 0.001) and 4 years postoperatively (P = 0.01). MPO activity of patients was significantly lower than controls' preoperatively, and 6 months and 4 years postoperatively (P < 0.05). MPO activity remained lower than that of the distal esophagus at 6 months and 4 years (P < 0.01 for both). CONCLUSIONS In GERD patients, proximal esophageal mucosal antioxidative defense is defective before and after antireflux surgery. Antireflux surgery seems not to change the level of oxidative stress in proximal esophagus, suggesting that defective mucosal antioxidative capacity plays a role in development of oxidative damage to the esophageal mucosa in GERD.
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Affiliation(s)
- Jari V Räsänen
- Division of General Thoracic and Esophageal Surgery, Department of Cardiothoracic Surgery, Helsinki University Central Hospital, Helsinki, Finland
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Takahama U, Hirota S, Takayuki O. Detection of Nitric Oxide and Its Derivatives in Human Mixed Saliva and Acidified Saliva. Methods Enzymol 2008; 440:381-96. [DOI: 10.1016/s0076-6879(07)00824-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Dantas RO, Aprile LRO. [Aging and esophageal motility in patients with gastroesophageal reflux disease]. ARQUIVOS DE GASTROENTEROLOGIA 2007; 43:107-11. [PMID: 17119664 DOI: 10.1590/s0004-28032006000200009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2005] [Accepted: 10/24/2005] [Indexed: 11/21/2022]
Abstract
BACKGROUND Alterations of esophageal contractions may worsen the esophageal lesions caused by gastroesophageal reflux. The impairment of the contractions may be localized only in the distal esophagus or in the entire esophageal body, and may be worse with the aging process. AIMS To evaluate the proximal and distal esophageal contractions in patients with gastroesophageal reflux symptoms with or without esophagitis. PATIENTS AND METHODS We studied esophageal motility in 104 patients with gastroesophageal reflux symptoms, 42 with normal esophageal endoscopic examination, 47 with mild esophagitis and 15 with severe esophagitis. The esophageal contractions were measured by the manometric method at 2, 7, 12 and 17 cm from the upper esophageal sphincter, after five swallows of a 5 mL bolus of water. RESULTS The amplitude and area under the curve of contractions were lower in patients with severe esophagitis than in patients without esophagitis or with mild esophagitis in the distal part of the esophageal body (17 cm from the upper esophageal sphincter). In the proximal esophageal body there was no difference in amplitude or area under the curve. In the entire esophageal body there was no difference between the three groups of patients in duration, velocity of peristaltic contractions, or proportion of failed, simultaneous, non-propagated or peristaltic contractions. There was no difference between the patients with less than 50 years or with more than 50 years of age. CONCLUSIONS Patients with severe esophagitis had lower distal esophageal contraction amplitude than patients without esophagitis or with moderate esophagitis. There was no effect of aging on esophageal contractions.
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Affiliation(s)
- Roberto Oliveira Dantas
- Departamento de Clínica Médica, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP.
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Clemons NJ, McColl KEL, Fitzgerald RC. Nitric oxide and acid induce double-strand DNA breaks in Barrett's esophagus carcinogenesis via distinct mechanisms. Gastroenterology 2007; 133:1198-209. [PMID: 17919494 DOI: 10.1053/j.gastro.2007.06.061] [Citation(s) in RCA: 73] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2007] [Accepted: 06/14/2007] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS The luminal microenvironment including acid and nitric oxide (NO) has been implicated in Barrett's esophagus carcinogenesis. We investigated the ability of acid and NO to induce DNA damage in esophageal cells. METHODS Transformed and primary Barrett's esophagus and adenocarcinoma cells were exposed to either acid, (pH 3.5), +/- antioxidant or NO from a donor or generated by acidification of nitrite in the presence of ascorbate +/- NO scavenger. Phosphorylation of histone H2AX and the neutral comet assay were used to detect DNA double-strand breaks (DSBs). Intracellular levels of reactive oxygen species and NO were detected with fluorescent dyes. Mitochondrial viability was measured with a rhodamine dye. Long-term survival was assessed by clonogenic assay. RESULTS Exposure to acid (pH 3.5) for > or =15 minutes induced DSBs in all cell lines (P < .05). There was a concomitant increase in intracellular reactive oxygen species in the absence of mitochondrial damage, and pretreatment with antioxidants inhibited DNA damage. Exposure to physiologic concentrations of NO produced from the NO donor or acidification of salivary nitrite induced DSBs in a dose- (>25 micromol/L) and cell-dependent manner (adenocarcinoma >Barrett's esophagus, P < .05). This occurred preferentially in S-phase cells consistent with stalled replication forks and was blocked with a NO scavenger. NO also induced DSBs in primary Barrett's esophagus cells treated ex vivo. Cells were able to survive when exposed to acid and NO. CONCLUSIONS Both acid and NO have the potential to generate DSBs in the esophagus and via distinct mechanisms.
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