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Duncan BC, Morris MT, Pascoe JL, Khadka S, Wang L, Hu G, Busada JT. Androgen Signaling in Type 2 Innate Lymphoid Cells Drives Sex Differences in Helicobacter -Induced Gastric Inflammation and Atrophy. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.14.643321. [PMID: 40166158 PMCID: PMC11956966 DOI: 10.1101/2025.03.14.643321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Background & Aims Gastric cancer is the fifth most common cancer worldwide. Men are disproportionately affected by gastric cancer, which ranks as the fourth most common cancer in men compared to eighth in women worldwide. Chronic inflammation driven by Helicobacter pylori infection remains the leading gastric cancer risk factor. Emerging evidence suggests that sex hormones modulate immune responses, contributing to sex differences in infection outcomes and cancer susceptibility. This study investigates how androgens influence the gastric inflammatory response to Helicobacter infection and contribute to sex disparities in disease progression. Methods Male and female C57BL/6 mice were colonized with Helicobacter felis to investigate sex differences in gastric inflammation. Androgen levels were manipulated by bilateral castration in males and dihydrotestosterone (DHT) treatment in females. Single-cell RNA sequencing was used to identify androgen-responsive leukocyte populations and to establish cell communication networks between leukocyte clusters. The functional roles of these cells were further defined using ILC2- and T cell-deficient mouse models. Results Infected female mice developed significantly more severe gastric inflammation, atrophy, and metaplasia infection compared to males. Androgen depletion by castration increased gastric inflammation and accelerated preneoplastic lesion development, while these pathological features were reduced by DHT treatment. Androgen-responsive type 2 innate lymphoid cells (ILC2s) were key initiators of gastric inflammation and ILC2 depletion abolished the sex differences in H. felis pathogenesis. Conclusions This study reveals that androgens suppress Helicobacter -induced gastric inflammation by modulating ILC2 activation. We found that androgens are protective, as androgen depletion exacerbated gastric inflammation and accelerated preneoplastic lesion development. These findings provide mechanistic insight into the age-related increase in male gastric cancer incidence, coinciding with declining androgen levels. Our results suggest that circulating androgen concentrations may serve as a prognostic biomarker for gastric cancer risk in men.
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Qiao Y, Zhou Y, Zhao L, Yang S, Zhang X, Liu S. Sex differences in Helicobacter pylori infection and recurrence rate among 81,754 Chinese adults: a cross-sectional study. BMC Gastroenterol 2024; 24:305. [PMID: 39261787 PMCID: PMC11389593 DOI: 10.1186/s12876-024-03404-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 09/04/2024] [Indexed: 09/13/2024] Open
Abstract
OBJECTIVE To compare the sex differences of Helicobacter pylori (HP) infection rate and 1-year recurrence rate. METHODS A cross-sectional study was conducted on the prevalence of HP infection in 81,754 people who underwent physical examination in physical examination centers and outpatient clinics of the Affiliated Hospital of Gansu University of Traditional Chinese Medicine, the Second People's Hospital of Zhangye City, Tianshui City Hospital of Integrated Chinese and Western Medicine, the First and Second Department of The First Hospital of Lanzhou University Physical Examination Center, from March 2010 to December 2019. Among them, 53,771 (65.77%) were males (18-91 years old) and 27,983 (34.23%) were females (18-94 years old). According to age, they were divided into young group, middle-aged group and old group. 1448 asymptomatic infected patients were selected and treated with bismuth-containing quadruple drug eradication therapy for 2 weeks. The eradication rate and recurrence rate after 1 year were compared between males and females. RESULTS The overall infection rate was 49.59%, including 49.74% in males and 49.3% in females. The risk of infection in young women was lower than that in men (OR = 0.908, 95%CI: 0.868-0.95, P < 0.01), the risk of infection in older women was higher than that in men (OR = 1.137, 95%CI: 1.041-1.243, P < 0.01). The female infection rate was positively correlated with age from 18 to 60, and Spearman's correlation coefficient was 0.825 (P < 0.01). The overall eradication rate was 84.67% in intention-to-treat analysis (ITT) and 88.46% in protocol analysis (PP). The eradication rates of ITT and PP in the older group were 78.38% and 82.27%, respectively, which were lower than 87.25% and 89.39% in the male group (P < 0.05). The 1-year overall recurrence rate was 3.86%, including 2.82% in males and 5.44% in females (P < 0.05), female was a risk factor for recurrence after eradication after controlling for age (OR = 2.177, 95%CI 1.166-4.066, P < 0.05). There were no obvious adverse reactions during the treatment. CONCLUSION There is a positive linear correlation between HP infection rate and age increase in women. Older women have the characteristics of high HP infection rate, low eradication rate and high recurrence rate.
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Affiliation(s)
- Yuqin Qiao
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, China
| | - Yun Zhou
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, China
- Department of Geriatrics, First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Li Zhao
- Department of Medical Ultrasound, Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Lanzhou, 730020, China
| | - Shengyi Yang
- Intensive Care Unit, Tianshui Combine Traditional Chinese and Western Medicine Hospital, Tianshui, 741020, China
| | - Xiaodong Zhang
- Intensive Care Unit, ZhangYe Second People's Hospital, Zhangye, 734000, China
| | - Shixiong Liu
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, 730000, China.
- Department of Geriatrics, First Hospital of Lanzhou University, Lanzhou, 730000, China.
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Filip AM, Munteanu SN, Mocan S, Huțanu D, Pantea M, Negovan A. Helicobacter pylori and autoimmunity in atrophic gastritis - comparison of clinical, endoscopic and histopathological features. ACTA MARISIENSIS - SERIA MEDICA 2024; 70:149-156. [DOI: 10.2478/amma-2024-0028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Abstract
Objective
This study aims to investigate the clinical, endoscopic, biologic and histopathological differences between Helicobacter pylori-associated and autoimmune gastric atrophy.
Methods
A retrospective analysis was conducted on 95 patients diagnosed with either H. pylori-related corporal and antral atrophy (43 patients) or autoimmune corporal atrophic gastritis (52 patients).
Results
A significant male predisposition for H. pylori-associated atrophic changes in both the antrum and corpus regions (p=0.007, OR=3.24) was observed in comparison with autoimmune etiology of atrophy. While comorbidities and lifestyle factors showed similar distributions across groups, only unintentional self-reported weight loss demonstrated a significant association with H. pylori atrophy (p=0.0177, OR=3.94). Corporal erosions were strongly associated with antral and corporeal atrophic gastritis (p=0.04, OR=8.27), but the rest of mucosal lesions are comparable among groups. Interestingly, patients with H. pylori-related pangastric atrophy exhibited lower frequencies of altered triglyceride (p=0.018) and cholesterol (p=0.029) levels compared to the autoimmune group. Linear regression analysis identified low triglyceride levels as an independent predictor for H. pylori-associated antral and corporal atrophic gastritis (p=0.04) in endoscopic population with atrophy, but no hematological or clinical parameters were predictive for these changes.
Conclusions
Male patients are more likely to present with corpus atrophic gastritis associated with H. pylori infection than with an autoimmune etiology. Patients with atrophic gastritis tend to have similar clinical characteristics, except for dyslipidemia, which is more prevalent in those with H. pylori pangastritis. Corporal erosions are associated with active H. pylori infection in atrophic mucosa.
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Affiliation(s)
- Ana-Maria Filip
- Internal Medicine Department , Emergency County Hospital of Targu Mures , Targu Mures , Romania
| | - Sabrina-Nicoleta Munteanu
- Department of Clinical Science-Internal Medicine , George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures , Romania
| | - Simona Mocan
- Pathology Department , Emergency County Hospital of Targu Mures , Targu Mures , Romania
| | - Dragoș Huțanu
- Pulmonology Department , Mures County Clinical Hospital , Targu Mures , Romania
| | - Monica Pantea
- Department of Clinical Science-Internal Medicine , George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures , Romania
| | - Anca Negovan
- Department of Clinical Science-Internal Medicine , George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures , Romania
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Chen L, Xu T, Lou J, Zhang T, Wu S, Xie R, Xu J. The beneficial roles and mechanisms of estrogens in immune health and infection disease. Steroids 2024; 207:109426. [PMID: 38685461 DOI: 10.1016/j.steroids.2024.109426] [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: 10/22/2023] [Revised: 02/28/2024] [Accepted: 04/21/2024] [Indexed: 05/02/2024]
Abstract
Multiple epidemiologic studies have revealed that gender is considered one of the important factors in the frequency and severity of certain infectious diseases, in which estrogens may play a vital role. There is growing evidence that estrogens as female sex hormone can modulate multiple biological functions outside of the reproductive system, such as in brain and cardiovascular system. However, it is largely unknown about the roles and mechanisms of estrogens/estrogen receptors in immune health and infection disease. Thence, by reading a lot of literature, we summarized the regulatory mechanisms of estrogens/estrogen receptors in immune cells and their roles in certain infectious diseases with gender differences. Therefore, estrogens may have therapeutic potentials to prevent and treat these infectious diseases, which needs further clinical investigation.
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Affiliation(s)
- Lan Chen
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ting Xu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Jun Lou
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Ting Zhang
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Sheng Wu
- Department of Gastroenterology, Liupanshui People's Hospital, Liupanshui City 553000, Guizhou Province, China
| | - Rui Xie
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
| | - Jingyu Xu
- Department of Gastroenterology, Digestive Disease Hospital, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
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Song M, Jayasekara H, Pelucchi C, Rabkin CS, Johnson KC, Hu J, Palli D, Ferraroni M, Liao LM, Bonzi R, Zaridze D, Maximovitch D, Aragonés N, Martin V, Castaño-Vinyals G, Guevara M, Tsugane S, Hamada GS, Hidaka A, Negri E, Ward MH, Sinha R, Lagiou A, Lagiou P, Boffetta P, Curado MP, Lunet N, Vioque J, Zhang ZF, La Vecchia C, Camargo MC. Reproductive factors, hormonal interventions, and gastric cancer risk in the Stomach cancer Pooling (StoP) Project. Cancer Causes Control 2024; 35:727-737. [PMID: 38123742 DOI: 10.1007/s10552-023-01829-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 11/10/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND Gastric cancer incidence is higher in men, and a protective hormone-related effect in women is postulated. We aimed to investigate and quantify the relationship in the Stomach cancer Pooling (StoP) Project consortium. METHODS A total of 2,084 cases and 7,102 controls from 11 studies in seven countries were included. Summary odds ratios (ORs) and 95% confidence intervals (CIs) assessing associations of key reproductive factors and menopausal hormone therapy (MHT) with gastric cancer were estimated by pooling study-specific ORs using random-effects meta-analysis. RESULTS A duration of fertility of ≥ 40 years (vs. < 20), was associated with a 25% lower risk of gastric cancer (OR = 0.75; 95% CI: 0.58-0.96). Compared with never use, ever, 5-9 years and ≥ 10 years use of MHT in postmenopausal women, showed ORs of 0.73 (95% CI: 0.58-0.92), 0.53 (95% CI: 0.34-0.84) and 0.71 (95% CI: 0.50-1.00), respectively. The associations were generally similar for anatomical and histologic subtypes. CONCLUSION Our results support the hypothesis that reproductive factors and MHT use may lower the risk of gastric cancer in women, regardless of anatomical or histologic subtypes. Given the variation in hormones over the lifespan, studies should address their effects in premenopausal and postmenopausal women. Furthermore, mechanistic studies may inform potential biological processes.
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Affiliation(s)
- Minkyo Song
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Harindra Jayasekara
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia
- School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Claudio Pelucchi
- Branch of Medical Statistics, Biometry, and Epidemiology "G. A. Maccacaro", Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Kenneth C Johnson
- School of Epidemiology and Public Health, Department of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Jinfu Hu
- Harbin Medical University, Harbin, China
| | - Domenico Palli
- Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network, ISPRO, Florence, Italy
| | - Monica Ferraroni
- Branch of Medical Statistics, Biometry, and Epidemiology "G. A. Maccacaro", Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Linda M Liao
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Rossella Bonzi
- Branch of Medical Statistics, Biometry, and Epidemiology "G. A. Maccacaro", Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - David Zaridze
- Department of Clinical Epidemiology, N.N. Blokhin National Medical Research Center for Oncology, Moscow, Russia
| | - Dmitry Maximovitch
- Department of Clinical Epidemiology, N.N. Blokhin National Medical Research Center for Oncology, Moscow, Russia
| | - Nuria Aragonés
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Cancer Registration and Surveillance Unit, Public Health Division, Department of Health of Madrid, Madrid, Spain
| | - Vicente Martin
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Instituto de Biomedicina (IBIOMED), Universidad de León, León, Spain
| | - Gemma Castaño-Vinyals
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Barcelona Institute for Global Health-ISGlobal, Barcelona, Spain
- IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Marcela Guevara
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Instituto de Salud Pública y Laboral de Navarra, 31003, Pamplona, Spain
- Navarra Institute for Health Research (IdiSNA), 31008, Pamplona, Spain
| | - Shoichiro Tsugane
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
- National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan
| | | | - Akihisa Hidaka
- Epidemiology and Prevention Group, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan
| | - Eva Negri
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Mary H Ward
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Rashmi Sinha
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA
| | - Areti Lagiou
- Department of Public and Community Health, School of Public Health, University of West Attica, Athens, Greece
| | - Pagona Lagiou
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Paolo Boffetta
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
- Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY, USA
| | - Maria Paula Curado
- Centro Internacional de Pesquisa, A. C. Camargo Cancer Center, São Paulo, Brazil
| | - Nuno Lunet
- EPIUnit - Instituto de Saúde Pública da Universidade do Porto, Porto, Portugal
- Laboratório Para a Investigação Integrativa e Translacional em Saúde Populacional (ITR), Porto, Portugal
- Departamento de Ciências da Saúde Pública e Forenses e Educação Médica, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
| | - Jesus Vioque
- Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain
- Instituto de Investigación Sanitaria y Biomédica de Alicante, Universidad Miguel Hernandez (ISABIAL-UMH), Alicante, Spain
| | - Zuo-Feng Zhang
- Department of Epidemiology, UCLA Fielding School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
| | - Carlo La Vecchia
- Branch of Medical Statistics, Biometry, and Epidemiology "G. A. Maccacaro", Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
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Xu X, Qian Y, Jin K, Chen J, Fu J, Chen C, Zhu Z. The impact of Helicobacter pylori infection on low skeletal muscle mass risk in Chinese women over 40: a cross-sectional analysis. Front Cell Infect Microbiol 2024; 13:1289909. [PMID: 38235492 PMCID: PMC10791812 DOI: 10.3389/fcimb.2023.1289909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 12/08/2023] [Indexed: 01/19/2024] Open
Abstract
Background Sarcopenia can lead to significant personal, social, and economic burdens. The diagnosis of sarcopenia heavily relies on the identification of Low Skeletal Muscle Mass (LSMM), which is an independent predictor of frailty, disability, and increased risk of death among seniors. Women have physiologically lower levels of skeletal muscle mass than men, and female sarcopenia appears to be more influenced by menopause. They also tend to have higher body fat levels than man, which increases the risk of sarcopenia obesity. On another front, it's also recognized that humans are largely prone to Helicobacter pylori (H. pylori) infection, with global prevalence rates often surpassing 50%. Nevertheless, the interconnection between H. pylori infection and LSMM remains relatively unexplored. Hence, our study specifically targeted women as the research population and sought to explore several risk factors for LSMM. Additionally, we delved into the potential correlation between LSMM and H. pylori infection in women, hoping to gain insights into potential preventative measures or treatment options that may enhance the quality of life for women affected by sarcopenia. Methods We conducted a cross-sectional study among women aged over 18 years undergoing physical examination. We performed 13C-urea breath test (UBT) for diagnosis of H. pylori infection and Bioelectrical impedance analysis (BIA) for the assessment of LSMM. Logistic regression models were used to analyze the associations of H. pylori infection with LSMM. Results This study enrolled 1984 Chinese women who were undergoing health check-ups. A univariate logistic regression analysis did not reveal a direct correlation between H. pylori infection and LSMM among this female population (OR=1.149, 95% CI 0.904-1.459, p=0.257). Yet, upon dividing the participants into age-based subgroups, an evident link was observed between H. pylori infection and LSMM in women aged 40 or above (OR=1.381, 95%CI 1.032-1.848, p= 0.030). After adjusting for variables including Age, BMI, TP, ALK, Cre, this relationship remained statistically relevant (OR=1.514, 95%CI 1.085-2.113, p= 0.015). Conclusions Women who are over 40 years old and currently infected with H. pylori have an increased risk of developing LSMM. Therefore, timely treatment for H. pylori eradication is recommended for this group of women to reduce the occurrence of LSMM.
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Affiliation(s)
- Xiaohui Xu
- Department of Medical Care Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yidan Qian
- Department of Medical Care Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kejia Jin
- Department of Medical Care Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Junpeng Chen
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Jiayue Fu
- The First School of Medicine, School of Information and Engineering, Wenzhou Medical University, Wenzhou, China
| | - Chengshui Chen
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Pulmonary and Critical Care Medicine, Quzhou People’s Hospital, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou, China
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zaisheng Zhu
- Department of Medical Care Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Key Laboratory of Interventional Pulmonology of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
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The Pathological Activation of Microglia Is Modulated by Sexually Dimorphic Pathways. Int J Mol Sci 2023; 24:ijms24054739. [PMID: 36902168 PMCID: PMC10003784 DOI: 10.3390/ijms24054739] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/11/2023] [Accepted: 02/22/2023] [Indexed: 03/05/2023] Open
Abstract
Microglia are the primary immunocompetent cells of the central nervous system (CNS). Their ability to survey, assess and respond to perturbations in their local environment is critical in their role of maintaining CNS homeostasis in health and disease. Microglia also have the capability of functioning in a heterogeneous manner depending on the nature of their local cues, as they can become activated on a spectrum from pro-inflammatory neurotoxic responses to anti-inflammatory protective responses. This review seeks to define the developmental and environmental cues that support microglial polarization towards these phenotypes, as well as discuss sexually dimorphic factors that can influence this process. Further, we describe a variety of CNS disorders including autoimmune disease, infection, and cancer that demonstrate disparities in disease severity or diagnosis rates between males and females, and posit that microglial sexual dimorphism underlies these differences. Understanding the mechanism behind differential CNS disease outcomes between men and women is crucial in the development of more effective targeted therapies.
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Yu Z, Sheng WD, Yin X, Bin Y. Coptis, Pinellia, and Scutellaria as a promising new drug combination for treatment of Helicobacter pylori infection. World J Clin Cases 2022; 10:12500-12514. [PMID: 36579091 PMCID: PMC9791531 DOI: 10.12998/wjcc.v10.i34.12500] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 10/09/2022] [Accepted: 11/07/2022] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori) is the most important infectious agent and plays an important role in the progression of chronic gastritis and the development of gastric cancer.
AIM To identify efficient therapeutic agents or strategies that can treat H. pylori infection.
METHODS We performed literature analysis, experimental validation, and network pharmacology. First, traditional Chinese medicine (TCM) prescriptions for the treatment of H. pylori infection were obtained from the China National Knowledge Infrastructure, China Biology Medicine, China Science and Technology Journal Database, and WanFang databases. In addition, we conducted a relevant search by Reference Citation Analysis (RCA) (https://www.referencecitationanalysis.com). Next, we used TCM Inheritance Support System V2.5 to identify core drug combinations in the TCM prescriptions. Then, an H. pylori-associated chronic mouse model of gastritis was established. The antibacterial properties and anti-inflammatory potential of the core drug combination were evaluated by the rapid urease test, modified Warthin-Starry silver staining, histopathological analysis, and enzyme linked immunosorbent assay. Finally, the active compounds, hub targets, and potential signaling pathways associated with the core drug combination were analyzed by network pharmacology.
RESULTS The TCM treatment of H. pylori was mainly based on reinforcing the healthy Qi and eliminating pathogenic factors by simultaneously applying pungent dispersing, bitter descending, cold and warm drugs. The combination of Coptis, Pinellia, and Scutellaria (CPS) was identified as the core drug combination from 207 prescriptions and 168 herbs. This drug combination eradicated H. pylori, alleviated the gastric pathology induced by H. pylori infection, and reduced the expression levels of tumor necrosis factor-α (P = 0.024) and interleukin-1β (P = 0.001). Moreover, a total of 35 compounds and 2807 targets of CPS were identified using online databases. Nine key compounds (tenaxin I, neobaicalein, norwogonin, skullcapflavone II, baicalein, 5,8,2'-trihydroxy-7-methoxyflavone, acacetin, panicolin, and wogonin) and nine hub target proteins (EGFR, PTGS2, STAT3, MAPK3, MAPK8, HSP90AA1, MAPK1, MMP9, and MTOR) were further explored. Seventy-seven signaling pathways were correlated with H. pylori-induced inflammation and carcinogenesis.
CONCLUSION In summary, we showed that CPS is the core drug combination for treating H. pylori infection. Animal experiments demonstrated that CPS has bacteriostatic properties and can reduce the release of inflammatory cytokines in the gastric mucosa. Network pharmacology predictions further revealed that CPS showed complex chemical compositions with multi-target and multi-pathway regulatory mechanisms. Although the results derived from network pharmacology are not necessarily comprehensive, they still expand our understanding of CPS for treating H. pylori infection.
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Affiliation(s)
- Zhang Yu
- Department of Internal Medicine, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
| | - Wu-Dong Sheng
- Department of Surgery, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
| | - Xu Yin
- Department of Internal Medicine, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
| | - Yu Bin
- Department of Internal Medicine, The First Hospital of Hunan University of Chinese Medicine, Changsha 410007, Hunan Province, China
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Abstract
There is a growing awareness of the importance of sex and gender in medicine and research. Women typically have stronger immune responses to self and foreign antigens than men, resulting in sex-based differences in autoimmunity and infectious diseases. In both animals and humans, males are generally more susceptible than females to bacterial infections. At the same time, gender differences in health-seeking behavior, quality of health care, and adherence to treatment recommendations have been reported. This review explores our current understanding of differences between males and females in bacterial diseases. We describe how genetic, immunological, hormonal, and anatomical factors interact to influence sex-based differences in pathophysiology, epidemiology, clinical presentation, disease severity, and prognosis, and how gender roles affect the behavior of patients and providers in the health care system.
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Kim WS, Choi Y, Kim N, Lim SH, Noh G, Kim KW, Park J, Jo H, Yoon H, Shin CM, Park YS, Lee DH. Long-term effect of the eradication of Helicobacter pylori on the hemoglobin A1c in type 2 diabetes or prediabetes patients. Korean J Intern Med 2022; 37:579-590. [PMID: 34991230 PMCID: PMC9082431 DOI: 10.3904/kjim.2021.194] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Accepted: 10/25/2021] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND/AIMS The long-term effect of Helicobacter pylori eradication on the metabolic syndrome or diabetes are unclear. The aim of this study was to evaluate the effect of H. pylori eradication on glycemic control in type 2 diabetes mellitus (T2DM) or prediabetes mellitus (preDM). METHODS A total of 124 asymptomatic subjects with T2DM or preDM were divided into H. pylori-negative (n = 40), H. pylori-positive with non-eradicated (n = 34), and eradicated (n = 50) groups. We measured H. pylori status (culture, histology, and rapid urease test) and glycated hemoglobin A1c (A1C) levels and followed-up at the 1st year and the 5th year of follow-up. RESULTS The A1C levels significantly decreased in the eradicated group compared to the negative group and the non-eradicated groups (at the 1st year, p = 0.024; at the 5th year, p = 0.009). The A1C levels decreased in male, and/or subjects < 65 years of age in subgroup analyses (in male subjects, p = 0.047 and p = 0.020 at the 1st and the 5th year; in subjects < 65 years of age, p = 0.028 and p = 0.006 at the 1st and the 5th year; in male subjects < 65 years of age, p = 0.039 and p = 0.032 at the 1st and the 5th year). The eradication of H. pylori was related to the decrease in A1C values throughout the follow-up period, compared to the non-eradicated group (p = 0.017). CONCLUSION H. pylori eradication was related to the decreasing of A1C levels in patients with T2DM or preDM over a long-term follow-up period, especially in male and subjects < 65 years of age.
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Affiliation(s)
- Won Seok Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Yonghoon Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Seon Hee Lim
- Department of Internal Medicine, Seoul National University Hospital Healthcare System Gangnam Center and Healthcare Research Institute, Seoul, Korea
| | - Gitark Noh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Ki Wook Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Jaehyung Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyeongho Jo
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Cheol Min Shin
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Soo Park
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Dong Ho Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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11
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Gastric Non-Helicobacter pylori Urease-Positive Staphylococcus epidermidis and Streptococcus salivarius Isolated from Humans Have Contrasting Effects on H. pylori-Associated Gastric Pathology and Host Immune Responses in a Murine Model of Gastric Cancer. mSphere 2022; 7:e0077221. [PMID: 35138124 PMCID: PMC8826947 DOI: 10.1128/msphere.00772-21] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
In populations with similar prevalence of Helicobacter pylori infection, cancer risk can vary dramatically. Changes in composition or structure of bacterial communities in the stomach, either at the time of exposure or over the course of H. pylori infection, may contribute to gastric pathology. In this study, a population of 37 patients from the low-gastric-cancer-risk (LGCR) region of Tumaco, Colombia, and the high-gastric-cancer-risk (HGCR) region of Túquerres, Colombia, were recruited for gastric endoscopy. Antral biopsy specimens were processed for histology and bacterial isolation. Fifty-nine distinct species among 26 genera were isolated by aerobic, anaerobic, and microaerobic culture and confirmed by 16S rRNA analysis. Urease-positive Staphylococcus epidermidis and Streptococcus salivarius were frequently isolated from gastric biopsy specimens. We asked whether coinfection of H. pylori with urease-positive S. salivarius and/or S. epidermidis had a demonstrable effect on H. pylori-induced gastritis in the germfree (GF) INS-GAS mouse model. Coinfections with S. salivarius and/or S. epidermidis did not affect gastric H. pylori colonization. At 5 months postinfection, GF INS-GAS mice coinfected with H. pylori and S. salivarius had statistically higher pathological scores in the stomachs than mice infected with H. pylori only or H. pylori with S. epidermidis (P < 0.05). S. epidermidis coinfection with H. pylori did not significantly change stomach pathology, but levels of the proinflammatory cytokine genes Il-1β, Il-17A , and Il-22 were significantly lower than in H. pylori-monoinfected mice. This study demonstrates that non-H. pylori urease-positive bacteria may play a role in the severity of H. pylori-induced gastric cancer in humans. IMPORTANCE Chronic infection with H. pylori is the main cause of gastric cancer, which is a global health problem. In two Colombian populations with high levels of H. pylori prevalence, the regional gastric cancer rates are considerably different. Host genetic background, H. pylori biotype, environmental toxins, and dietary choices are among the known risk factors for stomach cancer. The potential role of non-H. pylori gastric microbiota in gastric carcinogenesis is being increasingly recognized. In this study, we isolated 59 bacterial species from 37 stomach biopsy samples of Colombian patients from both low-gastric-cancer-risk and high-gastric-cancer-risk regions. Urease-positive S. epidermidis and S. salivarius commonly cultured from the stomachs, along with H. pylori, were inoculated into germfree INS-GAS mice. S. salivarius coinfection with H. pylori induced significantly higher gastric pathology than in H. pylori-monoinfected mice, whereas S. epidermidis coinfection caused significantly lower H. pylori-induced proinflammatory cytokine responses than in H. pylori-monoinfected mice. This study reinforces the argument that the non-H. pylori stomach microflora play a role in the severity of H. pylori-induced gastric cancer.
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12
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Wu SE, Chen WL. Detrimental relevance of Helicobacter pylori infection with sarcopenia. Gut Pathog 2021; 13:67. [PMID: 34782007 PMCID: PMC8591825 DOI: 10.1186/s13099-021-00464-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 11/09/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Helicobacter pylori (H. pylori), Gram negative microaerophilic bacteria, is a well-known pathogen of many gastrointestinal diseases. But several emerging evidences suggest it role in numerous other extra-gastric diseases. The current study investigates the relationship between H. pylori infection and sarcopenia, a clinical condition characterized by the loss of mass and function of skeletal muscle. A total of 3453 eligible participants from the Third National Health and Nutrition Examination Survey (NHANES III), the United States, were enrolled. Based on the serum laboratory results, subjects were categorized into three groups: normal (without evidence of any H. pylori infection), anti-H. pylori IgG positive [H. pylori (+)], and concurrent anti-H. pylori IgG and anti-cytotoxin-associated gene A IgG positive [CagA (+)]. Sarcopenia was determined as having a skeletal muscle index (SMI) value that is more than 1 standard deviation away from the mean value of sex-specific, healthy young adults between 20 and 39 years old. Risk of sarcopenia and its components are compared between subgroups. RESULTS Odds ratios (OR) for confirmed diagnosis of sarcopenia were higher in H. pylori (+) (OR = 2.052, 95% CI 1.697-2.481, p < 0.001) and CagA (+) (OR = 1.585, 95% CI 1.278-1.965, p < 0.001) groups. Moreover, negative beta regression coefficient of SMI were shown in H. pylori (+) (β: - 0.023, p < 0.001) and CagA (+) (β: - 0.017, p < 0.001). Sub-analyses which categorized participants by gender revealed that absolute value of beta regression coefficient for SMI were higher in female in H. pylori (+) subgroup (β: - 1.745 in male and - 2.942 in female, p were both < 0.001), and the CagA (+) subgroup (β: - 1.407 in male and - 2.159 in female, p were both < 0.001). CONCLUSIONS Positive serum H. pylori infectious markers including anti-H. pylori antibody and CagA seropositivity are correlated with sarcopenia and low muscle quantity. Therefore, H. pylori eradication therapy may bring benefits to sarcopenia patients with concurrent active H. pylori infection.
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Affiliation(s)
- Shou-En Wu
- Department of Dermatology, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China
- Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Number 325, Section 2, Chang-gong Rd, Nei-Hu District, Taipei, 114, Taiwan, Republic of China
| | - Wei-Liang Chen
- Division of Family Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Taipei, Taiwan, Republic of China.
- Division of Geriatric Medicine, Department of Family and Community Medicine, Tri-Service General Hospital; and School of Medicine, National Defense Medical Center, Number 325, Section 2, Chang-gong Rd, Nei-Hu District, Taipei, 114, Taiwan, Republic of China.
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, Republic of China.
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13
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Watts EL, Perez-Cornago A, Knuppel A, Tsilidis KK, Key TJ, Travis RC. Prospective analyses of testosterone and sex hormone-binding globulin with the risk of 19 types of cancer in men and postmenopausal women in UK Biobank. Int J Cancer 2021; 149:573-584. [PMID: 33720423 DOI: 10.1002/ijc.33555] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 12/16/2022]
Abstract
We investigated the associations of estimated free and total circulating testosterone and sex hormone-binding globulin (SHBG) with cancer risk in men and postmenopausal women, using a pan-cancer approach, including 19 cancers in UK Biobank. Risk was estimated using multivariable-adjusted Cox regression in up to 182 608 men and 122 112 postmenopausal women who were cancer-free at baseline. Participants diagnosed with cancer within 2 years of baseline were excluded. Hazard ratios (HRs) and confidence intervals (CIs) were corrected for regression dilution bias using repeat measurements. We accounted for multiple testing using the false discovery rate. In men, higher free testosterone was associated with higher risks of melanoma and prostate cancer (HR per 50 pmol/L increase = 1.35, 95% CI 1.14-1.61 and 1.10, 1.04-1.18, respectively). Higher total testosterone was associated with an elevated risk of liver cancer (HR per 5 nmol/L = 2.45, 1.56-3.84), and higher SHBG was associated with a higher risk of liver cancer (HR per 10 nmol/L = 1.56, 1.31-1.87) and a lower risk of prostate cancer (0.93, 0.91-0.96); the associations with liver cancer were partially attenuated after excluding men diagnosed within 4.7 years from baseline. In postmenopausal women, free and total testosterone and SHBG were associated with risks of endometrial (HR per 10 pmol/L = 1.59, 1.32-1.90; HR per 0.5 nmol/L = 1.34, 1.18-1.52 and HR per 25 nmol/L = 0.78, 0.67-0.91, respectively) and breast cancer (1.32, 1.22-1.43; 1.24, 1.17-1.31 and 0.88, 0.83-0.94, respectively). We report a novel association of free testosterone with malignant melanoma in men, and confirm known associations between testosterone and risks for prostate, breast and endometrial cancers. The association with liver cancer in men may be attributable to reverse causation.
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Affiliation(s)
- Eleanor L Watts
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Aurora Perez-Cornago
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Anika Knuppel
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Timothy J Key
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Ruth C Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
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14
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Gay L, Melenotte C, Lakbar I, Mezouar S, Devaux C, Raoult D, Bendiane MK, Leone M, Mège JL. Sexual Dimorphism and Gender in Infectious Diseases. Front Immunol 2021; 12:698121. [PMID: 34367158 PMCID: PMC8339590 DOI: 10.3389/fimmu.2021.698121] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 07/08/2021] [Indexed: 12/19/2022] Open
Abstract
Epidemiological studies and clinical observations show evidence of sexual dimorphism in infectious diseases. Women are at less risk than men when it comes to developing most infectious diseases. However, understanding these observations requires a gender approach that takes into account an analysis of both biological and social factors. The host’s response to infection differs in males and females because sex differences have an impact on hormonal and chromosomal control of immunity. Estradiol appears to confer protective immunity, while progesterone and testosterone suppress anti-infectious responses. In addition, genetic factors, including those associated with sex chromosomes, also affect susceptibility to infections. Finally, differences in occupational activities, lifestyle, and comorbidities play major roles in exposure to pathogens and management of diseases. Hence, considering sexual dimorphism as a critical variable for infectious diseases should be one of the steps taken toward developing personalized therapeutic approaches.
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Affiliation(s)
- Laetitia Gay
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - Cléa Melenotte
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.,Aix-Marseille Univ, INSERM, IRD, SESSTIM, Economy and Social Science, Health Care Systems and Societies, Marseille, France
| | - Ines Lakbar
- Department of Anaesthesia and Intensive Care, Hôpital Nord, Aix-Marseille Univ, APHM, Marseille, France
| | - Soraya Mezouar
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - Christian Devaux
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - Didier Raoult
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
| | - Marc-Karim Bendiane
- Aix-Marseille Univ, INSERM, IRD, SESSTIM, Economy and Social Science, Health Care Systems and Societies, Marseille, France
| | - Marc Leone
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France.,Department of Anaesthesia and Intensive Care, Hôpital Nord, Aix-Marseille Univ, APHM, Marseille, France
| | - Jean-Louis Mège
- Aix-Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France
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15
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Fong P, Wang QT. Protective effect of oral contraceptive against Helicobacter pylori infection in US adult females: NHANES 1999-2000. Epidemiol Infect 2021; 149:e120. [PMID: 33896437 PMCID: PMC8161376 DOI: 10.1017/s0950268821000923] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Revised: 03/29/2021] [Accepted: 04/14/2021] [Indexed: 12/22/2022] Open
Abstract
Recently, the antibacterial properties of oestrogen and progestogen were discovered. The aim of this study was to find the cross-sectional association between oral contraceptive use and Helicobacter pylori seroprevalence. Data were obtained from the US National Health and Nutrition Examination Survey (NHANES). The H. pylori immunoglobulin G (IgG) enzyme-linked immunosorbent assays were used to categorise participants as seropositive or seronegative. The study population included 799 female participants who had information on H. pylori seroprevalence and all other covariates and had not been taking any medications (except oral contraceptives). The bivariate Rao-Scott chi-square test indicated a significant association between H. pylori seroprevalence and contraceptive use (P < 0.01). The variables of race, education, poverty income ratio, smoking, and blood lead and cadmium levels were also significantly associated with H. pylori seroprevalence (P < 0.01). Multiple logistic regression analysis of the age-adjusted model revealed that contraceptive users are 65% less likely of being H. pylori seropositive as compared to non-contraceptive users (odds ratio (OR): 0.35, 95% confidence interval (CI): 0.18-0.68). This association is stronger with the final multivariate model (OR: 0.46, 95% CI: 0.23-0.89). Conclusions: This finding reveals the potential protective effect of oral contraceptives against H. pylori infection and serves as a foundation study for further investigations.
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Affiliation(s)
- P. Fong
- School of Health Sciences and Sports, Macao Polytechnic Institute, Macao, China
| | - Q. T. Wang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu610041, China
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16
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Leal YA, Song M, Zabaleta J, Medina-Escobedo G, Caron P, Lopez-Colombo A, Guillemette C, Camargo MC. Circulating Levels of Sex Steroid Hormones and Gastric Cancer. Arch Med Res 2021; 52:660-664. [PMID: 33781580 DOI: 10.1016/j.arcmed.2021.03.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 02/22/2021] [Accepted: 03/04/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Men develop gastric cancer more frequently than women, yet little is known about the mechanisms underlying this sex difference. Sex steroid hormones may influence gastric cancer risk. We therefore assessed whether major circulating adrenal precursors, androgens and estrogens were associated with gastric cancer in a high-risk Mexican population. METHODS Blood samples were collected at time of diagnosis from 50 noncardia gastric cancer patients and 50 histologically confirmed non-atrophic gastritis controls. Serum levels of estradiol, testosterone and dehydroepiandrosterone (DHEA) measured with a validated mass spectrometry method were categorized in tertiles as low (T1), middle (T2), and high (T3). Unconditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age, sex, and education. RESULTS Levels of DHEA were inversely associated with gastric cancer (p-trend per tertile increase: <0.0001), with adjusted ORs (95% CI) of T2 and T3 (vs. T1) of 0.25 (0.09-0.70) and 0.10 (0.03-0.34), respectively. Levels of estradiol and testosterone were not significantly associated with gastric cancer. CONCLUSIONS Our study provides evidence that higher concentration of circulating DHEA may be associated with lower risk of noncardia gastric cancer. Longitudinal studies are needed to evaluate the temporality of this association and investigate mechanisms of disease pathogenesis.
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Affiliation(s)
- Yelda A Leal
- Centro Institucional de Capacitación y Registro de Cáncer, Unidad Médica de Alta Especialidad, Centro Médico Nacional Ignacio García Téllez, Instituto Mexicano de Seguro Social, Mérida, Yucatán, México.
| | - Minkyo Song
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
| | - Jovanny Zabaleta
- Department of Pediatrics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA
| | - Gilberto Medina-Escobedo
- Departamento de Patología, Unidad Médica de Alta Especialidad, Centro Médico Nacional Ignacio García Téllez, Instituto Mexicano de Seguro Social, Mérida, Yucatán, México
| | - Patrick Caron
- Pharmacogenomics Laboratory, Centre Hospitalier de l'Universite Laval de Quebec, Research Center and Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada
| | - Aurelio Lopez-Colombo
- Unidad Médica de Alta Especialidad, Centro Médico Nacional Manuel Ávila Camacho, Instituto Mexicano de Seguro Social, Puebla, Puebla, México
| | - Chantal Guillemette
- Pharmacogenomics Laboratory, Centre Hospitalier de l'Universite Laval de Quebec, Research Center and Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada
| | - M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
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17
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Wang P, Wang Y, Langley SA, Zhou YX, Jen KY, Sun Q, Brislawn C, Rojas CM, Wahl KL, Wang T, Fan X, Jansson JK, Celniker SE, Zou X, Threadgill DW, Snijders AM, Mao JH. Diverse tumour susceptibility in Collaborative Cross mice: identification of a new mouse model for human gastric tumourigenesis. Gut 2019; 68:1942-1952. [PMID: 30842212 PMCID: PMC6839736 DOI: 10.1136/gutjnl-2018-316691] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Revised: 02/11/2019] [Accepted: 02/12/2019] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The Collaborative Cross (CC) is a mouse population model with diverse and reproducible genetic backgrounds used to identify novel disease models and genes that contribute to human disease. Since spontaneous tumour susceptibility in CC mice remains unexplored, we assessed tumour incidence and spectrum. DESIGN We monitored 293 mice from 18 CC strains for tumour development. Genetic association analysis and RNA sequencing were used to identify susceptibility loci and candidate genes. We analysed genomes of patients with gastric cancer to evaluate the relevance of genes identified in the CC mouse model and measured the expression levels of ISG15 by immunohistochemical staining using a gastric adenocarcinoma tissue microarray. Association of gene expression with overall survival (OS) was assessed by Kaplan-Meier analysis. RESULTS CC mice displayed a wide range in the incidence and types of spontaneous tumours. More than 40% of CC036 mice developed gastric tumours within 1 year. Genetic association analysis identified Nfκb1 as a candidate susceptibility gene, while RNA sequencing analysis of non-tumour gastric tissues from CC036 mice showed significantly higher expression of inflammatory response genes. In human gastric cancers, the majority of human orthologues of the 166 mouse genes were preferentially altered by amplification or deletion and were significantly associated with OS. Higher expression of the CC036 inflammatory response gene signature is associated with poor OS. Finally, ISG15 protein is elevated in gastric adenocarcinomas and correlated with shortened patient OS. CONCLUSIONS CC strains exhibit tremendous variation in tumour susceptibility, and we present CC036 as a spontaneous laboratory mouse model for studying human gastric tumourigenesis.
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Affiliation(s)
- Pin Wang
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China,Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA
| | - Yunshan Wang
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA,Clinical Laboratory, Second Hospital of Shandong University, Jinan, China
| | - Sasha A Langley
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA
| | - Yan-Xia Zhou
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA,College of Marine Science, Shandong University, Weihai, China
| | - Kuang-Yu Jen
- Department of Pathology, University of California Davis Medical Center, Sacramento, California, USA
| | - Qi Sun
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Colin Brislawn
- Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USA
| | - Carolina M Rojas
- Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, USA,Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas, USA
| | - Kimberly L Wahl
- Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, USA,Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas, USA
| | - Ting Wang
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Xiangshan Fan
- Department of Pathology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Janet K Jansson
- Earth and Biological Sciences Directorate, Pacific Northwest National Laboratory, Richland, Washington, USA
| | - Susan E Celniker
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA
| | - Xiaoping Zou
- Department of Gastroenterology, Nanjing Drum Tower Hospital, Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - David W Threadgill
- Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, USA,Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas, USA
| | - Antoine M Snijders
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA
| | - Jian-Hua Mao
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA
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18
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Dantsuka A, Ichii O, Hanberg A, Elewa YHA, Otsuka-Kanazawa S, Nakamura T, Kon Y. Histopathological features of the proper gastric glands in FVB/N-background mice carrying constitutively-active aryl-hydrocarbon receptor. BMC Gastroenterol 2019; 19:102. [PMID: 31226941 PMCID: PMC6588904 DOI: 10.1186/s12876-019-1009-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Accepted: 06/04/2019] [Indexed: 01/02/2023] Open
Abstract
Background Aryl-hydrocarbon receptor (AhR) is a multiple ligand-activated transcription factor that has important roles in xenobiotic, physiological, or pathological functions. Transgenic mice systemically expressing constitutively-active AhR (CA-AhR) have been created to mimic activated AhR signaling in vivo. However, their detailed histopathological features are unclear. In the present study, we generated CA-AhR-expressing FVB/N mice (FVB-CA-AhR mice) and clarified their phenotypes in detail. Methods Male and female FVB-CA-AhR and wild-type mice were histopathologically examined from 6 to 33 weeks of age. Results Among the systemic organs, only the stomachs in FVB-CA-AhR mice showed pathological changes including cystic structures beneath the serosa; in addition, stomach weights increased with age. Histopathologically, cystic structures and alcian blue-positive metaplasia were observed in the mucosa of the proper gastric glands, and these two histometric parameters were positively correlated. Furthermore, proliferating cells shifted from the isthmus to the base of the glands, and parietal cells decreased. Age-related histopathological changes were clearer in females than in males. Importantly, in FVB-CA-AhR mice, intramucosal cysts developed as extramucosal cysts beneath the serosa, penetrating the lamina muscularis mucosae and the muscularis propria. Their incidence reached 100% in 28-week-old male mice and 33-week-old female mice. Extramucosal cysts contained alcian blue-, Griffonia simplicifolia lectin II-, or trefoil factor 2-positive cells, suggesting a stomach origin for the cysts and spasmolytic polypeptide-expressing metaplasia-like lesions. Conclusions Disease onset occurred earlier in FVB-CA-AhR mice than previously reported in C57BL/6-derived CA-AhR mice. Importantly, the histopathological features were partly similar with gastritis cystica profunda in humans and animals. Excessive activation of AhR signaling aggravated abnormalities in the gastric mucosa and were affected by both genetic- and sex-related factors. Electronic supplementary material The online version of this article (10.1186/s12876-019-1009-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ai Dantsuka
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan, Kita 18, Nishi 9, Kita-ku, Sapporo, 060-0818, Japan
| | - Osamu Ichii
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan, Kita 18, Nishi 9, Kita-ku, Sapporo, 060-0818, Japan
| | - Annika Hanberg
- Institute of Environmental Medicine, Karolinska Institutet, SE-171 77, Stockholm, Sweden
| | - Yaser Hosny Ali Elewa
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan, Kita 18, Nishi 9, Kita-ku, Sapporo, 060-0818, Japan.,Department of Histology and Cytology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44519, Egypt
| | - Saori Otsuka-Kanazawa
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan, Kita 18, Nishi 9, Kita-ku, Sapporo, 060-0818, Japan
| | - Teppei Nakamura
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan, Kita 18, Nishi 9, Kita-ku, Sapporo, 060-0818, Japan.,Section of Biological Safety Research, Chitose Laboratory, Japan Food Research Laboratories, Bunkyo 2-3, Chitose, 066-0052, Japan
| | - Yasuhiro Kon
- Laboratory of Anatomy, Department of Basic Veterinary Sciences, Faculty of Veterinary Medicine, Hokkaido University, Sapporo, Japan, Kita 18, Nishi 9, Kita-ku, Sapporo, 060-0818, Japan.
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Miftahussurur M, Waskito LA, Syam AF, Nusi IA, Wibawa IDN, Rezkitha YAA, Siregar G, Yulizal OK, Akil F, Uwan WB, Simanjuntak D, Waleleng JB, Saudale AMJ, Yusuf F, Maulahela H, Richardo M, Rahman A, Namara YS, Sudarmo E, Adi P, Maimunah U, Setiawan PB, Fauzia KA, Doohan D, Uchida T, Lusida MI, Yamaoka Y. Analysis of risks of gastric cancer by gastric mucosa among Indonesian ethnic groups. PLoS One 2019; 14:e0216670. [PMID: 31071187 PMCID: PMC6508733 DOI: 10.1371/journal.pone.0216670] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 04/25/2019] [Indexed: 12/16/2022] Open
Abstract
Indonesia is a big country with multiethnic populations whose gastric cancer risks have not been elucidated. We performed a nationwide survey and obtained histological specimens from 1053 individuals in 19 cities across the country. We examined the gastric mucosa, the topography, the atrophic gastritis risk factors, and the gastric cancer risk scores. Almost half (46.1%) of the patients with dyspeptic symptoms had histological abnormalities; chronic (36.3%) and atrophic gastritis (28.9%) being the most frequent. Individuals of the Timor ethnicity had the highest prevalence of acute (52.6%) and chronic gastritis (68.4%), even those negative for H. pylori. Our topographic analysis showed the majority of patients had predominantly antral acute and chronic gastritis. A multivariate logistic regression model showed age (Odds ratio [OR], 1.107), Timor ethnicity (OR, 8.531), and H. pylori infection (OR, 22.643) as independent risk factors for presence of atrophic gastritis. In addition, the gastric cancer risk score was highest in those from Timor, Papuan, and Bugis ethnic populations. Overall, Indonesia is a low-risk gastric cancer country. However, several ethnic groups displayed severe gastric mucosa symptoms suggesting policy makers should focus on those ethnic groups to perform gastric cancer screenings and to eradicate H. pylori.
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Affiliation(s)
- Muhammad Miftahussurur
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Indonesia
- Institute of Tropical Diseases, Universitas Airlangga, Indonesia
- * E-mail: (YY); (MM)
| | - Langgeng Agung Waskito
- Institute of Tropical Diseases, Universitas Airlangga, Indonesia
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | - Ari Fahrial Syam
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Iswan Abbas Nusi
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Indonesia
| | - I Dewa Nyoman Wibawa
- Division of Gastroentero-hepatology, Department of Internal Medicine, Faculty of Medicine University of Udayana, Denpasar, Indonesia
| | - Yudith Annisa Ayu Rezkitha
- Institute of Tropical Diseases, Universitas Airlangga, Indonesia
- Faculty of Medicine, University of Muhammadiyah Surabaya, Surabaya, Indonesia
| | - Gontar Siregar
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Sumatera Utara, Medan, Indonesia
| | - OK Yulizal
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, University of Sumatera Utara, Medan, Indonesia
| | - Fardah Akil
- Center of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Willy Brodus Uwan
- Department of Internal Medicine, Santo Antonius Hospital, Pontianak, Indonesia
| | - David Simanjuntak
- Department of Internal Medicine, Yowari Hospital, Jayapura, Indonesia
| | - Jimmy Bradley Waleleng
- Division of Gastroentero-hepatology, Department of Internal Medicine, Faculty of Medicine, University of Sam Ratulangi, Prof. Dr. RD Kandou Hospital, Manado, Indonesia
| | | | - Fauzi Yusuf
- Division of Gastroenterohepatology, Department of Internal Medicine, Dr. Zainoel Abidin General Hospital, Banda Aceh, Indonesia
| | - Hasan Maulahela
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Marselino Richardo
- Department of Internal Medicine, Merauke City General Hospital, Merauke, Indonesia
| | - Abdul Rahman
- Department of Internal Medicine, Kolaka General Hospital, Kolaka, Indonesia
| | - Yoma Sari Namara
- Department of Internal Medicine, Anutapura General Hospital, Palu, Indonesia
| | - Eko Sudarmo
- Department of Internal Medicine, Dr. Hasan Busori General hospital, Ternate, Indonesia
| | - Pangestu Adi
- Institute of Tropical Diseases, Universitas Airlangga, Indonesia
| | - Ummi Maimunah
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Indonesia
| | - Poernomo Boedi Setiawan
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Indonesia
| | - Kartika Afrida Fauzia
- Institute of Tropical Diseases, Universitas Airlangga, Indonesia
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | - Dalla Doohan
- Institute of Tropical Diseases, Universitas Airlangga, Indonesia
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
| | - Tomohisa Uchida
- Department of Molecular Pathology, Oita University Faculty of Medicine, Hasama-machi, Yufu-City, Oita, Japan
| | | | - Yoshio Yamaoka
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Indonesia
- Department of Environmental and Preventive Medicine, Oita University Faculty of Medicine, Yufu, Japan
- Department of Medicine, Gastroenterology and Hepatology Section, Baylor College of Medicine, Houston, Texas, United States of America
- Global Oita Medical Advanced Research Center for Health, Hasama-machi, Yufu-City, Oita, Japan
- * E-mail: (YY); (MM)
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Ge Z, Feng Y, Sheh A, Muthupalani S, Gong G, Chawanthayatham S, Essigmann JM, Fox JG. Mutagenicity of Helicobacter hepaticus infection in the lower bowel mucosa of 129/SvEv Rag2 -/- Il10 -/- gpt delta mice is influenced by sex. Int J Cancer 2019; 145:1042-1054. [PMID: 30977112 DOI: 10.1002/ijc.32332] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 04/05/2019] [Indexed: 12/29/2022]
Abstract
Inflammatory bowel disease and colonic tumors induced by Helicobacter hepaticus (Hh) infection in susceptible mouse strains are utilized to dissect the mechanisms underlying similar human diseases. In our study, infection with genotoxic cytolethal distending toxin-producing Hh in 129/SvEv Rag2-/- Il10-/- gpt delta (RagIl10gpt) mice of both sexes for 21 weeks induced significantly more severe cecal and colonic pathology compared to uninfected controls. The mutation frequencies in the infected RagIl10gpt males were 2.1-fold higher for the cecum and 1.7-fold higher for the colon than male RagIl10gpt controls. In addition, there was a 12.5-fold increase of G:C-to-T:A transversions in the colon of Hh-infected males compared to controls. In contrast, there was no statistical significance in mutation frequencies between infected female Rag2Il10gpt mice and controls. Moreover, Hh infection in RagIl10gpt males significantly up-regulated transcription of Tnfα and iNos, and decreased mRNA levels of cecal Atm compared to the infected females; there was no significant difference in mRNA levels of Il-22, Il-17A, Ifnγ and Atr between the infected males and females. Significantly higher levels of cecal and colonic iNos expression and γH2AX-positive epithelial cells (a biomarker for double-strand DNA breaks [DSB]) in Hh-infected Rag2Il10gpt males vs. Hh-infected females were noted. Finally, Hh infection and associated inflammation increased levels of intestinal mucosa-associated genotoxic colibactin-producing pks+ Escherichia coli. Elevated Tnfα and iNos responses and bacterial genotoxins, in concert with suppression of the DSB repair responses, may have promoted mutagenesis in the lower bowel mucosa of Hh-infected male RagIl10gpt mice.
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Affiliation(s)
- Zhongming Ge
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Yan Feng
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Alexander Sheh
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | | | - Guanyu Gong
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | | | - John M Essigmann
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - James G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
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21
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Helicobacter pylori infection increases risk of incident metabolic syndrome and diabetes: A cohort study. PLoS One 2019; 14:e0208913. [PMID: 30779804 PMCID: PMC6380540 DOI: 10.1371/journal.pone.0208913] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 11/26/2018] [Indexed: 12/17/2022] Open
Abstract
Emerging studies have shed light on the association between Helicobacter pylori (HP) infection and cardiometabolic risk. However, there is no evidence to support a causal link for the relationship in the general population. Our aim was to determine whether HP infection is associated with the risks of incident type II diabetes mellitus (DM) in a population-based cohort consisting of adults from the general population. A total of 69235 adults enrolled in the study obtained health examinations at the Tri-Service General Hospital in Taiwan from 2010 to 2016. HP infection detection was performed by rapid urease tests (RUTs), and endoscopic examinations were used to diagnose gastroesophageal reflux disease (GERD), gastric ulcers (GUs) and duodenal ulcers (DUs). Cross-sectional and longitudinal analyses were performed to examine the association between HP infection and cardiometabolic diseases using logistic regression and Cox regression in a large population-based study. HP infection was significantly associated with the presence of metabolic syndrome (MetS) (OR = 1.26, 95%CI: 1.00-1.57) and DM (OR = 1.59, 95%CI: 1.17-2.17) only in male subjects, and abnormal endoscopic findings were also correlated with cardiometabolic diseases. Our findings demonstrated that participants with HP infection had an elevated risk of developing incident DM (HR = 1.54, 95%CI: 1.11-2.13). In addition, endoscopic findings of a DU (HR = 1.63, 95%CI: 1.02-2.63), rather than GERD or a GU, were also predictive of incident DM. In this cohort, HP infection was a statistically significant predictor of incident DM among male population.
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22
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Vázquez-Martínez ER, García-Gómez E, Camacho-Arroyo I, González-Pedrajo B. Sexual dimorphism in bacterial infections. Biol Sex Differ 2018; 9:27. [PMID: 29925409 PMCID: PMC6011518 DOI: 10.1186/s13293-018-0187-5] [Citation(s) in RCA: 87] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 06/08/2018] [Indexed: 12/21/2022] Open
Abstract
Background Sex differences are important epidemiological factors that impact in the frequency and severity of infectious diseases. A clear sexual dimorphism in bacterial infections has been reported in both humans and animal models. Nevertheless, the molecular mechanisms involved in this gender bias are just starting to be elucidated. In the present article, we aim to review the available data in the literature that report bacterial infections presenting a clear sexual dimorphism, without considering behavioral and social factors. Main body The sexual dimorphism in bacterial infections has been mainly attributed to the differential levels of sex hormones between males and females, as well as to genetic factors. In general, males are more susceptible to gastrointestinal and respiratory bacterial diseases and sepsis, while females are more susceptible to genitourinary tract bacterial infections. However, these incidences depend on the population evaluated, animal model and the bacterial species. Female protection against bacterial infections and the associated complications is assumed to be due to the pro-inflammatory effect of estradiol, while male susceptibility to those infections is associated with the testosterone-mediated immune suppression, probably via their specific receptors. Recent studies indicate that the protective effect of estradiol depends on the estrogen receptor subtype and the specific tissue compartment involved in the bacterial insult, suggesting that tissue-specific expression of particular sex steroid receptors contributes to the susceptibility to bacterial infections. Furthermore, this gender bias also depends on the effects of sex hormones on specific bacterial species. Finally, since a large number of genes related to immune functions are located on the X chromosome, X-linked mosaicism confers a highly polymorphic gene expression program that allows women to respond with a more expanded immune repertoire as compared with men. Conclusion Notwithstanding there is increasing evidence that confirms the sexual dimorphism in certain bacterial infections and the molecular mechanisms associated, further studies are required to clarify conflicting data and to determine the role of specific hormone receptors involved in the gender bias of bacterial infections, as well as their potential as therapeutic targets.
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Affiliation(s)
- Edgar Ricardo Vázquez-Martínez
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
| | - Elizabeth García-Gómez
- Unidad de Investigación en Reproducción Humana, Consejo Nacional de Ciencia y Tecnología (CONACyT)-Instituto Nacional de Perinatología, Ciudad de México, Mexico
| | - Ignacio Camacho-Arroyo
- Unidad de Investigación en Reproducción Humana, Instituto Nacional de Perinatología-Facultad de Química, Universidad Nacional Autónoma de México (UNAM), Ciudad de México, Mexico
| | - Bertha González-Pedrajo
- Departamento de Genética Molecular, Instituto de Fisiología Celular, UNAM, Ciudad Universitaria, Av. Universidad 3000, Coyoacán, 04510, Ciudad de México, Mexico.
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23
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Shimada S, Akiyama Y, Mogushi K, Ishigami-Yuasa M, Kagechika H, Nagasaki H, Fukamachi H, Yuasa Y, Tanaka S. Identification of selective inhibitors for diffuse-type gastric cancer cells by screening of annotated compounds in preclinical models. Br J Cancer 2018. [PMID: 29527007 PMCID: PMC5931092 DOI: 10.1038/s41416-018-0008-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Background Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and poor patient prognosis. We have previously established an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. In this study, we explored low-molecular-weight drugs selectively eliminating mouse and human DGC cells. Methods We derived mouse gastric cancer (GC) cell lines from DGC of the DCKO mice demonstrating enhanced tumourigenic activity in immunodeficient mice and acquired tolerance to cytotoxic anti-cancer agents. Results We performed a synthetic lethal screening of 1535 annotated chemical compounds, and identified 27 candidates selectively killing the GC cell lines. The most potent drug mestranol, an oestrogen derivative, and other oestrogen receptor modulators specifically attenuated cell viability of the GC cell lines by inducing apoptosis preceded by DNA damage. Moreover, mestranol could significantly suppress tumour growth of the GC cells subcutaneously transplanted into nude mice, consistent with longer survival time in the female DCKO mice than in the male. Expectedly, human E-cadherin-mutant and -low gastric cancer cells showed higher susceptibility to oestrogen drugs in contrast to E-cadherin-intact ones in vitro and in vivo. Conclusions These findings may lead to the development of novel therapeutic strategies targeting DGC.
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Affiliation(s)
- Shu Shimada
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
| | - Yoshimitsu Akiyama
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kaoru Mogushi
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.,Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, Tokyo, Japan
| | - Mari Ishigami-Yuasa
- Chemical Biology Screening Center, and Department of Organic and Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroyuki Kagechika
- Chemical Biology Screening Center, and Department of Organic and Medicinal Chemistry, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiromi Nagasaki
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroshi Fukamachi
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yasuhito Yuasa
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. .,Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
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Guven-Maiorov E, Tsai CJ, Ma B, Nussinov R. Prediction of Host-Pathogen Interactions for Helicobacter pylori by Interface Mimicry and Implications to Gastric Cancer. J Mol Biol 2017; 429:3925-3941. [PMID: 29106933 PMCID: PMC7906438 DOI: 10.1016/j.jmb.2017.10.023] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 10/16/2017] [Accepted: 10/16/2017] [Indexed: 02/07/2023]
Abstract
There is a strong correlation between some pathogens and certain cancer types. One example is Helicobacter pylori and gastric cancer. Exactly how they contribute to host tumorigenesis is, however, a mystery. Pathogens often interact with the host through proteins. To subvert defense, they may mimic host proteins at the sequence, structure, motif, or interface levels. Interface similarity permits pathogen proteins to compete with those of the host for a target protein and thereby alter the host signaling. Detection of host-pathogen interactions (HPIs) and mapping the re-wired superorganism HPI network-with structural details-can provide unprecedented clues to the underlying mechanisms and help therapeutics. Here, we describe the first computational approach exploiting solely interface mimicry to model potential HPIs. Interface mimicry can identify more HPIs than sequence or complete structural similarity since it appears more common than the other mimicry types. We illustrate the usefulness of this concept by modeling HPIs of H. pylori to understand how they modulate host immunity, persist lifelong, and contribute to tumorigenesis. H. pylori proteins interfere with multiple host pathways as they target several host hub proteins. Our results help illuminate the structural basis of resistance to apoptosis, immune evasion, and loss of cell junctions seen in H. pylori-infected host cells.
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Affiliation(s)
- Emine Guven-Maiorov
- Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
| | - Chung-Jung Tsai
- Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
| | - Buyong Ma
- Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
| | - Ruth Nussinov
- Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
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Frycz BA, Murawa D, Borejsza-Wysocki M, Wichtowski M, Spychała A, Marciniak R, Murawa P, Drews M, Jagodziński PP. mRNA expression of steroidogenic enzymes, steroid hormone receptors and their coregulators in gastric cancer. Oncol Lett 2017; 13:3369-3378. [PMID: 28521442 PMCID: PMC5431337 DOI: 10.3892/ol.2017.5881] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 12/12/2016] [Indexed: 02/07/2023] Open
Abstract
Epidemiological and experimental findings suggest that the development of gastric cancer (GC) is regulated by steroid hormones. In postmenopausal women and older men, the majority of steroid hormones are produced locally in peripheral tissue through the enzymatic conversion of steroid precursors. Therefore, using reverse transcription-quantitative polymerase chain reaction analysis, the mRNA expression of genes encoding steroidogenic enzymes, including steroid sulfatase (STS), hydroxy-delta-5-steroid dehydrogenase 3 beta- and steroid delta-isomerase 1 (HSD3B1), 17β-hydroxysteroid dehydrogenase type 7 and aromatase (CYP19A1), was investigated in primary tumoral and adjacent healthy gastric mucosa from 60 patients with GC. Furthermore, the mRNA levels for estrogen receptor α, estrogen receptor β (ESR2) and androgen receptor (AR), along with their coregulators, including proline, glutamate and leucine rich protein 1, CREB binding protein, nuclear receptor coactivator 1 (NCOA1), nuclear receptor corepressor 1 (NCOR1) and nuclear receptor subfamily 2 group F member 1 (NR2F1), were investigated. Additionally, the association between the mRNA expression of these genes and the clinicopathological features of patients with GC was examined. Significantly decreased levels of STS, HSD3B1, ESR2, AR, NCOA1 and NCOR1 mRNA, in addition to significantly increased levels of CYP19A1 mRNA were demonstrated in tumoral tissue samples compared with adjacent healthy gastric tissue samples. Deregulated expression of these genes in the analyzed tissue samples was associated with certain clinicopathological features of GC, such as age and localization of the tumor. The results of the current study suggest that all of the genes analyzed are expressed in tumoral and adjacent healthy gastric mucosa. In addition, the results indicate that abnormal expression of STS, ESR2, AR, NCOA1 and NCOR1 may serve a role in the development and progression of GC, and may be associated with specific clinicopathological features in patients with GC.
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Affiliation(s)
- Bartosz Adam Frycz
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, 60-781 Poznań, Poland
| | - Dawid Murawa
- First Department of Surgical Oncology and General Surgery, Greater Poland Cancer Centre, 61-866 Poznań, Poland.,Research and Development Centre, Regional Specialist Hospital of Wrocław, 51-124 Wrocław, Poland
| | - Maciej Borejsza-Wysocki
- Department of General and Endocrine Surgery and Gastroenterological Oncology, Heliodor Święcicki Clinical Hospital, Poznań University of Medical Sciences, 60-355 Poznań, Poland
| | - Mateusz Wichtowski
- First Department of Surgical Oncology and General Surgery, Greater Poland Cancer Centre, 61-866 Poznań, Poland
| | - Arkadiusz Spychała
- First Department of Surgical Oncology and General Surgery, Greater Poland Cancer Centre, 61-866 Poznań, Poland
| | - Ryszard Marciniak
- Department of General and Endocrine Surgery and Gastroenterological Oncology, Heliodor Święcicki Clinical Hospital, Poznań University of Medical Sciences, 60-355 Poznań, Poland
| | - Paweł Murawa
- First Department of Surgical Oncology and General Surgery, Greater Poland Cancer Centre, 61-866 Poznań, Poland
| | - Michał Drews
- Department of General and Endocrine Surgery and Gastroenterological Oncology, Heliodor Święcicki Clinical Hospital, Poznań University of Medical Sciences, 60-355 Poznań, Poland
| | - Paweł Piotr Jagodziński
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, 60-781 Poznań, Poland
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Wesołowska M, Pawlik P, Jagodziński P. The clinicopathologic significance of estrogen receptors in human gastric carcinoma. Biomed Pharmacother 2016; 83:314-322. [DOI: 10.1016/j.biopha.2016.06.048] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 06/27/2016] [Indexed: 02/07/2023] Open
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Miller CL, Muthupalani S, Shen Z, Drees F, Ge Z, Feng Y, Chen X, Gong G, Nagar KK, Wang TC, Gertler FB, Fox JG. Lamellipodin-Deficient Mice: A Model of Rectal Carcinoma. PLoS One 2016; 11:e0152940. [PMID: 27045955 PMCID: PMC4821566 DOI: 10.1371/journal.pone.0152940] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Accepted: 03/20/2016] [Indexed: 01/27/2023] Open
Abstract
During a survey of clinical rectal prolapse (RP) cases in the mouse population at MIT animal research facilities, a high incidence of RP in the lamellipodin knock-out strain, C57BL/6-Raph1tm1Fbg (Lpd-/-) was documented. Upon further investigation, the Lpd-/- colony was found to be infected with multiple endemic enterohepatic Helicobacter species (EHS). Lpd-/- mice, a transgenic mouse strain produced at MIT, have not previously shown a distinct immune phenotype and are not highly susceptible to other opportunistic infections. Predominantly male Lpd-/- mice with RP exhibited lesions consistent with invasive rectal carcinoma concomitant to clinically evident RP. Multiple inflammatory cytokines, CD11b+Gr1+ myeloid-derived suppressor cell (MDSC) populations, and epithelial cells positive for a DNA damage biomarker, H2AX, were elevated in affected tissue, supporting their role in the neoplastic process. An evaluation of Lpd-/- mice with RP compared to EHS-infected, but clinically normal (CN) Lpd-/- animals indicated that all of these mice exhibit some degree of lower bowel inflammation; however, mice with prolapses had significantly higher degree of focal lesions at the colo-rectal junction. When Helicobacter spp. infections were eliminated in Lpd-/- mice by embryo transfer rederivation, the disease phenotype was abrogated, implicating EHS as a contributing factor in the development of rectal carcinoma. Here we describe lesions in Lpd-/- male mice consistent with a focal inflammation-induced neoplastic transformation and propose this strain as a mouse model of rectal carcinoma.
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Affiliation(s)
- Cassandra L. Miller
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Sureshkumar Muthupalani
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Zeli Shen
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Frauke Drees
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Zhongming Ge
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Yan Feng
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Xiaowei Chen
- Division of Digestive and Liver Diseases, Columbia University, New York, NY, United States of America
| | - Guanyu Gong
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - Karan K. Nagar
- Division of Digestive and Liver Diseases, Columbia University, New York, NY, United States of America
| | - Timothy C. Wang
- Division of Digestive and Liver Diseases, Columbia University, New York, NY, United States of America
| | - Frank B. Gertler
- David H Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States of America
| | - James G. Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, United States of America
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, United States of America
- * E-mail:
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Wang Z, Butler LM, Wu AH, Koh WP, Jin A, Wang R, Yuan JM. Reproductive factors, hormone use and gastric cancer risk: The Singapore Chinese Health Study. Int J Cancer 2016; 138:2837-45. [PMID: 26829904 DOI: 10.1002/ijc.30024] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 12/22/2015] [Accepted: 01/19/2016] [Indexed: 12/16/2022]
Abstract
Gastric cancer incidence varies greatly worldwide, but is consistently twice as high in men than in women. The hormone-related factors hypothesized to be associated with lower risk of gastric cancer in women have not been fully explored in populations with a high background risk of gastric cancer. The Singapore Chinese Health Study (SCHS) is a prospective cohort study in which 34,022 of the participants enrolled between 1993 and 1998 were women between 45 and 74 years of age. Information on reproductive histories, hormone replacement therapy (HRT) and oral contraceptive (OC) use was collected through in-person interviews at baseline. As of December 31, 2013, 269 incident gastric cancer cases were identified. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated to evaluate gastric cancer risk associations. Older age at natural menopause (≥55 versus <45 years: HR = 0.50, 95% CI: 0.25-0.99), type of menopause (other versus natural: HR = 0.48, 95% CI: 0.27-0.87) and greater years of menstrual cycling (fourth versus first quartile: HR = 0.67, 95% CI: 0.46-0.96) were associated with a decreased risk of gastric cancer. Ever use of OCs and HRT was also associated with reduced risk of gastric cancer; the multivariable-adjusted HRs (95% CIs) were 0.40 (0.17-0.90) for use of HRT >3 years and 0.67 (0.47-0.94) for ever use of OCs, compared with never use. Reproductive factors associated with a longer window of fertility and the use of exogenous hormones were shown to reduce gastric cancer development in a cohort of Chinese women with a high background risk of gastric cancer.
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Affiliation(s)
- Zhensheng Wang
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA
| | - Lesley M Butler
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.,Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA
| | - Anna H Wu
- Department of Preventive Medicine, Keck School of Medicine, University of South California, Los Angeles, CA
| | - Woon-Puay Koh
- Office of Clinical Sciences, Duke-NUS Medical School, Singapore, Singapore.,Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
| | - Aizhen Jin
- National Registry of Diseases Office, Health Promotion Board, Singapore, Singapore
| | - Renwei Wang
- Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA
| | - Jian-Min Yuan
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA.,Division of Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute, Pittsburgh, PA
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29
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Frycz BA, Murawa D, Borejsza-Wysocki M, Marciniak R, Murawa P, Drews M, Jagodziński PP. Expression of 17β-hydroxysteroid dehydrogenase type 2 is associated with some clinicopathological features in gastric cancer. Biomed Pharmacother 2015; 70:24-7. [PMID: 25776474 DOI: 10.1016/j.biopha.2014.12.042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Accepted: 12/30/2014] [Indexed: 01/19/2023] Open
Abstract
In most populations, gastric cancer (GC) incidence is higher in men than in women, which may suggest the role of sex steroid hormones in gastric cancerogenesis. Both, androgens and estrogens can be synthetised in peripherial tissues. This process is controlled by expression of steroidogenic enzymes. Therefore, we evaluate the 17β-hydroxysteroid dehydrogenase type 2 (HSD17B2) transcript and protein levels in gastric tumoral and nontumoral tissue. We also determined the association between HSD17B2 transcript and protein levels and some clinicopathological features in GC. We found significantly decreased levels of HSD17B2 transcript (P=0.00072) and protein (P=0.00017) in primary tumoral tissues of GC patients, as compared to nontumoral tissues. In patients above 60 years of age the amounts of HSD17B2 transcript (P=0.00044) and protein (P=0.00027) were significantly lower in tumoral than nontumoral tissues. Similarly, lower HSD17B2 levels, both in terms of the transcript and protein, were observed in tumoral tissues of male (P=0.013, P=0.0014), patients stomach (P=0.0062, P=0.045) and cardia (P=0.02, P=0.02) site of tumor, T3 (P=0.018, P=0.014) depth of invasion, N0 (P=0.017, P=0.045) lymph node metastasis, G3 (P=0.0027, P=0.014) malignancy grade. We also observed significantly reduced level of HSD17B2 transcript in tumoral tissue specimens of females (P=0.014), T4 depth of invasion (P=0.02), N3 lymph node metastasis (P=0.037) and G2 malignancy grade (P=0.045). Furthermore, diffuse GC histological types were associated with lower HSD17B2 protein level (P=0.024) than nontumoral tissues. We demonstrated that HSD17B2 transcript and protein levels are linked to some clinicopathological features in GC.
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Affiliation(s)
- Bartosz Adam Frycz
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poznań, Poland
| | - Dawid Murawa
- First Department of Surgical Oncology and General Surgery, Wielkopolska Cancer Center, Poznań, Poland
| | - Maciej Borejsza-Wysocki
- Department of General Surgery, Oncological Gastroenterology and Plastic Surgery at the Poznań University of Medical Sciences, Poznań, Poland
| | - Ryszard Marciniak
- Department of General Surgery, Oncological Gastroenterology and Plastic Surgery at the Poznań University of Medical Sciences, Poznań, Poland
| | - Paweł Murawa
- First Department of Surgical Oncology and General Surgery, Wielkopolska Cancer Center, Poznań, Poland
| | - Michał Drews
- Department of General Surgery, Oncological Gastroenterology and Plastic Surgery at the Poznań University of Medical Sciences, Poznań, Poland
| | - Paweł Piotr Jagodziński
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, Poznań, Poland.
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The direct effect of estrogen on cell viability and apoptosis in human gastric cancer cells. Mol Cell Biochem 2014; 395:99-107. [PMID: 24934239 DOI: 10.1007/s11010-014-2115-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Accepted: 06/02/2014] [Indexed: 12/16/2022]
Abstract
Epidemiology researches indicated that gastric cancer is a male-predominant disease; both expression level of estrogen and expression pattern of estrogen receptors (ERs) influence its carcinogenesis. But the direct effect of estrogen on gastric cancer cells is still unclear. This study aimed to explore the direct effect of β-estradiol (E2) on gastric cancer cells. SGC7901 and BGC823 were treated with a serial of concentrations of E2. The survival rates of both the cell lines were significantly reduced, and the reduction of viability was due to apoptosis triggered by E2 treatment. Caspase 3 was activated in response to the increasing E2 concentration in both SGC7901 and BGC823. Cleaved Caspase 3 fragments were detected, and the expression levels of Bcl-2 and Bcl-xL were reduced. Apoptosis was further confirmed by flow cytometry. The expression level of PEG10, an androgen receptor target gene, was reduced during E2 treatment. Both ERα and ERβ were expressed in these cell lines, and the result of bioinformatics analysis of gastric cancer from GEO datasets indicated that the expression levels of both ERα and ERβ were significantly higher in noncancerous gastric tissues than in gastric cancer tissues. Our research indicated that estrogen can reduce cell viability and promote apoptosis in gastric cancer cells directly; ERs expression level is associated with gastric cancer. Our research will help to understand the mechanism of gender disparity in gastric cancer.
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31
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Wang DQ, Ding XP, Yin S. Roles of proinflammatory cytokines in precancerous lesions of gastric cancer. Shijie Huaren Xiaohua Zazhi 2014; 22:39-45. [DOI: 10.11569/wcjd.v22.i1.39] [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] [Indexed: 02/06/2023] Open
Abstract
Precancerous lesions of gastric cancer, including intestinal metaplasia and dysplasia, are important stages in the evolution from normal gastric tissue to gastric cancer. Gastric cancer has a very high mortality rate, mainly due to post-metastasis diagnosis. Therefore, diagnosis of precancerous lesions of gastric cancer is of great clinical significance. In recent years, it has been reported that some proinflammatory cytokines such as interleukin 1β (IL-1β), IL-8, IL-11, tumor necrosis factor α (TNF-α) and interferon-gamma (IFN-γ) play important roles in the development of precancerous lesions of gastric cancer. A more detailed understanding of the roles of proinflammatory cytokines may provide new therapeutic targets for precancerous lesions of gastric cancer. Here, we summarize the roles of some proinflammatory cytokines in the progression of precancerous lesions of gastric cancer.
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Abstract
Since its discovery in 1982, the global importance of Helicobacter pylori-induced disease, particularly in developing countries, remains high. The use of rodent models, particularly mice, and the unanticipated usefulness of the gerbil to study H. pylori pathogenesis have been used extensively to study the interactions of the host, the pathogen, and the environmental conditions influencing the outcome of persistent H. pylori infection. Dietary factors in humans are increasingly recognized as being important factors in modulating progression and severity of H. pylori-induced gastric cancer. Studies using rodent models to verify and help explain mechanisms whereby various dietary ingredients impact disease outcome should continue to be extremely productive.
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Affiliation(s)
- James G. Fox
- Division of Comparative Medicine, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts
| | - Timothy C. Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, New York
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33
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Frycz BA, Murawa D, Wysocki-Borejsza M, Marciniak R, Murawa P, Drews M, Jagodziński PP. Expression of 17β-hydroxysteroid dehydrogenase type 1 in gastric cancer. Biomed Pharmacother 2013; 67:651-7. [PMID: 23916544 DOI: 10.1016/j.biopha.2013.06.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2013] [Accepted: 06/17/2013] [Indexed: 12/15/2022] Open
Abstract
There are several findings suggesting the protective role of estrogens in gastric carcinogenesis. Extragonadal 17β-estradiol (E2) may be formed during estrone (E1) reduction to E2 by 17-β-hydroxysteroid dehydrogenase type 1 (HSD17B1). Therefore, we studied the HSD17B1 transcript and protein levels in primary nontumoral and tumoral gastric tissue from the same 21 patients with gastric cancer (GC). We also assessed the effect of 5-Aza-2'-deoxycytidine (5-dAzaC), on the methylation status of HSD17B1 and its expression and conversion of E1 to E2 in HGC-27 and EPG 85-257 GC cells. We identified the presence of HSD17B1 transcript and protein in HGC-27 and EPG 85-257 GC cells as well as in primary nontumoral and tumoral tissues from patients with GC. Moreover, we found that 5-dAzaC significantly up-regulated the HSD17B1 transcript and protein levels, which is associated with increased conversion of E1 to E2 in HGC-27 and EPG 85-257 GC cells. The changes in HSD17B1 expression in both HGC-27 and EPG 85-257 cells were accompanied by 5-dAzaC induced DNA demethylation in the 5' flanking region. Our results demonstrated that HSD17B1 expression and its ability to convert the weak estrogen E1 to the more potent E2 can be associated with DNA methylation in the 5' flanking region in GC cells.
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Affiliation(s)
- Bartosz Adam Frycz
- Department of Biochemistry and Molecular Biology, Poznań University of Medical Sciences, 6 Święcickiego St., 60-781 Poznań, Poland.
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Hayakawa Y, Fox JG, Gonda T, Worthley DL, Muthupalani S, Wang TC. Mouse models of gastric cancer. Cancers (Basel) 2013; 5:92-130. [PMID: 24216700 PMCID: PMC3730302 DOI: 10.3390/cancers5010092] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/08/2013] [Accepted: 01/15/2013] [Indexed: 12/12/2022] Open
Abstract
Animal models have greatly enriched our understanding of the molecular mechanisms of numerous types of cancers. Gastric cancer is one of the most common cancers worldwide, with a poor prognosis and high incidence of drug-resistance. However, most inbred strains of mice have proven resistant to gastric carcinogenesis. To establish useful models which mimic human gastric cancer phenotypes, investigators have utilized animals infected with Helicobacter species and treated with carcinogens. In addition, by exploiting genetic engineering, a variety of transgenic and knockout mouse models of gastric cancer have emerged, such as INS-GAS mice and TFF1 knockout mice. Investigators have used the combination of carcinogens and gene alteration to accelerate gastric cancer development, but rarely do mouse models show an aggressive and metastatic gastric cancer phenotype that could be relevant to preclinical studies, which may require more specific targeting of gastric progenitor cells. Here, we review current gastric carcinogenesis mouse models and provide our future perspectives on this field.
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Affiliation(s)
- Yoku Hayakawa
- Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY 10032, USA.
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35
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Camargo MC, Goto Y, Zabaleta J, Morgan DR, Correa P, Rabkin CS. Sex hormones, hormonal interventions, and gastric cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2012; 21:20-38. [PMID: 22028402 PMCID: PMC3315355 DOI: 10.1158/1055-9965.epi-11-0834] [Citation(s) in RCA: 195] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Estrogens may influence gastric cancer risk, but published studies are inconclusive. We therefore carried out a meta-analysis addressing the associations of gastric cancer in women with menstrual and reproductive factors and with use of estrogen- and antiestrogen-related therapies. Searches of PubMed up to June, 2011 and review of citations yielded a total of 28 independent studies, including at least one exposure of interest. Random effects pooled estimates of relative risk (RR) and corresponding 95% CIs were calculated for eight exposures reported in at least five studies, including: age at menarche, age at menopause, years of fertility, parity, age at first birth, oral contraceptive use, hormone replacement therapy (HRT), and tamoxifen treatment. Longer years of fertility (RR = 0.74, 95% CI: 0.63-0.86) and HRT (RR = 0.77; 95% CI: 0.64-0.92) were each associated with decreased gastric cancer risk. Conversely, tamoxifen treatment was associated with increased risk (RR = 1.82; 95% CI: 1.39-2.38). The other five exposures were not significantly associated. Our analysis supports the hypothesis that longer exposure to estrogen effects of either ovarian or exogenous origin may decrease risk of gastric cancer. Additional studies are warranted to extend this finding and to identify the underlying mechanisms.
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Affiliation(s)
- M Constanza Camargo
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, EPS/6116, Rockville, MD 20852, USA.
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Sheh A, Ge Z, Parry NMA, Muthupalani S, Rager JE, Raczynski AR, Mobley MW, McCabe AF, Fry RC, Wang TC, Fox JG. 17β-estradiol and tamoxifen prevent gastric cancer by modulating leukocyte recruitment and oncogenic pathways in Helicobacter pylori-infected INS-GAS male mice. Cancer Prev Res (Phila) 2011; 4:1426-35. [PMID: 21680705 DOI: 10.1158/1940-6207.capr-11-0219] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Helicobacter pylori infection promotes male predominant gastric adenocarcinoma in humans. Estrogens reduce gastric cancer risk and previous studies showed that prophylactic 17β-estradiol (E2) in INS-GAS mice decreases H. pylori-induced carcinogenesis. We examined the effect of E2 and tamoxifen (TAM) on H. pylori-induced gastric cancer in male and female INS-GAS mice. After confirming robust gastric pathology at 16 weeks postinfection (WPI), mice were implanted with E2, TAM, both E2 and TAM, or placebo pellets for 12 weeks. At 28 WPI, gastric histopathology, gene expression, and immune cell infiltration were evaluated and serum inflammatory cytokines measured. After treatment, no gastric cancer was observed in H. pylori-infected males receiving E2 and/or TAM, whereas 40% of infected untreated males developed gastric cancer. E2, TAM, and their combination significantly reduced gastric precancerous lesions in infected males compared with infected untreated males (P < 0.001, 0.01, and 0.01, respectively). However, TAM did not alter female pathology regardless of infection status. Differentially expressed genes from males treated with E2 or TAM (n = 363 and n = 144, Q < 0.05) associated highly with cancer and cellular movement, indicating overlapping pathways in the reduction of gastric lesions. E2 or TAM deregulated genes associated with metastasis (PLAUR and MMP10) and Wnt inhibition (FZD6 and SFRP2). Compared with controls, E2 decreased gastric mRNA (Q < 0.05) and serum levels (P < 0.05) of CXCL1, a neutrophil chemokine, leading to decreased neutrophil infiltration (P < 0.01). Prevention of H. pylori-induced gastric cancer by E2 and TAM may be mediated by estrogen signaling and is associated with decreased CXCL1, decreased neutrophil counts, and downregulation of oncogenic pathways.
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Affiliation(s)
- Alexander Sheh
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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37
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Bodelon C, Anderson GL, Rossing MA, Chlebowski RT, Ochs-Balcom HM, Vaughan TL, Mobley MW, McCabe AF, Fry RC, Wang TC, Fox JG. Hormonal factors and risks of esophageal squamous cell carcinoma and adenocarcinoma in postmenopausal women. CANCER PREVENTION RESEARCH (PHILADELPHIA, PA.) 2011. [PMID: 21505180 DOI: 10.1158/1940-6207] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The incidences of esophageal adenocarcinoma and squamous cell carcinoma (SCC) are higher in males than in females. We investigated whether female-related hormonal factors are associated with risks of these two types of esophageal cancer. We examined the association between use of hormone therapy (HT) and the risks of esophageal adenocarcinoma and SCC in postmenopausal women enrolled in the Women's Health Initiative (WHI) clinical trials and observational studies. Twenty-three esophageal adenocarcinoma and 34 esophageal SCC cases were confirmed among the 161,080 participants, after a median of 11.82 years of follow-up. Risk of esophageal SCC was lower among HT users (past users: HR = 0.25, 95% CI: 0.06-1.10 in 2 cases; current users: HR = 0.41, 95% CI: 0.18-0.94 in 9 cases). A decreased esophageal SCC risk was observed for current users of estrogen plus progestin (E+P) therapy (HR = 0.25, 95% CI: 0.07-0.86 in 3 cases) but not for current users of estrogen-only therapy (HR = 0.96, 95% CI: 0.28-3.29 in 6 cases). No association was observed between the use of HT and the risk of esophageal adenocarcinoma. No other reproductive or hormonal factors were significantly associated with the risk of either SCC or adenocarcinoma. Current use of E+P therapy was found to be associated with a decreased risk of esophageal SCC, but no association was observed with esophageal adenocarcinoma. To provide more definitive evidence, a pooled analysis of all available studies or a much larger study would be needed.
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Affiliation(s)
- Clara Bodelon
- Department of Epidemiology, School of Public Health, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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