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1
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Altfillisch C, Meyer C, Yuquimpo K, Jackson K, Saha S, Montgomery R, Madan R, Buckles D, Bansal A. Females Have a Higher Prevalence of Severe and Dysplastic Fundic Gland Polyposis: A Case-Control Study. J Clin Gastroenterol 2025:00004836-990000000-00423. [PMID: 39998955 DOI: 10.1097/mcg.0000000000002135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 12/28/2024] [Indexed: 02/27/2025]
Abstract
GOALS The purpose of this study was to determine risk factors associated with the development of Fundic Gland Polyps (FGP) and its association with gastric cancer. BACKGROUND Gastric cancer incidence is increasing and may be linked to PPIs. FGP are common and a possible intermediary between PPI use and the risk of gastric cancer. STUDY This single-center retrospective case-control study compared multiple risk factors between cases with FGP and controls between January 1, 2021 and December 31, 2021. Severe FGP was defined by innumerable, diffuse, or >50 polyps by endoscopic reporting and dysplasia by histopathology. Patient outcomes with severe polyposis and dysplasia were reviewed. Gastrectomy specimens and endoscopic reports were reviewed for FGP in an independent cohort of patients with known gastric cancer. Univariate and multivariate models using logistic regression were constructed. RESULTS The main logistic regression model included 591 participants (330 cases and 261 controls). Increasing age [OR: 1.02 (1.01 to 1.03)] and >2 years of PPI use [OR: 2.76 (1.72 to 4.47)] were associated with increased risk of FGP whereas smoking was protective [OR: 5.41 (2.58 to 12.24)]. Most patients with severe FGP (87.5%), low-grade (77%), and high-grade dysplasia (80%) were females. No patients developed gastric cancer on follow-up (mean: 13.9 mo). None of the patients within an independent cohort of gastric cancers diagnosed between January 1, 2021 and December 31, 2021 had FGP. CONCLUSIONS Although FGP are equally common among sexes, severe and dysplastic FGP are more common among females, but none progressed to cancer. These data could be useful to counsel patients with FGP.
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Affiliation(s)
| | | | | | | | | | | | - Rashna Madan
- Department of Pathology and Laboratory Medicine, University of Kansas Health System
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2
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Roelofs JJM, Camps G, Leenders LM, Marciani L, Spiller RC, Van Eijnatten EJM, Alyami J, Deng R, Freitas D, Grimm M, Karhunen LJ, Krishnasamy S, Le Feunteun S, Lobo DN, Mackie AR, Mayar M, Weitschies W, Smeets PAM. Intra- and interindividual variability in fasted gastric content volume. Neurogastroenterol Motil 2024; 36:e14904. [PMID: 39189312 DOI: 10.1111/nmo.14904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 07/15/2024] [Accepted: 08/18/2024] [Indexed: 08/28/2024]
Abstract
BACKGROUND Gastric fluid plays a key role in food digestion and drug dissolution, therefore, the amount of gastric fluid present in a fasted state may influence subsequent digestion and drug delivery. We aimed to describe intra- and interindividual variation in fasted gastric content volume (FGCV) and to determine the association with age, sex, and body size characteristics. METHODS Data from 24 MRI studies measuring FGCV in healthy, mostly young individuals after an overnight fast were pooled. The analysis included 366 participants who had up to 6 repeated measurements, with a total of 870 measurements. Linear mixed model analysis was performed to calculate intra- and interindividual variability and to assess the effects of age, sex, weight, height, weight*height as a proxy for body size, and body mass index (BMI). RESULTS FGCV ranged from 0 to 156 mL, with a mean (± SD) value of 33 ± 25 mL. The overall coefficient of variation within the study population was 75.6%, interindividual SD was 15 mL, and the intraindividual SD was 19 mL. Age, weight, height, weight*height, and BMI had no effect on FGCV. Women had lower volumes compared to men (MD: -6 mL), when corrected for the aforementioned factors. CONCLUSION FGCV is highly variable, with higher intraindividual compared to interindividual variability, indicating that FGCV is subject to day-to-day and within-day variation and is not a stable personal characteristic. This highlights the importance of considering FGCV when studying digestion and drug dissolution. Exact implications remain to be studied.
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Affiliation(s)
- Julia J M Roelofs
- Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Guido Camps
- Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Louise M Leenders
- Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Luca Marciani
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | - Robin C Spiller
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | | | - Jaber Alyami
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
- Radiological Sciences Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ruoxuan Deng
- Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Daniela Freitas
- Université Paris-Saclay, INRAE, AgroParisTech, UMR SayFood, Thiverval-Grignon, France
| | - Michael Grimm
- Institute of Pharmacy, Center of Drug Absorption and Transport, University of Greifswald, Greifswald, Germany
| | - Leila J Karhunen
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Shanthi Krishnasamy
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
| | | | - Dileep N Lobo
- Nottingham Digestive Diseases Centre, NIHR Nottingham Biomedical Research Centre (BRC), Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, UK
- Division of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alan R Mackie
- Food Colloids and Processing Group, School of Food Science and Nutrition, University of Leeds, Leeds, UK
| | - Morwarid Mayar
- Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
| | - Werner Weitschies
- Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Paul A M Smeets
- Division of Human Nutrition and Health, Wageningen University, Wageningen, The Netherlands
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3
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Ethier R, Krishnamurthy A, Jeffrey M, Tompkins TA. Profiling of Metabolites in a Fermented Soy Dietary Supplement Reinforces its Role in the Management of Intestinal Inflammation. Mol Nutr Food Res 2024; 68:e2300770. [PMID: 38522032 DOI: 10.1002/mnfr.202300770] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 02/19/2024] [Indexed: 03/25/2024]
Abstract
SCOPE Gastro-AD (GAD) is a soy flour derived product that undergoes an industrial fermentation with Lactobacillus delbrueckii R0187 and has demonstrated clinical effects in gastroesophageal reflux and peptic ulcer symptom resolution. The aim of this study is to describe and link GAD's metabolomic profile to plausible mechanisms that manifest and explain the documented clinical outcomes. METHODS AND RESULTS 1H NMR spectroscopy with multivariate statistical analysis is used to characterize the prefermented soy flour and GAD products. The acquired spectra are screened using various resources and the molecular assignments are confirmed using total correlation spectroscopy (TOCSY). Peaks corresponding to different metabolites are integrated and compared between the two products for relative changes. HPLC and GC are used to quantify some specific molecules. NMR analyses demonstrate significant changes in the composition of various assigned bioactive moieties. HPLC and GC analysis demonstrate deglycation of isoflavones after fermentation, resulting in estrogenically active secondary metabolites that have been previously shown to help to reduce inflammation. CONCLUSION The identification of bioactive molecules, such as genistein and SCFAs, capable of modulating anti-inflammatory signaling cascades in the stomach's gastric and neuroendocrine tissues can explain the reported biological effects in GAD and is supported by in vivo data.
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Affiliation(s)
- Richard Ethier
- Richard Ethier Consulting, Montreal, Quebec, H4C 2J9, Canada
| | - Arun Krishnamurthy
- Purity-IQ Inc., Suite# 102, 150 Research Lane, Guelph, Ontario, N1G 4T2, Canada
| | - Michael Jeffrey
- Faculty of Science, Engineering & Information Technology, Durham College, Oshawa, Ontario, L1G 0C5, Canada
| | - Thomas A Tompkins
- Lallemand Bio-Ingredients, 1620 rue Prefontaine, Montreal, Quebec, H1W 2N8, Canada
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4
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Wang Y, Jiang Y, Jiang L, Xiong W, Wang Y, Gao X, Chen Q, Lin L, Yu T, Tang Y. Estrogen increases the expression of BKCa and impairs the contraction of colon smooth muscle via upregulation of sphingosine kinase 1. J Cell Physiol 2023; 238:2390-2406. [PMID: 37642352 DOI: 10.1002/jcp.31106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 06/03/2023] [Accepted: 07/20/2023] [Indexed: 08/31/2023]
Abstract
Estrogen (E2) may impair the contraction of colonic smooth muscle (SM) leading to constipation. Large conductance Ca2+ -activated K+ channels (BKCa ) are widely expressed in the smooth muscle cells (SMCs) contributing to hyperpolarization and relaxation of SMCs. Sphingosine kinase 1 (SphK1) is known to influence the expression of BKCa . We aimed to elucidate the potential underlying molecular mechanism of BKCa and SphK1 that may influence E2-induced colonic dysmotility. In ovariectomized rats, SM contraction and expression of BKCa , SphK1, sphingosine-1-phosphate receptor (S1PR) were analyzed after the treatment with vehicle, BSA-E2, E2, and E2 receptor antagonist. The role of BKCa , SphK1, and S1PR in E2-induced SM dysmotility was investigated in rat colonic SMCs. The effect of SphK1 on SM contraction as well as on the expression of BKCa and S1PR was analyzed in SphK1 knock-out mutant mice and wild-type (WT) mice treated with or without E2. The E2-treated group exhibited a weak contraction of colonic SM and a delayed colonic transit. The treatment with E2 significantly upregulated the expression of BKCa , SphK1, S1PR1, and S1PR2, but not S1PR3, in colon SM and SMCs. Inhibition of BKCa , SphK1, S1PR1, and S1PR2 expression attenuated the effect of E2 on Ca2+ mobilization in rat colon SMCs. WT mice treated with E2 showed impaired gastrointestinal motility and enhanced expression of BKCa , S1PR1, and S1PR2 compared with those without E2 treatment. Conversely, in SphK1 knock-out mice treated with E2, these effects were partially reversed. E2 increased the release of S1P which in turn could have activated S1PR1 and S1PR2. Loss of SphK1 attenuated the effect of E2 on the upregulation of S1PR1 and S1PR2 expression. These findings indicated that E2 impaired the contraction of colon SM through activation of BKCa via the upregulation of SphK1 and the release of S1P. In the E2-induced BKCa upregulation, S1PR1 and S1PR2 might also be involved. These results may provide further insights into a therapeutic target and optional treatment approaches for patients with constipation.
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Affiliation(s)
- Yan Wang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ya Jiang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ling Jiang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wenjie Xiong
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yanjuan Wang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiangyue Gao
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qi Chen
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lin Lin
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Ting Yu
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yurong Tang
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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5
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The Comparison of the Influence of Bisphenol A (BPA) and Its Analogue Bisphenol S (BPS) on the Enteric Nervous System of the Distal Colon in Mice. Nutrients 2022; 15:nu15010200. [PMID: 36615857 PMCID: PMC9824883 DOI: 10.3390/nu15010200] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/04/2023] Open
Abstract
Bisphenol A (BPA), commonly used as a plasticizer in various branches of industry has a strong negative effect on living organisms. Therefore, more and more often it is replaced in production of plastics by other substances. One of them is bisphenol S (BPS). This study for the first time compares the impact of BPA and BPS on the enteric neurons using double immunofluorescence technique. It has been shown that both BPA and BPS affect the number of enteric neurons containing substance P (SP), galanin (GAL), vasoactive intestinal polypeptide (VIP), neuronal isoform of nitric oxide synthase (nNOS-a marker of nitrergic neurons) and/or vesicular acetylcholine transporter (VAChT- a marker of cholinergic neurons). The changes noted under the impact of both bisphenols are similar and consisted of an increase in the number of enteric neurons immunoreactive to all neuronal factors studied. The impact of BPS on some populations of neurons was stronger than that noted under the influence of BPA. The obtained results clearly show that BPS (similarly to BPA) administered for long time is not neutral for the enteric neurons even in relatively low doses and may be more potent than BPA for certain neuronal populations.
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6
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Vins N, Sugathan S, Al Menhali A, Karam SM. Overgrowth of Squamocolumnar Junction and Dysregulation of Stem Cell Lineages in the Stomach of Vitamin A-Deficient Mice. Nutrients 2022; 14:3334. [PMID: 36014840 PMCID: PMC9412427 DOI: 10.3390/nu14163334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 08/05/2022] [Accepted: 08/09/2022] [Indexed: 11/24/2022] Open
Abstract
Junctional epithelia are common sites for pathological transformations. In mice, the stratified epithelium of the forestomach joins the simple glandular epithelium of the cardia at the limiting ridge. We previously demonstrated the expression of vitamin A receptors in the gastric stem/progenitor cells and their progeny and found that excess retinoic acid enhances cellular dynamics of gastric epithelium. This study examines how deficiency of vitamin A would alter gastric epithelial stem cell lineages. Three-week-old mice of both genders were weaned and fed with a vitamin A deficient (VAD) diet for 4 or 8 months. Sex- and weight-matched littermate mice received a standard (control) diet. To label S-phase cells, all mice received a single intraperitoneal injection of 5-bromo-2-deoxyuridine before being euthanized. Stomach tissues were processed for microscopic examination and protein analysis to investigate stem cell lineages using different stains, lectins, or antibodies. The Student's t-test was used to compare quantified data showing differences between control and VAD groups. Eight-month-vitamin-A deficiency caused enlarged forestomach and overgrowth of the squamocolumnar junction with metaplastic and dysplastic cardiac glands, formation of intramucosal cysts, loss of surface mucosal integrity, increased amount of luminal surface mucus, and upregulation of trefoil factor 1 and H+,K+-ATPase. These changes were associated with decreased cell proliferation and upregulation of p63. In conclusion, vitamin A is necessary for maintaining gastric epithelial integrity and its deficiency predisposes the mouse stomach to precancerous lesions.
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Affiliation(s)
- Neethu Vins
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Subi Sugathan
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Asma Al Menhali
- Department of Biology, College of Science, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Zayed Bin Sultan Centre for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
| | - Sherif M. Karam
- Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
- Zayed Bin Sultan Centre for Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates
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7
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Bhave S, Ho WLN, Cheng K, Omer M, Bousquet N, Guyer RA, Hotta R, Goldstein AM. Tamoxifen administration alters gastrointestinal motility in mice. Neurogastroenterol Motil 2022; 34:e14357. [PMID: 35279902 DOI: 10.1111/nmo.14357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 12/13/2021] [Accepted: 01/28/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND Tamoxifen is widely used for Cre-estrogen receptor-mediated genomic recombination in transgenic mouse models to mark cells for lineage tracing and to study gene function. However, recent studies have highlighted off-target effects of tamoxifen in various tissues and cell types when used for induction of Cre recombination. Despite the widespread use of these transgenic Cre models to assess gastrointestinal (GI) function, the effect of tamoxifen exposure on GI motility has not been described. METHODS We examined the effects of tamoxifen on GI motility by measuring total GI transit, gastric emptying, small intestinal transit, and colonic contractility in wild-type adult mice. KEY RESULTS We observed a significant delay in total GI transit in tamoxifen-treated mice, with unaltered gastric emptying, accelerated small intestinal transit, and abnormal colonic motility. CONCLUSION Our findings highlight the importance of considering GI motility alterations induced by tamoxifen when designing protocols that utilize tamoxifen as a Cre-driver for studying GI function.
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Affiliation(s)
- Sukhada Bhave
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Wing Lam N Ho
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Katarina Cheng
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Meredith Omer
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Nicole Bousquet
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Richard A Guyer
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ryo Hotta
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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8
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Wakui S, Takahashi H, Muto T. In Utero Exposure to 3,3',4,4', 5-Pentachlorobiphenyl Dose-Dependently Induces N-butyl-4-(hydroxybutyl) Nitrosamine in Rats With Urinary Bladder Carcinoma. Toxicol Pathol 2022; 50:366-380. [PMID: 35045775 DOI: 10.1177/01926233211064180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Polychlorinated biphenyls (PCBs) are fat-soluble environmental pollutants that can accumulate in adipose tissue or be secreted in milk. N-butyl-4-(hydroxy butyl) (BBN), a rat bladder carcinogen, recruits the host metabolism to yield its ultimate carcinogenic form via CYP1s. Since estrogen receptors (ERs) mediate biological responses important for the growth of bladder carcinoma, we investigated PCNA, Cyclin D1, ERs, CYP1s, and AhR expression in BBN rat bladder carcinomas with prenatal PCB exposure. Female SD rats were treated with 7.5 μg, 250 ng, and 2.5 ng of 3,3',4,4',5-pentachlorobiphenyl (PCB126)/kg or vehicle on days 13 to 19 post-pregnancy. Six-week-old male offspring were treated with 0.05% BBN for 10 weeks before being anesthetized and the urinary bladder wall incised to expose the bladder carcinomas. N-butyl-4-(hydroxybutyl) bladder carcinoma incidence increased with prenatal PCB exposure dose-dependently. In bladder carcinoma, PCB126 exposure significantly increased PCNA, D1, ERα, CYPIA1, CYP1B1, and AhR expression dose-dependently, and increased ERα expression was particularly prominent. However, the expression of ERβ was low, independent of the volume of PCB126 given, indicating similarity to the Vehicle group. We conclude that prenatal PCB126 exposure in rats can induce PCB126 to dose-dependently metabolize BBN via CYP1A1, and contribute to bladder carcinogenesis with upregulation of ERα expression.
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Affiliation(s)
- Shin Wakui
- Laboratory of Toxicology, Azabu University School of Veterinary Medicine, Kanagawa, Japan
| | - Hiroyuki Takahashi
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan. Muto is now with Kumiai Chemical Industry Co., Ltd. Japan
| | - Tomoko Muto
- Laboratory of Toxicology, Azabu University School of Veterinary Medicine, Kanagawa, Japan
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9
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Balasuriya GK, Nugapitiya SS, Hill-Yardin EL, Bornstein JC. Nitric Oxide Regulates Estrus Cycle Dependent Colonic Motility in Mice. Front Neurosci 2021; 15:647555. [PMID: 34658750 PMCID: PMC8511480 DOI: 10.3389/fnins.2021.647555] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 08/12/2021] [Indexed: 11/23/2022] Open
Abstract
Women are more susceptible to functional bowel disorders than men and the severity of their symptoms such as diarrhea, constipation, abdominal pain and bloating changes over the menstrual cycle, suggesting a role for sex hormones in gastrointestinal function. Nitric oxide (NO) is a major inhibitory neurotransmitter in the gut and blockade of nitric oxide synthase (NOS; responsible for NO synthesis) increases colonic motility in male mice ex vivo. We assessed the effects of NOS inhibition on colonic motility in female mice using video imaging analysis of colonic motor complexes (CMCs). To understand interactions between NO and estrogen in the gut, we also quantified neuronal NOS and estrogen receptor alpha (ERα)-expressing myenteric neurons in estrus and proestrus female mice using immunofluorescence. Mice in estrus had fewer CMCs under control conditions (6 ± 1 per 15 min, n = 22) compared to proestrus (8 ± 1 per 15 min, n = 22, One-way ANOVA, p = 0.041). During proestrus, the NOS antagonist N-nitro-L-arginine (NOLA) increased CMC numbers compared to controls (189 ± 46%). In contrast, NOLA had no significant effect on CMC numbers during estrus. During estrus, we observed more NOS-expressing myenteric neurons (48 ± 2%) than during proestrus (39 ± 1%, n = 3, p = 0.035). Increased nuclear expression of ERα was observed in estrus which coincided with an altered motility response to NOLA in contrast with proestrus when ERα was largely cytoplasmic. In conclusion, we confirm a cyclic and sexually dimorphic effect of NOS activity in female mouse colon, which could be due to genomic effects of estrogens via ERα.
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Affiliation(s)
- Gayathri K Balasuriya
- Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.,School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
| | - Saseema S Nugapitiya
- Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.,Faculty of Medicine, The University of Queensland, Herston, QLD, Australia
| | - Elisa L Hill-Yardin
- Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.,School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC, Australia
| | - Joel C Bornstein
- Department of Physiology, The University of Melbourne, Parkville, VIC, Australia
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10
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Sleeve gastrectomy-induced endocrine changes in the remnant stomachs of premenopausal and postmenopausal rats: role of the estrogen receptors. Surg Obes Relat Dis 2020; 17:193-207. [PMID: 33011072 DOI: 10.1016/j.soard.2020.08.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/02/2020] [Accepted: 08/12/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Although alterations in the plasma levels of leptin, glucagon-like peptide-1, and gastrin were linked with bariatric surgery outcomes, gastric production of these peptides was not elucidated before. OBJECTIVE The aim was to evaluate the impact of estrogen depletion and estrogen receptors (ERs) on sleeve gastrectomy (SG)-induced alterations in gastric hormone production, gastric mucosal integrity, and bone mass. SETTING Physiology Research Lab at the University. METHODS Female Sprague-Dawley rats underwent ovariectomy or sham operation (control), and 2 months later SG or sham SG was performed. Rats received either nonselective agonist 17 β, ER-α agonist, ER-β agonist, or vehicle for 3 weeks. Trunk blood and gastric tissues were collected for biochemical measurements, while histopathologic examination was performed in gastric and femur samples. RESULTS In the presence of intact ovaries, SG-induced weight loss was accompanied by reductions in the gastric synthesis of leptin and gastrin, while gastric glucagon-like peptide-1 was additionally decreased when SG was performed at the postmenopausal state. SG elevated the depleted serum estradiol levels of menopause, implicating a beneficial effect, but the occurrence of severe gastric mucosal injury was triggered. On the other hand, using ER agonists upregulated gastrin-expressing cells, ameliorated gastric injury, and improved bone loss. CONCLUSIONS SG, either at premenopausal or postmenopausal state, resulted in considerable loss in bone mass, along with reductions in the gastric levels of gastrin and leptin. Functional status of the ovaries needs to be taken into consideration when monitoring the outcomes of SG, and ER agonists could be of value in controlling SG-induced complications.
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11
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Sprouse J, Sampath C, Gangula PR. Role of sex hormones and their receptors on gastric Nrf2 and neuronal nitric oxide synthase function in an experimental hyperglycemia model. BMC Gastroenterol 2020; 20:313. [PMID: 32967621 PMCID: PMC7513483 DOI: 10.1186/s12876-020-01453-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 09/15/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Gastroparesis, a condition of abnormal gastric emptying, is most commonly observed in diabetic women. To date, the role of ovarian hormones and/or gastric hormone receptors on regulating nitrergic-mediated gastric motility remains inconclusive. AIM The purpose of this study is to investigate whether sex hormones/their receptors can attenuate altered Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), neuronal Nitric Oxide Synthase (nNOS) expression and nitrergic relaxation in gastric neuromuscular tissues exposed to in-vitro hyperglycemia (HG). METHODS Gastric neuromuscular sections from adult female C57BL/6 J mice were incubated in normoglycemic (NG, 5 mM) or hyperglycemic (30 mM or 50 mM) conditions in the presence or absence of selective estrogen receptor (ER) agonists (ERα /PPT or ERβ: DPN); or non-selective sex hormone receptor antagonists (ER/ICI 182,780, or progesterone receptor (PR)/ RU486) for 48 h. mRNA, protein expression and nitrergic relaxation of circular gastric neuromuscular strips were assessed. RESULTS Our findings in HG, compared to NG, demonstrate a significant reduction in ER, Nrf2, and nNOS expression in gastric specimens. In addition, in-vitro treatment with sex hormones and/or their agonists significantly (*p < 0.05) restored Nrf2/nNOSα expression and total nitrite production. Conversely, ER, but not PR, antagonist significantly reduced Nrf2/nNOSα expression and nitrergic relaxation. CONCLUSIONS Our data suggest that ER's can regulate nitrergic function by improving Nrf2/nNOS expression in experimental hyperglycemia.
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Affiliation(s)
- Jeremy Sprouse
- School of Graduate Studies, Meharry Medical College, Nashville, TN, 37208, USA.,Department of ODS & Research, School of Dentistry, Nashville, TN, 37208, USA
| | - Chethan Sampath
- Department of ODS & Research, School of Dentistry, Nashville, TN, 37208, USA
| | - Pandu R Gangula
- Department of ODS & Research, School of Dentistry, Nashville, TN, 37208, USA.
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12
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Loss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury. Cell Death Dis 2020; 11:138. [PMID: 32080178 PMCID: PMC7033132 DOI: 10.1038/s41419-020-2269-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 01/08/2020] [Accepted: 01/10/2020] [Indexed: 12/14/2022]
Abstract
Regulation of pancreas plasticity is critical for preventing injury and promoting regeneration upon tissue damage. The intricate process of pancreatic differentiation is governed by an orchestrated network of positive and negative transcription factors for appropriate gene expression. While the transcriptional repressor REST is well characterized as a silencer of neuronal genes in non-neuronal cells, the role of REST in regulating exocrine pancreas cell identity remains largely unexplored. Rest expression is increased upon injury in the mouse pancreas, such as induced acute and chronic pancreatitis and ductal adenocarcinoma. At the cellular level, Rest expression is lower in mature acinar cells compared with pancreas progenitor and ductal cells. To investigate the role of REST activity in pancreatic transdifferentiation and homeostasis, we developed a novel mouse model (Cre/RESTfl/fl) with conditional knockout (KO) of Rest expression within pancreas cells. The high Cre-mediated excision efficiency of Rest exon two KO caused decreased Rest expression and activity within the pancreas. Short-term organoid cultures of pancreatic acini to undergo acinar-to-ductal metaplasia (ADM) showed that loss of REST impedes induced ADM, while overexpression of REST increases ADM. Interestingly, REST ablation accelerated acute pancreatitis in mice treated with the cholecystokinin analog caerulein, as indicated by cellular morphology, elevated serum amylase levels and pancreatic edema. Furthermore, Cre/RESTfl/fl mice were more sensitive to acute pancreatitis injury and displayed augmented tissue damage and cellular lesions. These results suggest REST has a novel protective role against pancreatic tissue damage by acting as a regulator of exocrine cell identity.
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13
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Sun LH, Zhang WX, Xu Q, Wu H, Jiao CC, Chen XZ. Estrogen modulation of visceral pain. J Zhejiang Univ Sci B 2020; 20:628-636. [PMID: 31273960 DOI: 10.1631/jzus.b1800582] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
It is commonly accepted that females and males differ in their experience of pain. Gender differences have been found in the prevalence and severity of pain in both clinical and animal studies. Sex-related hormones are found to be involved in pain transmission and have critical effects on visceral pain sensitivity. Studies have pointed out the idea that serum estrogen is closely related to visceral nociceptive sensitivity. This review aims to summarize the literature relating to the role of estrogen in modulating visceral pain with emphasis on deciphering the potential central and peripheral mechanisms.
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Affiliation(s)
- Li-Hong Sun
- Department of Anesthesiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Wen-Xin Zhang
- Department of Anesthesiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Qi Xu
- Department of Anesthesiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Hui Wu
- Department of Anesthesiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Cui-Cui Jiao
- Department of Anesthesiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
| | - Xin-Zhong Chen
- Department of Anesthesiology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China
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14
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Estrogen synthesis in gastric parietal cells and secretion into portal vein. Anat Sci Int 2019; 95:22-30. [PMID: 31734841 DOI: 10.1007/s12565-019-00510-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 11/07/2019] [Indexed: 10/25/2022]
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15
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Liu JYH, Lin G, Fang M, Rudd JA. Localization of estrogen receptor ERα, ERβ and GPR30 on myenteric neurons of the gastrointestinal tract and their role in motility. Gen Comp Endocrinol 2019; 272:63-75. [PMID: 30502347 DOI: 10.1016/j.ygcen.2018.11.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 10/19/2018] [Accepted: 11/27/2018] [Indexed: 12/19/2022]
Abstract
Estrogen is well known to have a modulatory role on gastrointestinal tract, particularly through its interaction with nuclear estrogen receptors (ERs), alpha and beta (ERα/β). Recent functional studies also indicate that estrogen can activate a G-protein coupled estrogen receptor, GPR30, or GPER1. The present study was designed to identify either the presence or absence of nuclear ERs and GPR30 in the myenteric plexus of the stomach, duodenum, jejunum, ileum and colon of female and male mice. Immunofluorescence staining revealed a high expression of GPR30 in the cytoplasm but not within the nucleus of enteric neurons in female and male mice. ERβ localization was similar to GPR30, where it was expressed in cytoplasm of enteric neurons, but was absent from nuclei, opening up the possibility that ERβ and GPR30 might work together to manifest estrogenic effects. Comparatively, ERα was mainly located in the nuclei of enteric neurons. ERα, ERβ and GPR30 were also expressed in the cytoplasm of glial cells in the stomach and small intestine, but levels were lower in the colon. The expression nuclear:cytoplasm ratio of ERα was higher in male than female mice, which might relate to sex-dependent translocation of ERα from cytoplasm to nucleus in response to known plasma levels of estrogen. A functional study using isolated ileal segments showed that ERα, ERβ and GPR30 are involved in the neuronal-mediated contractions in female tissues, but only ERα was involved in male tissues. This may indicate although expression level was similar between males and females, the downstream mechanisms of ERβ and GPR30 could be different between sexes. The present study provides a rationale for the action of estrogen to modulate gastrointestinal function in health and disease in different sexes.
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Affiliation(s)
- Julia Y H Liu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region.
| | - Ge Lin
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region.
| | - Marong Fang
- Institute of Neurosciences, Zhejiang University School of Medicine, Hangzhou, PR China.
| | - John A Rudd
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region; Brain and Mind Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong Special Administrative Region.
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16
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Della Torre S, Rando G, Meda C, Ciana P, Ottobrini L, Maggi A. Transcriptional activity of oestrogen receptors in the course of embryo development. J Endocrinol 2018; 238:165-176. [PMID: 30012715 PMCID: PMC6084787 DOI: 10.1530/joe-18-0003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 06/11/2018] [Indexed: 12/16/2022]
Abstract
Oestrogens are well-known proliferation and differentiation factors that play an essential role in the correct development of sex-related organs and behaviour in mammals. With the use of the ERE-Luc reporter mouse model, we show herein that throughout mouse development, oestrogen receptors (ERs) are active starting from day 12 post conception. Most interestingly, we show that prenatal luciferase expression in each organ is proportionally different in relation to the germ layer of the origin. The luciferase content is highest in ectoderm-derived organs (such as brain and skin) and is lowest in endoderm-derived organs (such as liver, lung, thymus and intestine). Consistent with the testosterone surge occurring in male mice at the end of pregnancy, in the first 2 days after birth, we observed a significant increase in the luciferase content in several organs, including the liver, bone, gonads and hindbrain. The results of the present study show a widespread transcriptional activity of ERs in developing embryos, pointing to the potential contribution of these receptors in the development of non-reproductive as well as reproductive organs. Consequently, the findings reported here might be relevant in explaining the significant differences in male and female physiopathology reported by a growing number of studies and may underline the necessity for more systematic analyses aimed at the identification of the prenatal effects of drugs interfering with ER signalling, such as aromatase inhibitors or endocrine disrupter chemicals.
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Affiliation(s)
- Sara Della Torre
- Center of Excellence on Neurodegenerative DiseasesUniversity of Milan, Milan, Italy
- Department of Pharmacological and Biomolecular SciencesUniversity of Milan, Milan, Italy
| | - Gianpaolo Rando
- Center of Excellence on Neurodegenerative DiseasesUniversity of Milan, Milan, Italy
- Department of Pharmacological and Biomolecular SciencesUniversity of Milan, Milan, Italy
| | - Clara Meda
- Center of Excellence on Neurodegenerative DiseasesUniversity of Milan, Milan, Italy
- Department of Pharmacological and Biomolecular SciencesUniversity of Milan, Milan, Italy
| | - Paolo Ciana
- Department of Oncology and Hemato-OncologyUniversity of Milan, Milan, Italy
| | - Luisa Ottobrini
- Department of Pathophysiology and TransplantationUniversity of Milan, Milan, Italy
| | - Adriana Maggi
- Center of Excellence on Neurodegenerative DiseasesUniversity of Milan, Milan, Italy
- Department of Pharmacological and Biomolecular SciencesUniversity of Milan, Milan, Italy
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17
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Szymanska K, Gonkowski S. Bisphenol A—Induced changes in the enteric nervous system of the porcine duodenum. Neurotoxicology 2018; 66:78-86. [DOI: 10.1016/j.neuro.2018.03.008] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 03/06/2018] [Accepted: 03/19/2018] [Indexed: 12/11/2022]
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18
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Rao M, Rastelli D, Dong L, Chiu S, Setlik W, Gershon MD, Corfas G. Enteric Glia Regulate Gastrointestinal Motility but Are Not Required for Maintenance of the Epithelium in Mice. Gastroenterology 2017; 153:1068-1081.e7. [PMID: 28711628 PMCID: PMC5623141 DOI: 10.1053/j.gastro.2017.07.002] [Citation(s) in RCA: 137] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Revised: 06/30/2017] [Accepted: 07/04/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS When the glial fibrillary acidic protein (GFAP) promoter is used to express cellular toxins that eliminate glia in mice, intestinal epithelial permeability and proliferation increase; this led to the concept that glia are required for maintenance of the gastrointestinal epithelium. Many enteric glia, however, particularly in the mucosa, do not express GFAP. In contrast, virtually all enteric glia express proteolipid protein 1 (PLP1). We investigated whether elimination of PLP1-expressing cells compromises epithelial maintenance or gastrointestinal motility. METHODS We generated mice that express tamoxifen-inducible Cre recombinase under control of the Plp1 promoter and carry the diptheria toxin subunit A (DTA) transgene in the Rosa26 locus (Plp1CreER;Rosa26DTA mice). In these mice, PLP1-expressing glia are selectively eliminated without affecting neighboring cells. We measured epithelial barrier function and gastrointestinal motility in these mice and littermate controls, and analyzed epithelial cell proliferation and ultrastructure from their intestinal tissues. To compare our findings with those from previous studies, we also eliminated glia with ganciclovir in GfapHSV-TK mice. RESULTS Expression of DTA in PLP1-expressing cells selectively eliminated enteric glia from the small and large intestines, but caused no defects in epithelial proliferation, barrier integrity, or ultrastructure. In contrast, administration of ganciclovir to GfapHSV-TK mice eliminated fewer glia but caused considerable non-glial toxicity and epithelial cell death. Elimination of PLP1-expressing cells did not reduce survival of neurons in the intestine, but altered gastrointestinal motility in female, but not male, mice. CONCLUSIONS Using the Plp1 promoter to selectively eliminate glia in mice, we found that enteric glia are not required for maintenance of the intestinal epithelium, but are required for regulation of intestinal motility in females. Previous observations supporting the concept that maintenance of the intestinal epithelium requires enteric glia can be attributed to non-glial toxicity in GfapHSV-TK mice and epithelial-cell expression of GFAP. Contrary to widespread notions, enteric glia are therefore not required for epithelial homeostasis. However, they regulate intestinal motility in a sex-dependent manner.
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Affiliation(s)
- Meenakshi Rao
- Department of Pediatrics, Columbia University Medical Center, New York, New York.
| | - Daniella Rastelli
- Department of Pediatrics, Columbia University Medical Center, New York, NY, USA
| | - Lauren Dong
- Department of Pediatrics, Columbia University Medical Center, New York, NY, USA
| | - Sophia Chiu
- Institute of Human Nutrition, Columbia University
| | - Wanda Setlik
- Department of Pathology and Cell Biology, Columbia University
| | | | - Gabriel Corfas
- Department of Otolaryngology-Head and Neck Surgery, Kresge Hearing Research Institute, Ann Arbor, MI, USA
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19
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Zielińska M, Fichna J, Bashashati M, Habibi S, Sibaev A, Timmermans JP, Storr M. G protein-coupled estrogen receptor and estrogen receptor ligands regulate colonic motility and visceral pain. Neurogastroenterol Motil 2017; 29. [PMID: 28191706 DOI: 10.1111/nmo.13025] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 11/21/2016] [Accepted: 12/08/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Diarrhea-predominant irritable bowel syndrome (IBS-D) is a functional gastrointestinal (GI) disorder, which occurs more frequently in women than men. The aim of our study was to determine the role of activation of classical estrogen receptors (ER) and novel membrane receptor, G protein-coupled estrogen receptor (GPER) in human and mouse tissue and to assess the possible cross talk between these receptors in the GI tract. METHODS Immunohistochemistry was used to determine the expression of GPER in human and mouse intestines. The effect of G-1, a GPER selective agonist, and estradiol, a non-selective ER agonist, on muscle contractility was characterized in isolated preparations of the human and mouse colon. To characterize the effect of G-1 and estradiol in vivo, colonic bead expulsion test was performed. G-1 and estradiol activity on the visceral pain signaling was assessed in the mustard oil-induced abdominal pain model. KEY RESULTS GPER is expressed in the human colon and in the mouse colon and ileum. G-1 and estradiol inhibited muscle contractility in vitro in human and mouse colon. G-1 or estradiol administered intravenously at the dose of 20 mg/kg significantly prolonged the time to bead expulsion in females. Moreover, G-1 prolonged the time to bead expulsion and inhibited GI hypermotility in both genders. The injection of G-1 or estradiol resulted in a significant reduction in the number of pain-induced behaviors in mice. CONCLUSIONS AND INFERENCES GPER and ER receptors are involved in the regulation of GI motility and visceral pain. Both may thus constitute an important pharmacological target in the IBS-D therapy.
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Affiliation(s)
- M Zielińska
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - J Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
| | - M Bashashati
- Division of Gastroenterology, Department of Internal Medicine, Texas Tech University Health Sciences Center/Paul L. Foster School of Medicine, El Paso, TX, USA.,Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - S Habibi
- Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
| | - A Sibaev
- Division of Gastroenterology, Department of Medicine, Ludwig Maximilians University of Munich, Munich, Germany
| | - J-P Timmermans
- Department of Veterinary Sciences, Laboratory of Cell Biology and Histology, University of Antwerp, Antwerp, Belgium
| | - M Storr
- Hotchkiss Brain Institute and Snyder Institute for Chronic Diseases, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.,Division of Gastroenterology, Department of Medicine, Ludwig Maximilians University of Munich, Munich, Germany.,Walter Brendel Center of Experimental Medicine, University of Munich, Munich, Germany
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20
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Mohibbi H, Qasimi MI, Nagaoka K, Watanabe G. Steroidogenic enzyme expression in estrogen production in the goat gastrointestinal (GI) tract and the effect of castration. J Vet Med Sci 2017; 79:1253-1260. [PMID: 28579582 PMCID: PMC5559373 DOI: 10.1292/jvms.17-0093] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Extragonadal tissues are known to produce estrogens. At these sites, the C19 precursor is important for aromatase expression for the production of estrogen. Aromatase expression is tissue-specific and is controlled by hormones.
Recent studies have shown that rat gastric parietal cells expressed aromatase. Our first objective was to investigate steroidogenic enzyme expression in estrogen biosynthesis; the second objective was to investigate which site(s)
of the GI tract expressed steroidogenic enzymes; and the third objective was to assess the effects of castration on steroidogenic enzyme expression. CYP19A1, 17β-HSD3, CYP17A1,
3β-HSD and P450scc were quantified in the GI tract by real-time PCR. CYP19A1 was detected mainly in the body and pyloric regions of the abomasum, while we detected weak
expression of CYP19A1 in other parts of GI tract. In addition, the expression of 17β-HSD3 and CYP17A1 was detected in abomasum. 3β-HSD expression was observed in
duodenum and jejunum, while P450scc was not detectable in any part of GI tract. Immunohistochemical results showed immunolocalization of aromatase in parietal cells. Aromatase expression was observed to increase
after castration. Furthermore, immunohistochemical results demonstrated that parietal cells also produced luteinizing hormone receptor (LHR). These results indicate steroidogenic enzymes required for the biosynthesis of estrogen
were expressed, and the abomasum appeared to be the responsible organ for estrogen biosynthesis in the goat GI tract. In addition, parietal cells were responsible for estrogen production and the expression of LHR. Castration
increased aromatase expression in abomasum through LH mediation.
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Affiliation(s)
- Hadi Mohibbi
- Department of Basic Veterinary Science, The United Graduated School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan.,Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
| | - Mohammad Ibrahim Qasimi
- Department of Basic Veterinary Science, The United Graduated School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan.,Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
| | - Kentaro Nagaoka
- Department of Basic Veterinary Science, The United Graduated School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan.,Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
| | - Gen Watanabe
- Department of Basic Veterinary Science, The United Graduated School of Veterinary Sciences, Gifu University, Gifu 501-1193, Japan.,Laboratory of Veterinary Physiology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo 183-8509, Japan
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21
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The Influence of Low Doses of Zearalenone and T-2 Toxin on Calcitonin Gene Related Peptide-Like Immunoreactive (CGRP-LI) Neurons in the ENS of the Porcine Descending Colon. Toxins (Basel) 2017; 9:toxins9030098. [PMID: 28287437 PMCID: PMC5371853 DOI: 10.3390/toxins9030098] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Revised: 03/02/2017] [Accepted: 03/07/2017] [Indexed: 12/25/2022] Open
Abstract
The enteric nervous system (ENS) can undergo adaptive and reparative changes in response to physiological and pathological stimuli. These manifest primarily as alterations in the levels of active substances expressed by the enteric neuron. While it is known that mycotoxins can affect the function of the central and peripheral nervous systems, knowledge about their influence on the ENS is limited. Therefore, the aim of the present study was to investigate the influence of low doses of zearalenone (ZEN) and T-2 toxin on calcitonin gene related peptide-like immunoreactive (CGRP-LI) neurons in the ENS of the porcine descending colon using a double immunofluorescence technique. Both mycotoxins led to an increase in the percentage of CGRP-LI neurons in all types of enteric plexuses and changed the degree of co-localization of CGRP with other neuronal active substances, such as substance P, galanin, nitric oxide synthase, and cocaine- and amphetamine-regulated transcript peptide. The obtained results demonstrate that even low doses of ZEN and T-2 can affect living organisms and cause changes in the neurochemical profile of enteric neurons.
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22
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Barakat R, Oakley O, Kim H, Jin J, Ko CJ. Extra-gonadal sites of estrogen biosynthesis and function. BMB Rep 2017; 49:488-96. [PMID: 27530684 PMCID: PMC5227141 DOI: 10.5483/bmbrep.2016.49.9.141] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Indexed: 12/23/2022] Open
Abstract
Estrogens are the key hormones regulating the development and function of reproductive organs in all vertebrates. Recent evidence indicates that estrogens play important roles in the immune system, cancer development, and other critical biological processes related to human well-being. Obviously, the gonads (ovary and testis) are the primary sites of estrogen synthesis, but estrogens synthesized in extra- gonadal sites play an equally important role in controlling biological activities. Understanding non-gonadal sites of estrogen synthesis and function is crucial and will lead to therapeutic interventions targeting estrogen signaling in disease prevention and treatment. Developing a rationale targeting strategy remains challenging because knowledge of extra-gonadal biosynthesis of estrogens, and the mechanism by which estrogen activity is exerted, is very limited. In this review, we will summarize recent discoveries of extra-gonadal sites of estrogen biosynthesis and their local functions and discuss the significance of the most recent novel discovery of intestinal estrogen biosynthesis. [BMB Reports 2016; 49(9): 488-496]
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Affiliation(s)
- Radwa Barakat
- Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Illinois 61802, Unites States; Department of Toxicology, Faculty of Veterinary Medicine, Benha University, Benha 13518, Egypt
| | - Oliver Oakley
- Department of Biology, College of Arts and Sciences, Eastern Kentucky University, Kentucky 40475, United States
| | - Heehyen Kim
- Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea
| | - Jooyoung Jin
- Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Korea
| | - CheMyong Jay Ko
- Department of Comparative Biosciences, University of Illinois at Urbana-Champaign, Illinois 61802, Unites States
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23
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Million M, Larauche M. Stress, sex, and the enteric nervous system. Neurogastroenterol Motil 2016; 28:1283-9. [PMID: 27561694 PMCID: PMC5003424 DOI: 10.1111/nmo.12937] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Accepted: 08/08/2016] [Indexed: 12/31/2022]
Abstract
Made up of millions of enteric neurons and glial cells, the enteric nervous system (ENS) is in a key position to modulate the secretomotor function and visceral pain of the gastrointestinal tract. The early life developmental period, through which most of the ENS development occurs, is highly susceptible to microenvironmental perturbation. Over the past decade, accumulating evidence has shown the impact of stress and early life adversity (ELA) on host gastrointestinal pathophysiology. While most of the focus has been on alterations in brain structure and function, limited experimental work in rodents suggest that the enteric nervous system can also be directly affected, as shown by changes in the number, phenotype, and reactivity of enteric nerves. The work of Medland et al. in the current issue of this journal demonstrates that such alterations also occur in pigs, a larger mammalian species with high translational value to human. This work also highlights a sex-differential susceptibility of the ENS to the effect of ELA, which could contribute to the higher prevalence of GI disorders in women. In this mini-review, we will discuss the development and composition of the ENS and related gastrointestinal sensory motor and secretory functions. We will then focus on the influence of stress on the enteric nervous system, with a particular emphasis on neurodevelopmental changes. Finally, we will discuss the influence of sex on those parameters.
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Affiliation(s)
- Mulugeta Million
- CURE: Digestive Diseases Research Center and Oppenheimer Family Center for Neurobiology of Stress and Resilience, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90025, USA
- VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
| | - Muriel Larauche
- CURE: Digestive Diseases Research Center and Oppenheimer Family Center for Neurobiology of Stress and Resilience, Department of Medicine, Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90025, USA
- VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
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24
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Wibowo E, Pollock PA, Hollis N, Wassersug RJ. Tamoxifen in men: a review of adverse events. Andrology 2016; 4:776-88. [DOI: 10.1111/andr.12197] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2015] [Revised: 03/09/2016] [Accepted: 03/12/2016] [Indexed: 12/16/2022]
Affiliation(s)
- E. Wibowo
- Vancouver Prostate Centre; Vancouver Coastal Health Research Institute; Vancouver BC Canada
| | - P. A. Pollock
- Vancouver Prostate Centre; Vancouver Coastal Health Research Institute; Vancouver BC Canada
| | - N. Hollis
- Solid Organ Transplant Clinic; Vancouver General Hospital; Vancouver BC Canada
| | - R. J. Wassersug
- Department of Urologic Sciences; University of British Columbia; Vancouver BC Canada
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25
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Pigrau M, Rodiño-Janeiro BK, Casado-Bedmar M, Lobo B, Vicario M, Santos J, Alonso-Cotoner C. The joint power of sex and stress to modulate brain-gut-microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome. Neurogastroenterol Motil 2016; 28:463-86. [PMID: 26556786 DOI: 10.1111/nmo.12717] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/05/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intestinal homeostasis is a dynamic process that takes place at the interface between the lumen and the mucosa of the gastrointestinal tract, where a constant scrutiny for antigens and toxins derived from food and microorganisms is carried out by the vast gut-associated immune system. Intestinal homeostasis is preserved by the ability of the mucus layer and the mucosal barrier to keep the passage of small-sized and antigenic molecules across the epithelium highly selective. When combined and preserved, immune surveillance and barrier's selective permeability, the host capacity of preventing the development of intestinal inflammation is optimized, and viceversa. In addition, the brain-gut-microbiome axis, a multidirectional communication system that integrates distant and local regulatory networks through neural, immunological, metabolic, and hormonal signaling pathways, also regulates intestinal function. Dysfunction of the brain-gut-microbiome axis may induce the loss of gut mucosal homeostasis, leading to uncontrolled permeation of toxins and immunogenic particles, increasing the risk of appearance of intestinal inflammation, mucosal damage, and gut disorders. Irritable bowel syndrome is prevalent stress-sensitive gastrointestinal disorder that shows a female predominance. Interestingly, the role of stress, sex and gonadal hormones in the regulation of intestinal mucosal and the brain-gut-microbiome axis functioning is being increasingly recognized. PURPOSE We aim to critically review the evidence linking sex, and stress to intestinal barrier and brain-gut-microbiome axis dysfunction and the implications for irritable bowel syndrome.
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Affiliation(s)
- M Pigrau
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON, Canada.,Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - B K Rodiño-Janeiro
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Casado-Bedmar
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - B Lobo
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Vicario
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - J Santos
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - C Alonso-Cotoner
- Laboratory of Neuro-immuno-gastroenterology, Digestive Diseases Research Unit. Vall d'Hebron Institut de Recerca, Department of Gastroenterology, Hospital Universitario Vall d'Hebron & Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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Cacioppo JA, Koo Y, Lin PCP, Osmulski SA, Ko CD, Ko C. Generation of an estrogen receptor beta-iCre knock-in mouse. Genesis 2016; 54:38-52. [PMID: 26663382 DOI: 10.1002/dvg.22911] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2015] [Revised: 11/30/2015] [Accepted: 12/02/2015] [Indexed: 02/06/2023]
Abstract
A novel knock-in mouse that expresses codon-improved Cre recombinase (iCre) under regulation of the estrogen receptor beta (Esr2) promoter was developed for conditional deletion of genes and for the spatial and/or temporal localization of Esr2 expression. ESR2 is one of two classical nuclear estrogen receptors and displays a spatiotemporal expression pattern and functions that are different from the other estrogen receptor, ESR1. A cassette was constructed that contained iCre, a polyadenylation sequence, and a neomycin selection marker. This construct was used to insert iCre in front of the endogenous start codon of the Esr2 gene of a C57BL/6J embryonic stem cell line via homologous recombination. Resulting Esr2-iCre mice were bred with ROSA26-lacZ and Ai9-RFP reporter mice to visualize cells of functional iCre expression. Strong expression was observed in the ovary, the pituitary, the interstitium of the testes, the head and tail but not body of the epididymis, skeletal muscle, the coagulation gland (anterior prostate), the lung, and the preputial gland. Additional diffuse or patchy expression was observed in the cerebrum, the hypothalamus, the heart, the adrenal gland, the colon, the bladder, and the pads of the paws. Overall, Esr2-iCre mice will serve as a novel line for conditionally ablating genes in Esr2-expressing tissues, identifying novel Esr2-expressing cells, and differentiating the functions of ESR2 and ESR1.
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Affiliation(s)
- Joseph A Cacioppo
- Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana-Champaign, Illinois, 61802
| | - Yongbum Koo
- Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana-Champaign, Illinois, 61802.,School of Biological Sciences, Inje University, Gimhae, South Korea
| | - Po-Ching Patrick Lin
- Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana-Champaign, Illinois, 61802
| | - Sarah A Osmulski
- Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana-Champaign, Illinois, 61802
| | - Chunjoo D Ko
- Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana-Champaign, Illinois, 61802
| | - CheMyong Ko
- Comparative Biosciences, College of Veterinary Medicine, University of Illinois, Urbana-Champaign, Illinois, 61802
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Sex Differences in Gastrointestinal Physiology and Diseases. SEX DIFFERENCES IN PHYSIOLOGY 2016. [DOI: 10.1016/b978-0-12-802388-4.00008-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Estrogen alleviates acetic acid-induced gastric or colonic damage via both ERα- and ERβ-mediated and direct antioxidant mechanisms in rats. Inflammation 2015; 37:694-705. [PMID: 24323397 DOI: 10.1007/s10753-013-9786-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
In order to demonstrate the possible protective effects of estrogen receptor (ER)-α and ERβ receptor subtypes in the pathogenesis of colonic and gastric oxidant damage, experimental ulcer and colitis were induced by acetic acid, and the animals were randomly divided as colitis, ulcer, and their corresponding non-ulcer and non-colitis control groups. Each group of rats was treated intramuscularly with the vehicle, selective ERα agonist propylpyrazole-triol (1 mg/kg), ERβ agonist diarylpropionitrile (1 mg/kg), non-selective ER agonist 17β estradiol (E2; 1 mg/kg), or E2 plus non-selective ER antagonist ICI-182780 (1 mg/kg). The results revealed that induction of ulcer or colitis resulted in systemic inflammation as assessed by increased levels of plasma TNF-α and IL-6 levels. In both tissues, the presence of oxidant damage was verified by histological analysis and elevated myleoperoxidase activity. In the colitis and ulcer groups, both ER agonists and the non-selective E2 reversed the oxidative damage in a similar manner. These findings indicate that estrogen acts via both ERα- and ERβ-mediated and direct antioxidant mechanisms, where both ER subtypes play equal and efficient roles in the anti-inflammatory action of estrogen, in limiting the migration of neutrophils to the inflamed tissue, reducing the release and activation of cytokines and thereby alleviating tissue damage.
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Gonkowski S, Obremski K, Calka J. The Influence of Low Doses of Zearalenone on Distribution of Selected Active Substances in Nerve Fibers Within the Circular Muscle Layer of Porcine Ileum. J Mol Neurosci 2015; 56:878-886. [PMID: 25772391 PMCID: PMC4529468 DOI: 10.1007/s12031-015-0537-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 02/27/2015] [Indexed: 11/30/2022]
Abstract
The aim of this study was to investigate, whether low doses (25 % of no observable adverse effect levels values) of zearalenone (ZEN) can affect the expression of active substances in nerve fibers in the muscular layer of porcine ileum. The study was performed on ten immature pigs divided into two groups: experimental group (n = 5), where zearalenone (10 μg/kg body weight) was given for 42 days, and control animals (n = 5), where placebo was administered. Fragments of ileum of all animals were processed for single-labelling immunofluorescence technique using the antibodies against vasoactive intestinal peptide, neuronal form of nitric oxide synthase, cocaine and amphetamine regulatory peptide, galanin, pituitary adenylate cyclase-activating peptide-27 and substance P. The number of nerve fibers immunoreactive to particular substances was evaluated by the counting of nerves per observation field (0.1 mm2). Low doses of zearalenone caused the clear changes in the expression of substances studied. The number of nerve fibers immunoreactive to the majority of substances increased in experimental animals. The exception was only galanin, the expression of which was less after administration of zearalenone. The obtained results for the first time show that even low doses of zearalenone can affect the nerve fibers in the digestive tract.
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Affiliation(s)
- Sławomir Gonkowski
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowski Str. 13, Olsztyn, 10-718 Poland
| | - Kazimierz Obremski
- Department of Veterinary Prevention and Feed Hygiene, Faculty of Veterinary Medicine, University of Warmia and Mazury in Olsztyn, Oczapowski Str. 13, 10-718 Olsztyn, Poland
| | - Jaroslaw Calka
- Department of Clinical Physiology, Faculty of Veterinary Medicine, University of Warmia and Mazury, Oczapowski Str. 13, Olsztyn, 10-718 Poland
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Sand E, Roth B, Weström B, Bonn P, Ekblad E, Ohlsson B. Structural and functional consequences of buserelin-induced enteric neuropathy in rat. BMC Gastroenterol 2014; 14:209. [PMID: 25496312 PMCID: PMC4275936 DOI: 10.1186/s12876-014-0209-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2014] [Accepted: 11/28/2014] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Women treated with gonadotropin-releasing hormone (GnRH) analogs may develop enteric neuropathy and dysmotility. Administration of a GnRH analog to rats leads to similar degenerative neuropathy and ganglioneuritis. The aim of this study on rat was to evaluate the early GnRH-induced enteric neuropathy in terms of distribution of neuronal subpopulations and gastrointestinal (GI) function. METHODS Forty rats were given the GnRH analog buserelin (20 μg, 1 mg/ml) or saline subcutaneously, once daily for 5 days, followed by 3 weeks of recovery, representing one treatment session. Two weeks after the fourth treatment session, the animals were tested for GI transit time and galactose absorption, and fecal weight and fat content was analyzed. After sacrifice, enteric neuronal subpopulations were analyzed. Blood samples were analyzed for zonulin and antibodies against GnRH and luteinizing hormone, and their receptors. RESULTS Buserelin treatment transiently increased the body weight after 5 and 9 weeks (p < 0.001). Increased estradiol in plasma and thickened uterine muscle layers indicate high estrogen activity. The numbers of both submucous and myenteric neurons were reduced by 27%-61% in ileum and colon. The relative numbers of neurons containing calcitonin gene-related peptide (CGRP), cocaine- and amphetamine-related transcript (CART), galanin, gastrin-releasing peptide (GRP), neuropeptide Y (NPY), nitric oxide synthase (NOS), serotonin, substance P (SP), vasoactive intestinal peptide (VIP) or vesicular acetylcholine transporter (VAchT), and their nerve fiber density, were unchanged after buserelin treatment, but the relative number of submucous neurons containing somatostatin tended to be increased (p = 0.062). The feces weight decreased in buserelin-treated rats (p < 0.01), whereas feces fat content increased (p < 0.05), compared to control rats. Total GI transit time, galactose absorption, zonulin levels in plasma, and antibody titers in serum were unaffected by buserelin treatment. CONCLUSIONS A marked enteric neuronal loss with modest effects on GI function is found after buserelin treatment. Increased feces fat content is suggested an early sign of dysfunction.
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Affiliation(s)
- Elin Sand
- Department of Clinical Sciences, Division of Internal Medicine Skåne University Hospital, Lund University, Inga Marie Nilssons street 32, S-205 02, Malmö, Sweden. .,Department of Experimental Medical Science, Neurogastroenterology Unit, BMC B11, Lund University, 221 84, Lund, Sweden.
| | - Bodil Roth
- Department of Clinical Sciences, Division of Internal Medicine Skåne University Hospital, Lund University, Inga Marie Nilssons street 32, S-205 02, Malmö, Sweden.
| | - Björn Weström
- Department of Biology, Functional Biology, Lund University, 221 00, Lund, Sweden.
| | - Peter Bonn
- Department of Medicinal Chemistry, CVMD, AstraZeneca, Mölndal, Sweden.
| | - Eva Ekblad
- Department of Experimental Medical Science, Neurogastroenterology Unit, BMC B11, Lund University, 221 84, Lund, Sweden.
| | - Bodil Ohlsson
- Department of Clinical Sciences, Division of Internal Medicine Skåne University Hospital, Lund University, Inga Marie Nilssons street 32, S-205 02, Malmö, Sweden.
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Meleine M, Matricon J. Gender-related differences in irritable bowel syndrome: Potential mechanisms of sex hormones. World J Gastroenterol 2014; 20:6725-6743. [PMID: 24944465 PMCID: PMC4051914 DOI: 10.3748/wjg.v20.i22.6725] [Citation(s) in RCA: 148] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 02/08/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
According to epidemiological studies, twice as many women as men are affected by irritable bowel syndrome (IBS) in western countries, suggesting a role for sex hormones in IBS pathophysiology. Despite growing evidence about the implications of sex hormones in IBS symptom modulation, data on mechanisms by which they influence disease development are sparse. This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS. The scientific bibliography was searched using the following keywords: irritable bowel syndrome, sex, gender, ovarian hormone, estradiol, progesterone, testosterone, symptoms, pain, sensitivity, motility, permeability, stress, immune system, brain activity, spinal, supraspinal, imaging. Ovarian hormones variations along the menstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations. They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception. These hormones can also modulate the susceptibility to stress, which is a pivotal factor in IBS occurrence and symptom severity. For instance, estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function. In conclusion, whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS, they arguably modulate IBS onset and symptomatology. However, our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender. Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS. Finally, investigation of brain-gut interactions is critical to decipher how stress, ovarian hormones, and female brain processing of pain can translate into gut dysfunctions.
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Moon CM, Kim SH, Lee SK, Hyeon J, Koo JS, Lee S, Wang JS, Huh WJ, Khurana SS, Mills JC. Chronic tamoxifen use is associated with a decreased risk of intestinal metaplasia in human gastric epithelium. Dig Dis Sci 2014; 59:1244-1254. [PMID: 24368421 PMCID: PMC4035390 DOI: 10.1007/s10620-013-2994-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2013] [Accepted: 12/10/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Intestinal metaplasia (IM), a premalignant lesion, is associated with an increased risk of gastric cancer. Although estrogen exposure, including tamoxifen, has been studied in correlation with gastric cancer, little has been investigated about its effects on IM. AIMS Therefore, we investigated whether chronic tamoxifen use was associated with the risk of IM in human stomach. METHODS We evaluated 512 gastric biopsies from 433 female breast cancer patients that underwent endoscopic gastroduodenoscopy (EGD) ≥6 months after breast surgery. Histopathological findings were scored according to the updated Sydney classification. Demographic and clinical characteristics were also included to identify predictive factors for IM. RESULTS In a multivariate logistic regression analysis, age at EGD (odds ratio [OR], 1.04; P = 0.002), biopsies from antrum (OR 2.08; P < 0.001), and Helicobacter pylori positivity (OR 1.68; P = 0.016) were significantly associated with an increased risk of IM, whereas chronic tamoxifen use (≥3 months) was associated with a decreased risk of IM (OR 0.59; P = 0.025). After stratifying by biopsy site, association between tamoxifen use and IM persisted for corpus (OR 0.42; P = 0.026) but not for antrum (OR 0.74; P = 0.327). In analysis limited to patients with follow-up EGD, chronic tamoxifen use also correlated with improved IM score compared to no tamoxifen use (improved, 77.8 vs. 22.2%; no change, 65.4 vs. 34.6%; worsened, 30.0 vs. 70.0%; P = 0.019). CONCLUSIONS This study suggests that chronic tamoxifen use can decrease the risk of IM in human stomach. The effect of tamoxifen is predominantly observed in the corpus.
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Affiliation(s)
- Chang Mo Moon
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108, Pyung-Dong, Jongro-gu, Seoul, Republic of Korea 110-746
- Division of Gastroenterology, Departments of Medicine, Developmental Biology, and Pathology & Immunology, Washington University School of Medicine, Campus Box 8124, 660 South Euclid Ave. St. Louis, Missouri 63110
| | - Seok-Hyung Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul, Republic of Korea 135-710
| | - Sang Kil Lee
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea 120-752
| | - Jiyeon Hyeon
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-gu, Seoul, Republic of Korea 135-710
| | - Ja Seung Koo
- Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea 120-752
| | - Sangheun Lee
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, Republic of Korea 120-752
| | - Jean S. Wang
- Division of Gastroenterology, Departments of Medicine, Washington University School of Medicine, Campus Box 8124, 660 South Euclid Ave. St. Louis, Missouri 63110
| | - Won Jae Huh
- Division of Gastroenterology, Departments of Medicine, Developmental Biology, and Pathology & Immunology, Washington University School of Medicine, Campus Box 8124, 660 South Euclid Ave. St. Louis, Missouri 63110
| | - Shradha S. Khurana
- Division of Gastroenterology, Departments of Medicine, Developmental Biology, and Pathology & Immunology, Washington University School of Medicine, Campus Box 8124, 660 South Euclid Ave. St. Louis, Missouri 63110
| | - Jason C. Mills
- Division of Gastroenterology, Departments of Medicine, Developmental Biology, and Pathology & Immunology, Washington University School of Medicine, Campus Box 8124, 660 South Euclid Ave. St. Louis, Missouri 63110
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Yan XJ, Feng CC, Liu Q, Zhang LY, Dong X, Liu ZL, Cao ZJ, Mo JZ, Li Y, Fang JY, Chen SL. Vagal Afferents Mediate Antinociception of Estrogen in a Rat Model of Visceral Pain: The Involvement of Intestinal Mucosal Mast Cells and 5-Hydroxytryptamine 3 Signaling. THE JOURNAL OF PAIN 2014; 15:204-17. [DOI: 10.1016/j.jpain.2013.10.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2013] [Revised: 09/14/2013] [Accepted: 10/31/2013] [Indexed: 12/19/2022]
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Hara A, Sasazuki S, Inoue M, Miura T, Iwasaki M, Sawada N, Shimazu T, Yamaji T, Tsugane S. Plasma isoflavone concentrations are not associated with gastric cancer risk among Japanese men and women. J Nutr 2013; 143:1293-8. [PMID: 23761654 DOI: 10.3945/jn.113.175505] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The incidence of gastric cancer throughout the world is ~2-3 times higher in men than in women. Previous research suggested that isoflavones, which are structurally similar to 17β-estradiol, may prevent gastric cancer. Based on a large, population-based, prospective study, we recently reported a null association between dietary isoflavone intake and gastric cancer. However, epidemiologic studies using blood concentrations of isoflavones might better reflect the effect of isoflavones on gastric cancer carcinogenesis than dietary assessment. We therefore conducted a nested case-control study within the Japan Public Health Center-Based Prospective Study. Participants were followed-up from 1990 to 2004. Among 36,745 participants who answered the baseline questionnaire and provided blood samples, 483 gastric cancer cases matched to 483 controls were used in the analysis. ORs and 95% CIs were estimated with a conditional logistic regression model. The overall distribution of plasma isoflavone concentrations was not associated with the development of gastric cancer. Compared with groups with the lowest plasma concentrations (reference groups), the groups with the highest daidzein and genistein concentrations had adjusted ORs and 95% CIs of 1.11 (0.74-1.66; P-trend = 0.6) and 0.96 (0.64-1.44; P-trend = 0.9), respectively. The results did not change when analysis was based on sex, subsite, or histological type. We found no association of plasma isoflavone concentrations with gastric cancer risk. Our data support the previously observed null association between isoflavone intake and gastric cancer risk.
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Affiliation(s)
- Azusa Hara
- Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
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Jannot AS, Pelet A, Henrion-Caude A, Chaoui A, Masse-Morel M, Arnold S, Sanlaville D, Ceccherini I, Borrego S, Hofstra RMW, Munnich A, Bondurand N, Chakravarti A, Clerget-Darpoux F, Amiel J, Lyonnet S. Chromosome 21 scan in Down syndrome reveals DSCAM as a predisposing locus in Hirschsprung disease. PLoS One 2013; 8:e62519. [PMID: 23671607 PMCID: PMC3646051 DOI: 10.1371/journal.pone.0062519] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Accepted: 03/20/2013] [Indexed: 12/19/2022] Open
Abstract
Hirschsprung disease (HSCR) genetics is a paradigm for the study and understanding of multigenic disorders. Association between Down syndrome and HSCR suggests that genetic factors that predispose to HSCR map to chromosome 21. To identify these additional factors, we performed a dose-dependent association study on chromosome 21 in Down syndrome patients with HSCR. Assessing 10,895 SNPs in 26 Caucasian cases and their parents led to identify two associated SNPs (rs2837770 and rs8134673) at chromosome-wide level. Those SNPs, which were located in intron 3 of the DSCAM gene within a 19 kb-linkage disequilibrium block region were in complete association and are consistent with DSCAM expression during enteric nervous system development. We replicated the association of HSCR with this region in an independent sample of 220 non-syndromic HSCR Caucasian patients and their parents. At last, we provide the functional rationale to the involvement of DSCAM by network analysis and assessment of SOX10 regulation. Our results reveal the involvement of DSCAM as a HSCR susceptibility locus, both in Down syndrome and HSCR isolated cases. This study further ascertains the chromosome-scan dose-dependent methodology used herein as a mean to map the genetic bases of other sub-phenotypes both in Down syndrome and other aneuploidies.
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Affiliation(s)
- Anne-Sophie Jannot
- INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France
- Département de Génétique, Université Paris Descartes, Faculté de Médecine, Paris, France
| | - Anna Pelet
- INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France
- Département de Génétique, Université Paris Descartes, Faculté de Médecine, Paris, France
| | - Alexandra Henrion-Caude
- INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France
- Département de Génétique, Université Paris Descartes, Faculté de Médecine, Paris, France
| | | | - Marine Masse-Morel
- INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France
- Département de Génétique, Université Paris Descartes, Faculté de Médecine, Paris, France
| | - Stacey Arnold
- Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Damien Sanlaville
- HCL, Service de génétique, Bron, France
- INSERM U-1028, CNRS UMR5292, Université Claude Bernard Lyon 1, Equipe TIGER, Lyon, France
| | | | - Salud Borrego
- Unidad de Gestión Clínica de Genética, Reproducción y Medicina Fetal, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- CIBER de Enfermedades Raras, ISCIII, Sevilla, Spain
| | - Robert M. W. Hofstra
- Department of Clinical Genetics, ErasmusMC, University of Rotterdam, Rotterdam, The Netherlands
| | - Arnold Munnich
- INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France
- Département de Génétique, Université Paris Descartes, Faculté de Médecine, Paris, France
| | | | - Aravinda Chakravarti
- Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Françoise Clerget-Darpoux
- INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France
- Département de Génétique, Université Paris Descartes, Faculté de Médecine, Paris, France
| | - Jeanne Amiel
- INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France
- Département de Génétique, Université Paris Descartes, Faculté de Médecine, Paris, France
| | - Stanislas Lyonnet
- INSERM U-781, AP-HP Hôpital Necker-Enfants Malades, Paris, France
- Département de Génétique, Université Paris Descartes, Faculté de Médecine, Paris, France
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Ryu WS, Kim JH, Jang YJ, Park SS, Um JW, Park SH, Kim SJ, Mok YJ, Kim CS. Expression of estrogen receptors in gastric cancer and their clinical significance. J Surg Oncol 2012; 106:456-61. [PMID: 22422271 DOI: 10.1002/jso.23097] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Accepted: 02/21/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUNDS AND OBJECTIVES The male predominance of gastric cancer suggests that female sex hormones may have a protective effect against gastric cancer. We evaluated the expression of estrogen receptors in gastric cancer tissue and cells and the clinical significance of ER-β expression in gastric cancer. METHOD ER-α, ER-β proteins extracted from normal stomach, gastric cancer tissues, and cultured gastric cancer cells (KATO-III, mkn28, mkn45, and mkn74) were assessed by Western blot analysis. The clinical significance of ER-β was explored using tissue microarray methods and immunohistochemical staining of specimens from 148 gastric cancers. RESULTS Both ER-α and β protein expression were noted in normal and gastric cancer tissues. However, in cultured gastric cells, only ER-β was noted in mkn28 and mkn74. Of 148 gastric cancers, 67 (45.3%) were ER-β positive. The ER-β positive group was associated with lower tumor stage, Lauren's intestinal type, negative perineural invasion, and free of recurrence. The ER-β positive group had a better 3-year survival compared with the negative group in survival analysis. CONCLUSION Our results suggest that the presence of ER-β in gastric cancer could have a protective effect against invasiveness of gastric cancer. Further studies are needed to clarify the role of ER-β in gastric cancers.
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Affiliation(s)
- Woo-Sang Ryu
- Department of Surgery, Korea University College of Medicine, Seoul, Korea
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Minimizing the cancer-promotional activity of cox-2 as a central strategy in cancer prevention. Med Hypotheses 2012; 78:45-57. [DOI: 10.1016/j.mehy.2011.09.039] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Accepted: 09/19/2011] [Indexed: 02/06/2023]
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Moghanibashi M, Mohamadynejad P, Rasekhi M, Ghaderi A, Mohammadianpanah M. Polymorphism of estrogen response element in TFF1 gene promoter is associated with an increased susceptibility to gastric cancer. Gene 2012; 492:100-3. [DOI: 10.1016/j.gene.2011.10.048] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Revised: 10/25/2011] [Accepted: 10/27/2011] [Indexed: 12/12/2022]
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Risk of fracture and pneumonia from acid suppressive drugs. World J Methodol 2011; 1:15-21. [PMID: 25237609 PMCID: PMC4145558 DOI: 10.5662/wjm.v1.i1.15] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2011] [Revised: 09/08/2011] [Accepted: 09/19/2011] [Indexed: 02/06/2023] Open
Abstract
A recently published systematic review and meta-analysis, incorporating all relevant studies on the association of acid suppressive medications and pneumonia identified up to August 2009, revealed that for every 200 patients, treated with acid suppressive medication, one will develop pneumonia. They showed the overall risk of pneumonia was higher among people using proton pump inhibitors (PPIs) [adjusted odds ratio (OR) = 1.27, 95% CI: 1.11-1.46, I2 = 90.5%] and Histamine-2 receptor antagonists (H2RAs) (adjusted OR = 1.22, 95% CI: 1.09-1.36, I2 = 0.0%). In the randomized controlled trials, use of H2RAs was associated with an elevated risk of hospital-acquired pneumonia (relative risk 1.22, 95% CI: 1.01-1.48, I2 = 30.6%). Another meta-analysis of 11 studies published between 1997 and 2011 found that PPIs, which reduce stomach acid production, were associated with increased risk of fracture. The pooled OR for fracture was 1.29 (95% CI: 1.18-1.41) with use of PPIs and 1.10 (95% CI: 0.99-1.23) with use of H2RAs, when compared with non-use of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30, 95% CI: 1.15-1.48) and of hip fracture risk (adjusted OR = 1.34, 95% CI: 1.09-1.66), whereas long-term H2RA use was not significantly associated with fracture risk. Clinicians should carefully consider when deciding to prescribe acid-suppressive drugs, especially for patients who are already at risk for pneumonia and fracture. Since it is unnecessary to achieve an achlorhydric state in order to resolve symptoms, we recommend using the only minimum effective dose of drug required to achieve the desired therapeutic goals.
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Motohashi M, Wakui S, Muto T, Suzuki Y, Shirai M, Takahashi H, Hano H. Cyclin D1/cdk4, estrogen receptors α and β, in N-methyl-N'-nitro-N-nitrosoguanidine-induced rat gastric carcinogenesis: immunohistochemical study. J Toxicol Sci 2011; 36:373-8. [PMID: 21628965 DOI: 10.2131/jts.36.373] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Hyperproliferative cell growth due to cyclin D1/cdk4, marker of cellular proliferation, is considered to be regulated by the expression of estrogen receptors (ERs). We investigated the immunohistochemical expression of cyclin D1/cdk4 and ERs in N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced rat gastric carcinogenesis. The gastric cancer incidence and expression of cyclin D1/ckd4 in gastric carcinogenesis were significantly higher in males than females. Although the ERα expression index was similar in both sexes, the ERβ expression in preneoplastic hyperplastic lesions as well as gastric cancers was significantly higher in females than in males. The present study revealed a gender difference in MNNG-induced rat gastric carcinogenesis that seemed to involve the sex difference in cyclin D1/cdk4 expression, and ERβ expression became evident at the preneoplastic promotion stage in gastric carcinogenesis.
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Affiliation(s)
- Masaya Motohashi
- Department of Toxicology and Biochemistry, Azabu University School of Veterinary Medicine, 1-17-71 Fuchinobe, Sagamihara, Cyuo, Kanagawa 252-5201, Japan
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41
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Repaci A, Gambineri A, Pagotto U, Pasquali R. Ghrelin and reproductive disorders. Mol Cell Endocrinol 2011; 340:70-9. [PMID: 21453749 DOI: 10.1016/j.mce.2011.02.022] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Revised: 02/26/2011] [Accepted: 02/26/2011] [Indexed: 12/13/2022]
Abstract
Ghrelin is an important factor involved in most of the metabolic and hormonal signals which adapt the reproductive functions in conditions of altered energy balance. Moreover, the coordinated role of leptin and ghrelin appears in fact to have a specific role in the regulation of puberty. Systemic action of ghrelin on the reproductive axis involves the control of the hypothalamic-pituitary-gondal axis. In addition, it has been shown that ghrelin may directly act at a gonadal level in both females and males. Available data also demonstrate that sex steroid hormones and gonadotropins may in turn regulate the gonadal effect of ghrelin, as documented by studies performed in females with the polycystic ovary syndrome and in hypogonadal men. Notably, recent studies also confirm a potentially important role for ghrelin in fetal and neonatal energy balance, and specifically in allowing fetal adaptation to an adverse intrauterine environment.
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Affiliation(s)
- Andrea Repaci
- St. Orsola-Malpighi Hospital, University Alma Mater Studiorum, Bologna, Italy
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42
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Eom CS, Park SM, Myung SK, Yun JM, Ahn JS. Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med 2011; 9:257-67. [PMID: 21555754 PMCID: PMC3090435 DOI: 10.1370/afm.1243] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
PURPOSE Previous studies have reported inconsistent findings regarding the association between the use of acid-suppressive drugs such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H(2)RAs) and fracture risk. We investigated this association using meta-analysis. METHODS We searched MEDLINE (PubMed), EMBASE, and the Cochrane Library from inception through December 2010 using common key words. We included case-control, nested case-control, and cohort studies. Two evaluators independently reviewed and selected articles. We determined pooled effect estimates by using random-effects meta-analysis, because of heterogeneity. RESULTS Of 1,809 articles meeting our initial inclusion criteria, 5 case-control studies, 3 nested case-control studies, and 3 cohort studies were included in the final analyses. The pooled odds ratio (OR) for fracture was 1.29 (95% confidence interval [CI], 1.18-1.41) with use of PPIs and 1.10 (95% CI, 0.99-1.23) with use of H(2)RAs when compared with nonuse of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30; 95% CI, 1.15-1.48) and hip fracture risk (adjusted OR = 1.34; 95% CI, 1.09-1.66), whereas long-term H(2)RA use was not significantly associated with fracture risk. CONCLUSIONS We found possible evidence linking PPI use to an increased risk of fracture, but no association between H(2)RA use and fracture risk. Widespread use of PPIs with the potential risk of fracture is of great importance to public health. Clinicians should carefully consider their decision to prescribe PPIs for patients already having an elevated risk of fracture because of age or other factors.
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Affiliation(s)
- Chun-Sick Eom
- Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
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Araújo AP, Costa BM, Pinto-Correia AL, Fragoso M, Ferreira P, Dinis-Ribeiro M, Costa S, Reis RM, Medeiros R. Association between EGF +61A/G polymorphism and gastric cancer in Caucasians. World J Gastroenterol 2011; 17:488-92. [PMID: 21274378 PMCID: PMC3027015 DOI: 10.3748/wjg.v17.i4.488] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2010] [Revised: 04/30/2010] [Accepted: 05/07/2010] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between epidermal growth factor (EGF) +61A/G polymorphism and susceptibility to gastric cancer, through a cross-sectional study.
METHODS: Polymerase chain reaction resctriction fragment lenght polymorphism analyses were used to genotype EGF +61 in 207 patients with gastric lesions (162 patients with gastric adenocarcinomas, 45 with atrophy or intestinal metaplasia) and 984 controls. All subjects were Caucasian.
RESULTS: Genotype distribution was 23.5% for GG and 76.5% for GA/AA in the control group, 18.4% for GG and 68.6% for GA/AA in the entire group with gastric lesions and 17.9% for GG and 82.1% for GA/AA in the group with gastric adenocarcinoma. No statistically significant associations were found between EGF +61 variants and risk for developing gastric cancer [odds ratios (OR) = 1.41, 95% confidence intervals (CI): 0.90-2.21, P = 0.116]. However, the stratification of individuals by gender revealed that males carrying A alleles (EGF +61A/G or AA) had an increased risk for developing gastric cancer as compared to GG homozygous males (OR = 1.55, 95% CI: 1.05-2.28, P = 0.021).
CONCLUSION: In summary, we found that males who were A carriers for EGF +61 had an increased risk for developing gastric cancer. This result may be explained by the suggestion that women secrete less gastric acid than men.
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Giroux V, Bernatchez G, Carrier JC. Chemopreventive effect of ERβ-Selective agonist on intestinal tumorigenesis in Apc(Min/+) mice. Mol Carcinog 2010; 50:359-69. [PMID: 21480389 DOI: 10.1002/mc.20719] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Revised: 11/02/2010] [Accepted: 11/03/2010] [Indexed: 12/17/2022]
Abstract
Epidemiological and experimental evidence suggests that estrogen replacement therapy reduces the risk of colon cancer in postmenopausal women. Estrogen receptor beta (ERβ) is thought to be the principal mediator of the estrogen effect in the colon. Recent studies by our team suggested positive regulation of the transforming growth factor (TGF)β pathway by estrogen in mice colonocytes. We therefore wanted to investigate the effects of ERβ agonist treatment on intestinal tumorigenesis in Apc(Min/+) mice. Weaned Apc(Min/+) mice were injected subcutaneously three times a week for 12 wk with vehicle or ERβ-selective agonist, diarylpropionitrile (DPN, 5 mg/kg). DPN administration resulted in a significant reduction in small intestinal polyp multiplicity in both Apc(Min/+) male and female mice. Furthermore, the mean diameter of small intestinal polyps was lower in DPN-treated than vehicle-treated males, along with lower BrdU incorporation indices in jejunal and colon epithelial cells of both sexes. DPN treatment also increased apoptosis in colon epithelium as measured by TUNEL assay and cleaved caspase 3 quantification. The effect of DPN on various components of the TGFβ pathway was also studied in colonocytes. DPN treatment increased expression of TGFβ1 and TGFβ3 transcripts, levels of nuclear and phosphorylated Smad2 as well as p27 cell-cycle inhibitor, a TGFβ pathway target gene. Our results demonstrate that DPN treatment reduces intestinal tumorigenesis in Apc(Min/+) mice. Furthermore, we suggest that positive regulation of the TGFβ pathway by ERβ activation could contribute to the protective role of estrogen in intestinal tumor development.
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Affiliation(s)
- Véronique Giroux
- Faculty of Medicine and Health Sciences, Department of Medicine and Anatomy and Cellular Biology, CIHR Team on Digestive Epithelium, Université de Sherbrooke, Sherbrooke, Québec, Canada
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Al-Massadi O, Crujeiras AB, González RC, Pardo M, Diéguez C, Casanueva FF, Seoane LM. Age, sex, and lactating status regulate ghrelin secretion and GOAT mRNA levels from isolated rat stomach. Am J Physiol Endocrinol Metab 2010; 299:E341-50. [PMID: 20501877 DOI: 10.1152/ajpendo.00057.2010] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Ghrelin is a stomach derivate peptide involved in energy homeostasis regulation, and ghrelin O-acyltransferase (GOAT) is the enzyme responsible for ghrelin acylation. Puberty is a period characterized by profound changes in the metabolic requirements and notable variations of sexual hormone levels. On the other hand, the weaning process is a fundamental modification of the diet, which implicates several adaptations of the gastrointestinal tract physiology. Until now the direct secretion of ghrelin by the stomach in these conditions, without interferences from other organs, has never been studied. The main objective of this article was to investigate how the stomach modulates ghrelin production and secretion as well as GOAT expression on these periods of life. Gastric ghrelin secretion is regulated through postnatal life in an independent way of gastric expression and circulating levels of this hormone. The present work shows a strong regulation of gastric ghrelin secretion by estrogens. The weaning strongly regulates gastric ghrelin secretion. Animals subjected to delayed weaning present a lower body weight than the corresponding controls. For the first time, it is shown that a noticeable decrease in circulating levels of testosterone and estrogens is associated with delay of weaning. GOAT mRNA levels in the stomach are strongly regulated by age, breastfeeding, and testosterone. In conclusion, the stomach itself regulates ghrelin and GOAT production to adapt the organism to the metabolic requirements demanded through each stage of life.
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Affiliation(s)
- O Al-Massadi
- Instituto de Investigaciones Sanitarias de Santiago, Complejo Hospitalario Universitario de Santiago, Spain
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Svejda B, Kidd M, Giovinazzo F, Eltawil K, Gustafsson BI, Pfragner R, Modlin IM. The 5-HT2B receptor plays a key regulatory role in both neuroendocrine tumor cell proliferation and the modulation of the fibroblast component of the neoplastic microenvironment. Cancer 2010; 116:2902-12. [DOI: 10.1002/cncr.25049] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Isse K, Specht SM, Lunz JG, Kang LI, Mizuguchi Y, Demetris AJ. Estrogen stimulates female biliary epithelial cell interleukin-6 expression in mice and humans. Hepatology 2010; 51:869-80. [PMID: 20043322 DOI: 10.1002/hep.23386] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
UNLABELLED Females are more susceptible than males to several biliary tract diseases. Interleukin-6 (IL-6) is critical to triggering autoimmune reactions and contributes substantially to biliary epithelial cell (BEC) barrier function and wound repair, and estrogen differentially regulates IL-6 expression in various cell types. We hypothesized that estrogen might stimulate BEC IL-6 production. Exposure to physiologic levels of estradiol, in vitro, increased female mouse BEC (mBEC) IL-6 messenger RNA (mRNA) and protein expression, but either inhibited or had no effect on male mBECs. Female mBECs expressed higher concentrations of estrogen receptor-alpha (ERalpha) mRNA and protein and were also more dependent on estradiol for survival, in vitro. In vivo, elevated estrogen during estrous cycling in mice, and estrogen treatment of mice harboring an ERalpha(+) human cholangiocarcinoma resulted in increased BEC IL-6 mRNA and tumor viability, respectively. Both responses could be blocked by an ERalpha antagonist. Human cholangiocarcinoma cell lines differentially expressing ERalpha were treated with specific ERalpha and ERbeta agonists/antagonists to further test the relationship between estrogen stimulation, ERalpha expression, and IL-6 production. Results show that ERalpha, and not the underlying BEC sex, was responsible for estrogen-induced IL-6 production. Estrogen-induced proliferation of ERalpha-expressing cholangiocarcinoma was blocked by anti-IL-6 antibodies, indicating that at least some of the estrogen-trophic effects are mediated via IL-6. Finally, an association between ERalpha, IL-6, and phosphorylated signal transducer and activator of transcription 3 (pSTAT3) signaling was shown in female-predominant polycystic livers using immunohistochemical analyses, including multiplex quantum dot labeling. CONCLUSION Estrogens stimulate IL-6 production in non-neoplastic female BECs and in neoplastic BECs expressing ERalpha. An association between these signaling pathways was demonstrated for female-predominant polycystic livers and might also influence autoimmune hepatitis, primary biliary cirrhosis, and cholangiocarcinogenesis.
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Affiliation(s)
- Kumiko Isse
- Department of Pathology, Division of Transplantation, and Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
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Du D, Ma X, Zhang J, Zhang Y, Zhou X, Li Y. Cellular and molecular mechanisms of 17beta-estradiol postconditioning protection against gastric mucosal injury induced by ischemia/reperfusion in rats. Life Sci 2009; 86:30-8. [PMID: 19931544 DOI: 10.1016/j.lfs.2009.11.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2009] [Revised: 10/29/2009] [Accepted: 10/30/2009] [Indexed: 12/15/2022]
Abstract
AIMS To investigate the protective effects of 17beta-estradiol postconditioning against ischemia/reperfusion (I-R)-induced gastric mucosal injury in rats. MAIN METHODS The animal model of gastric ischemia/reperfusion was established by clamping of the celiac artery for 30 min and reperfusion for 30 min, 1h, 3h, 6h, 12h or 24h. 17beta-estradiol at doses of 5, 50 or 100 microg/kg (rat) was administered via peripheral veins 2 min before reperfusion. In a subgroup of rats, the estrogen receptor antagonist fulvestrant (Ful, 2mg/kg) was intravenously injected prior to 17beta-estradiol administration. Histological and immunohistochemical methods were employed to assess the gastric mucosal injury index and gastric mucosal cell apoptosis and proliferation. The malondialdehyde (MDA) concentration, superoxide dismutase (SOD) activity, xanthine oxidase (XOD) activity and hydroxyl free radical (-OH) inhibitory ability were determined by colorimetric assays. Subsequently, the expression of Bcl-2 and Bax in rat gastric mucosa was examined by western blotting. KEY FINDINGS 17beta-estradiol dose-dependently inhibited gastric I-R (GI-R) injury, and 17beta-estradiol (50 microg/kg) markedly attenuated GI-R injury 1h after reperfusion. 17beta-estradiol inhibited gastric mucosal cell apoptosis and promoted gastric mucosal cell proliferation in addition to increasing SOD activity and -OH inhibitory ability and decreasing the MDA content and XOD activity. The Bax protein level increased 1h after GI-R and was markedly reduced by intravenous administration of 17beta-estradiol. In contrast, the level of Bcl-2 protein decreased 1h after GI-R and was restored to normal levels by intravenous administration of 17beta-estradiol. These effects of 17beta-estradiol were inhibited by pretreatment with fulvestrant. SIGNIFICANCE 17beta-estradiol postconditioning should be investigated further as a possible strategy against gastric mucosal injury.
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Affiliation(s)
- Dongshu Du
- Department of Physiology, Xuzhou Medical College, 84 West Huaihai Road, Xuzhou 221002, Jiangsu Province, China
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Roux C, Briot K, Gossec L, Kolta S, Blenk T, Felsenberg D, Reid DM, Eastell R, Glüer CC. Increase in vertebral fracture risk in postmenopausal women using omeprazole. Calcif Tissue Int 2009; 84:13-9. [PMID: 19023510 DOI: 10.1007/s00223-008-9188-4] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2008] [Accepted: 10/19/2008] [Indexed: 01/08/2023]
Abstract
Proton pump inhibitors are taken by millions of patients for prevention and treatment of gastroesophageal diseases. Case-control studies have suggested that use of omeprazole is associated with an increased risk of hip fractures. The aim of this prospective study was to assess the risk of vertebral fractures in postmenopausal women using omeprazole. We studied 1,211 postmenopausal women enrolled in the Osteoporosis and Ultrasound Study from the general population. Information on omeprazole and other risk factors for fractures including prevalent fractures and bone mineral density was obtained at baseline. Vertebral fractures were assessed on X-rays obtained at baseline and at the end of the 6-year follow-up and analyzed centrally. At baseline, 5% of this population was using omeprazole. Age-adjusted rates for vertebral fractures were 1.89 and 0.60 for 100 person-years for omeprazole users and nonusers, respectively (P = 0.009). In the multivariate analysis, omeprazole use was a significant and independent predictor of vertebral fractures (RR = 3.50, 95% CI 1.14-8.44). The other predictors were age higher than 65 years (RR = 2.34, 95% CI 1.02-5.34), prevalent vertebral fractures (RR = 3.62, 95% CI 1.63-8.08), and lumbar spine T score </= -2.5 (RR = 2.38, 95% CI 1.03-5.49). Omeprazole use is associated with an increased risk of vertebral fractures in postmenopausal women. Further studies are required to determine the mechanism of the association between the underlying gastric disease, omeprazole use, and risk of osteoporotic fractures.
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Affiliation(s)
- Christian Roux
- Rheumatology Department, AP-HP Cochin Hospital, Paris Descartes University, 27 rue Faubourg Saint Jacques, Paris 75014, France.
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Elhumeed FA, Yousif WB. Light and electron microscopic studies on the effect of a contraceptive drug on the stomach of mouse. Pak J Biol Sci 2008; 11:153-63. [PMID: 18817184 DOI: 10.3923/pjbs.2008.153.163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
The present study was an investigation of the effect of the contraceptive drug, Nordette, on the stomach of the mouse when administered daily at a recommended therapeutic dose rate of 0.0026 mg kg(-1) for 30 days. Extensive light and electron microscopic changes were noticed. The drug caused enlargement in the all types of cells. The oxyntic cells appeared hypertrophied with irregular cell boundaries, enlarged nuclei and faintly stained cytoplasm. Their cytoplasm contained irregularly distributed mitochondria with dense matrix, decreased rER, obviously increased sER, disorganized intracellular canaliculi and some lysosomes. The peptic cells appeared enlarged and contained hypertrophied rough endoplasmic reticulum and an increase amount of ribosomes and secretory granules. There was an increase in the amount of the secretory granules in the lumen of the gastric gland. The mucus cells at the upper region of the gastric gland were greatly decreased. Smooth muscle fibers showed enlargement and degeneration. The submucosa and lamina propria showed vacuolation. The most pathological effects were restricted to the obvious decrease of the lymphoid cells in the submucosa and lamina propria. Dilatation and congestion of the blood vessels and blood capillaries were noticed. Blood capillaries lined by enlarged endothelial cells containing enlarged heterochromatic nuclei.
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Affiliation(s)
- Fatma A Elhumeed
- Department of Zoology, Faculty of Education of Girls, Saudi Arabia
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