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Wang S, Wang J, Zhang J, Wu X, Guo Q, Wang Y, Tao L, Shen X, Chen Y. Chitosan-based food-grade Pickering emulsion loading with Rosa roxburghii extract against precancerous lesions of gastric carcinoma. Int J Biol Macromol 2024; 258:128093. [PMID: 37981272 DOI: 10.1016/j.ijbiomac.2023.128093] [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: 05/22/2023] [Revised: 10/09/2023] [Accepted: 11/12/2023] [Indexed: 11/21/2023]
Abstract
Precancerous lesions of gastric carcinoma (PLGC) are the most important stage in the development of gastric cancer, accompanied by significant oxidative stress and inflammatory response. Rosa roxburghii extract (RRE) has unique advantages in anti-PLGC due to its multi-component, high antioxidant and anti-inflammatory activities. However, the astringency and instability of RRE in the digestive tract seriously hinder its clinical application. Herein, we report a chitosan-based food-grade Pickering emulsion (PE) for loading RRE to block unpleasant taste, improve stability, and promote the entry of RRE into gastric epithelial cells through the gastric adhesion of chitosan, thereby enhancing preventive and therapeutic effects against PLGC. This Pickering emulsion is constructed as a water-in-oil (W/O) emulsion stabilized by the food-grade nanoparticles composed of soybean protein isolate (SPI) and chitosan (CS) through electrostatic interaction (defined as RRE@PE). The experimental results showed that RRE@PE performed better efficacy against PLGC than RRE by scavenging or inhibiting reactive oxygen species generation and reducing inflammatory cytokines. This Pickering emulsion enhances the application potential of RRE and is expected to be used for the treatment of clinical patients with PLGC.
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Affiliation(s)
- Sibu Wang
- The State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China; The Department of Pharmacology of Materia Medical (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Junyu Wang
- The State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China; The Department of Pharmacology of Materia Medical (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Jun Zhang
- The State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China; The Department of Pharmacology of Materia Medical (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Xingjie Wu
- The State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China; The Department of Pharmacology of Materia Medical (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Qianqian Guo
- The State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China; The Department of Pharmacology of Materia Medical (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Yu'e Wang
- The State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China; The Department of Pharmacology of Materia Medical (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China
| | - Ling Tao
- The State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China; The Department of Pharmacology of Materia Medical (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China.
| | - Xiangchun Shen
- The State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China; The Department of Pharmacology of Materia Medical (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China.
| | - Ying Chen
- The State Key Laboratory of Functions and Applications of Medicinal Plants & School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China; The Department of Pharmacology of Materia Medical (the High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, the Key Laboratory of Optimal Utilization of Natural Medicine Resources), Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China.
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Lenti MV, Facciotti F, Miceli E, Vanoli A, Fornasa G, Lahner E, Spadoni I, Giuffrida P, Arpa G, Pasini A, Rovedatti L, Caprioli F, Travelli C, Lattanzi G, Conti L, Klersy C, Vecchi M, Paulli M, Annibale B, Corazza GR, Rescigno M, Di Sabatino A. Mucosal Overexpression of Thymic Stromal Lymphopoietin and Proinflammatory Cytokines in Patients With Autoimmune Atrophic Gastritis. Clin Transl Gastroenterol 2022; 13:e00510. [PMID: 35905420 PMCID: PMC10476748 DOI: 10.14309/ctg.0000000000000510] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/06/2022] [Indexed: 09/06/2023] Open
Abstract
INTRODUCTION The immune mechanisms underlying human autoimmune atrophic gastritis (AAG) are poorly understood. We sought to assess immune mucosal alterations in patients with AAG. METHODS In 2017-2021, we collected gastric corpus biopsies from 24 patients with AAG (median age 62 years, interquartile range 56-67, 14 women), 26 age-matched and sex-matched healthy controls (HCs), and 14 patients with Helicobacter pylori infection (HP). We investigated the lamina propria mononuclear cell (LPMC) populations and the mucosal expression of thymic stromal lymphopoietin (TSLP) and nicotinamide phosphoribosyltransferase (NAMPT). Ex vivo cytokine production by organ culture biopsies, under different stimuli (short TSLP and zinc-l-carnosine), and the gastric vascular barrier through plasmalemma vesicle-associated protein-1 (PV1) were also assessed. RESULTS In the subset of CD19+ LPMC, CD38+ cells (plasma cells) were significantly higher in AAG compared with HC. Ex vivo production of tumor necrosis factor (TNF)-α, interleukin (IL)-15, and transforming growth factor β1 was significantly higher in AAG compared with HC. At immunofluorescence, both IL-7R and TSLP were more expressed in AAG compared with HC and HP, and short TSLP transcripts were significantly increased in AAG compared with HC. In the supernatants of AAG corpus mucosa, short TSLP significantly reduced TNF-α, while zinc-l-carnosine significantly reduced interferon-γ, TNF-α, IL-21, IL-6, and IL-15. NAMPT transcripts were significantly increased in AAG compared with HC. PV1 was almost absent in AAG, mildly expressed in HC, and overexpressed in HP. DISCUSSION Plasma cells, proinflammatory cytokines, and altered gastric vascular barrier may play a major role in AAG. TSLP and NAMPT may represent potential therapeutic targets, while zinc-l-carnosine may dampen mucosal inflammation.
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Affiliation(s)
- Marco Vincenzo Lenti
- First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Federica Facciotti
- Department of Experimental Oncology, IRCCS European Institute of Oncology, Milan, Italy
- Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
| | - Emanuela Miceli
- First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Alessandro Vanoli
- Unit of Anatomic Pathology, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Giulia Fornasa
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Edith Lahner
- Department of Medical-Surgical Sciences and Translational Medicine, Sant'Andrea Hospital, University La Sapienza, Rome, Italy
| | - Ilaria Spadoni
- Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy
| | - Paolo Giuffrida
- First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Giovanni Arpa
- Unit of Anatomic Pathology, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Alessandra Pasini
- First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Laura Rovedatti
- First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Flavio Caprioli
- Gastroenterology and Endoscopy Unit, IRCCS Ca' Granda Hospital Foundation, University of Milan, Milan, Italy
| | - Cristina Travelli
- Department of Pharmaceutical Sciences, University of Pavia, Pavia, Italy
| | - Georgia Lattanzi
- Department of Experimental Oncology, IRCCS European Institute of Oncology, Milan, Italy
| | - Laura Conti
- Department of Medical-Surgical Sciences and Translational Medicine, Sant'Andrea Hospital, University La Sapienza, Rome, Italy
| | - Catherine Klersy
- Clinical Epidemiology & Biometry, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, IRCCS Ca' Granda Hospital Foundation, University of Milan, Milan, Italy
| | - Marco Paulli
- Unit of Anatomic Pathology, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Bruno Annibale
- Department of Medical-Surgical Sciences and Translational Medicine, Sant'Andrea Hospital, University La Sapienza, Rome, Italy
| | - Gino Roberto Corazza
- First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
| | - Maria Rescigno
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
- Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy
| | - Antonio Di Sabatino
- First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
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Xu W, Li B, Xu M, Yang T, Hao X. Traditional Chinese medicine for precancerous lesions of gastric cancer: A review. Biomed Pharmacother 2021; 146:112542. [PMID: 34929576 DOI: 10.1016/j.biopha.2021.112542] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 12/12/2021] [Accepted: 12/13/2021] [Indexed: 01/30/2023] Open
Abstract
Gastric cancer (GC) is the fifth most common type of cancer and the third leading cause of death due to cancer worldwide. The gastric mucosa often undergoes many years of precancerous lesions of gastric cancer (PLGC) stages before progressing to gastric malignancy. Unfortunately, there are no effective Western drugs for patients with PLGC. In recent years, traditional Chinese medicine (TCM) has been proven effective in treating PLGC. Classical TCM formulas and chemical components isolated from some Chinese herbal medicines have been administered to treat PLGC, and the main advantage is their comprehensive intervention with multiple approaches and multiple targets. In this review, we focus on recent studies using TCM treatment for PLGC, including clinical observations and experimental research, with a focus on targets and mechanisms of drugs. This review provides some ideas and a theoretical basis for applying TCM to treat PLGC and prevent GC.
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Affiliation(s)
- Weichao Xu
- Hebei Hospital of Traditional Chinese Medicine, Shijiazhuang 050011, China; Hebei Key Laboratory of Integrated Traditional Chinese and Western Medicine Gastroenterology, Shijiazhuang 050011, China
| | - Bolin Li
- Hebei Hospital of Traditional Chinese Medicine, Shijiazhuang 050011, China; Hebei Key Laboratory of Integrated Traditional Chinese and Western Medicine Gastroenterology, Shijiazhuang 050011, China
| | - Miaochan Xu
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Tianxiao Yang
- Hebei University of Chinese Medicine, Shijiazhuang 050200, China
| | - Xinyu Hao
- Peking University Third Hospital, Beijing 100191, China.
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Osteopontin depletion decreases inflammation and gastric epithelial proliferation during Helicobacter pylori infection in mice. J Transl Med 2015; 95:660-71. [PMID: 25867766 DOI: 10.1038/labinvest.2015.47] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Revised: 01/22/2015] [Accepted: 01/28/2015] [Indexed: 12/16/2022] Open
Abstract
Osteopontin (OPN) is a multifunctional protein that plays a role in many physiological and pathological processes, including inflammation and tumorigenesis. Here, we investigated the involvement of OPN in Helicobacter pylori (HP)-induced gastritis using OPN knockout (KO) mice and OPN knockdown (KD) cell lines. HP-infected OPN KO mice showed significantly reduced gastritis compared with wild-type (WT) mice with decreased infiltration of macrophages and a reduction in HP-induced upregulation of IL-1β, TNF-α, and IFN-γ. HP-exposed OPN KD gastric cancer cells and macrophage-like cells showed an attenuated induction of these cytokines. We also demonstrated a reduction in the migration of monocytic and macrophage-like cells toward conditioned media harvested from HP-exposed OPN KD gastric cancer cells as well as reduced migration ability of OPN KD cells itself. In addition, HP-infected OPN KO mice showed decreased epithelial cell proliferation compared with HP-infected WT mice, in association with a reduction in MAPK pathway activation. OPN KD gastric cancer cell lines also showed lower proliferative activity and reduced MAPK activation than shRNA control cells after HP co-culture or after IL-1β and TNF-α treatment. Taken together, these results indicate that OPN exerts a considerable influence on HP-induced gastritis by modulating the production of cytokines and contributing to macrophage infiltration. Moreover, OPN-mediated activation of the MAPK pathway in gastric epithelial cells might contribute to epithelial changes following HP infection.
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Gao W, Li HY, Wang LX, Hao LJ, Gao JL, Zheng RJ, Cai CJ, Si YL. Protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats. ASIAN PAC J TROP MED 2015; 7:402-6. [PMID: 25063070 DOI: 10.1016/s1995-7645(14)60065-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 01/15/2014] [Accepted: 03/15/2014] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVE To observe the protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats. METHODS All rats were randomly divided into normal control group, cirrhosis and treatment group. Thioacetamide was used to establish rat model of cirrhotic portal hypertension. The necrotic tissue of gastric mucosa ulcer focus, degree of neutrophils infiltration at the ulcer margin, portal pressure, portal venous flow, abdominal aortic pressure, abdominal aortic blood flow at front end, gastric mucosal blood flow (GMBF), glycoprotein (GP) of gastric mucosa, basal acid secretion, H(+)back -diffusion, gastric mucosal damage index, NO, prostaglandin E2(PGE2) and tumor necrosis factor-α (TNF-α) were determined respectively, and the pathological changes of gastric mucosa were also observed by microscope. RESULTS Compared with cirrhosis group and the control group, the ulcer bottom necrotic material, gastric neutrophil infiltration and UI of the treatment group were all decreased significantly (P<0.01), GMBF value, GP values, serum NO, PGE2, TNF-α were all significantly increased. CONCLUSIONS Omeprazole has an important protective effect on gastric mucosal and it can increase gastric mucosal blood flow and related to many factors.
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Affiliation(s)
- Wei Gao
- Department of Gastroenterology, Tangshan Workers' Hospital, Tangshan 063000, China
| | - Hai-Ying Li
- Department of Gastroenterology, Tangshan Workers' Hospital, Tangshan 063000, China
| | - Li-Xin Wang
- Department of Gastroenterology, Tangshan Workers' Hospital, Tangshan 063000, China
| | - Li-Jun Hao
- Department of Gastroenterology, Tangshan Workers' Hospital, Tangshan 063000, China
| | - Jian-Li Gao
- Department of Gastroenterology, Tangshan Workers' Hospital, Tangshan 063000, China
| | - Rong-Juan Zheng
- Department of Gastroenterology, Tangshan Workers' Hospital, Tangshan 063000, China
| | - Chun-Jiang Cai
- Department of Spleen and Stomach, Tangshan TCM Hospital, Tangshan 063003, China.
| | - Yan-Ling Si
- Department of Gastroenterology, Tangshan Workers' Hospital, Tangshan 063000, China.
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Kristek M, Collins LE, DeCourcey J, McEvoy FA, Loscher CE. Soluble factors from colonic epithelial cells contribute to gut homeostasis by modulating macrophage phenotype. Innate Immun 2014; 21:358-69. [PMID: 25298104 DOI: 10.1177/1753425914538294] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 05/06/2014] [Indexed: 11/17/2022] Open
Abstract
Intestinal macrophages originate from inflammatory blood monocytes which migrate to the intestine, where they differentiate into anti-inflammatory macrophages through a number of transitional stages. These macrophages typically remain hypo-responsive to commensal bacteria and food Ags in the intestine, yet also retain the ability to react to invading pathogens. In this study we examined the role of epithelial cells in inducing this intestinal macrophage phenotype. Using an in vitro system we showed that, in two-dimensional culture, epithelial cell-derived factors from a murine cell line, CMT-93, are sufficient to induce phenotypic changes in macrophages. Exposure of monocyte-derived macrophages, J774A.1, to soluble factors derived from epithelial cells, induced an altered phenotype similar to that of intestinal macrophages with decreased production of IL-12p40, IL-6 and IL-23 and expression of MHC ІІ and CD80 following TLR ligation. Furthermore, these conditioned macrophages showed enhanced phagocytic activity in parallel with low respiratory burst and NO production, similar to the response seen in intestinal macrophages. Our findings suggest a role for colonic epithelial cells in modulation of macrophage phenotype for maintenance of gut homeostasis. Further understanding of the cell interactions that maintain homeostasis in the gut could reveal novel therapeutic strategies to restore the balance in disease.
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Affiliation(s)
- Maja Kristek
- Immunomodulation Research Group, School of Biotechnology, Dublin City University, Ireland
| | - Laura E Collins
- Immunomodulation Research Group, School of Biotechnology, Dublin City University, Ireland
| | - Joseph DeCourcey
- Immunomodulation Research Group, School of Biotechnology, Dublin City University, Ireland
| | - Fiona A McEvoy
- Immunomodulation Research Group, School of Biotechnology, Dublin City University, Ireland
| | - Christine E Loscher
- Immunomodulation Research Group, School of Biotechnology, Dublin City University, Ireland
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Abstract
Eosinophilic esophagitis (EoE) is a recently recognized, immune-mediated disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil-predominant inflammation. The chronic esophageal eosinophilia of EoE is associated with tissue remodeling that includes epithelial hyperplasia, subepithelial fibrosis, and hypertrophy of esophageal smooth muscle. This remodeling causes the esophageal rings and strictures that frequently complicate EoE and underlies the mucosal fragility that predisposes to painful mucosal tears in the EoE esophagus. The pathogenesis of tissue remodeling in EoE is not completely understood, but emerging studies suggest that secretory products of eosinophils and mast cells, as well as cytokines produced by other inflammatory cells, epithelial cells, and stromal cells in the esophagus, all contribute to the process. Interleukin (IL)-4 and IL-13, Th2 cytokines overproduced in allergic disorders, have direct profibrotic and remodeling effects in EoE. The EoE esophagus exhibits increased expression of transforming growth factor (TGF)-β1, which is a potent activator of fibroblasts and a strong inducer of epithelial-mesenchymal transition. In addition, IL-4, IL-13, and TGF-β all have a role in regulating periostin, an extracellular matrix protein that might influence remodeling by acting as a ligand for integrins, by its effects on eosinophils or by activating fibrogenic genes in the esophagus. Presently, few treatments have been shown to affect the tissue remodeling that causes EoE complications. This report reviews the potential roles of fibroblasts, eosinophils, mast cells, and profibrotic cytokines in esophageal remodeling in EoE and identifies potential targets for future therapies that might prevent EoE complications.
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Affiliation(s)
| | - Rhonda F. Souza
- 2Internal Medicine, Children's Medical Center and the VA North Texas Health Care System, Harold C. Simmons Comprehensive Cancer Center, and the University of Texas Southwestern Medical Center, Dallas, Texas
| | - Stuart J. Spechler
- 2Internal Medicine, Children's Medical Center and the VA North Texas Health Care System, Harold C. Simmons Comprehensive Cancer Center, and the University of Texas Southwestern Medical Center, Dallas, Texas
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Luo JC, Huo TI, Hou MC, Lin HY, Li CP, Lin HC, Chang FY, Lee FY. Clopidogrel delays gastric ulcer healing in rats. Eur J Pharmacol 2012; 695:112-9. [PMID: 22975710 DOI: 10.1016/j.ejphar.2012.07.054] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2012] [Revised: 07/10/2012] [Accepted: 07/27/2012] [Indexed: 01/05/2023]
Abstract
Clopidogrel is not safe enough for the gastric mucosa in patients with high risk of peptic ulcer. This study aimed to explore if clopidogrel delays gastric ulcer healing and elucidate the involved mechanisms. Gastric ulcer was induced in rats and the ulcer size, mucosal epithelial cell proliferation of the ulcer margin, expression of growth factors [epidermal growth factor (EGF), basic fibroblast growth factor] and their receptors, and signal transduction pathways for cell proliferation were measured and compared between the clopidogrel-treated group and untreated controls. For the in vitro part, rat gastric mucosal epithelial cell line (RGM-1 cells) was used to establish EGF receptor over-expressed cells. Cell proliferation and molecular change under EGF treatment (10ng/ml) with and without clopidogrel (10(-6)M) were demonstrated. Ulcer size was significantly larger in the clopidogrel-treated group compared to the control and mucosal epithelial cell proliferation of the ulcer margin was significantly decreased in the clopidogrel-treated group (P<0.05). Clopidogrel (2mg and 10mg/kg/day) significantly decreased ulcer-induced gastric epithelial cell proliferation and ulcer-stimulated expressions of EGF receptor and phosphorylated extracellular signal-regulated kinase (PERK) at the ulcer margin (P<0.05). Clopidogrel (10(-6)M) also inhibited EGF-stimulated EGF receptor, PERK expression, and cell proliferation in RGM-1 cells (P<0.05), and caused much less inhibition of EGF-stimulated cell proliferation in EGF receptor over-expressed RGM-1 cells than in RGM-1 cells (22% vs. 32% reduction). In conclusion, clopidogrel delays gastric ulcer healing in rats via inhibiting gastric epithelial cell proliferation, at least by inhibition of the EGF receptor-ERK signal transduction pathway.
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Affiliation(s)
- Jiing-Chyuan Luo
- Department of Medicine, National Yang-Ming University, School of Medicine, No. 155 Section 2 Linong Street, Taipei, Taiwan.
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Hobbs SS, Goettel JA, Liang D, Yan F, Edelblum KL, Frey MR, Mullane MT, Polk DB. TNF transactivation of EGFR stimulates cytoprotective COX-2 expression in gastrointestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2011; 301:G220-9. [PMID: 21566012 PMCID: PMC3154604 DOI: 10.1152/ajpgi.00383.2010] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
TNF and epidermal growth factor (EGF) are well-known stimuli of cyclooxygenase (COX)-2 expression, and TNF stimulates transactivation of EGF receptor (EGFR) signaling to promote survival in colon epithelial cells. We hypothesized that COX-2 induction and cell survival signaling downstream of TNF are mediated by EGFR transactivation. TNF treatment was more cytotoxic to COX-2(-/-) mouse colon epithelial (MCE) cells than wild-type (WT) young adult mouse colon (YAMC) epithelial cells or COX-1(-/-) cells. TNF also induced COX-2 protein and mRNA expression in YAMC cells, but blockade of EGFR kinase activity or expression inhibited COX-2 upregulation. TNF-induced COX-2 expression was reduced and absent in EGFR(-/-) and TNF receptor-1 (TNFR1) knockout MCE cells, respectively, but was restored upon expression of the WT receptors. Inhibition of mediators of EGFR transactivation, Src family kinases and p38 MAPK, blocked TNF-induced COX-2 protein and mRNA expression. Finally, TNF injection increased COX-2 expression in colon epithelium of WT, but not kinase-defective EGFR(wa2) and EGFR(wa5), mice. These data indicate that TNFR1-dependent transactivation of EGFR through a p38- and/or an Src-dependent mechanism stimulates COX-2 expression to promote cell survival. This highlights an EGFR-dependent cell signaling pathway and response that may be significant in colitis-associated carcinoma.
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Affiliation(s)
- Stuart S. Hobbs
- 1Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics,
| | - Jeremy A. Goettel
- 2Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; and
| | - Dongchun Liang
- 1Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics,
| | - Fang Yan
- 1Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics,
| | - Karen L. Edelblum
- 2Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee; and
| | - Mark R. Frey
- 3Departments of Pediatrics and Biochemistry and Molecular Biology, The Saban Research Institute of Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California
| | - Matthew T. Mullane
- 1Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics,
| | - D. Brent Polk
- 3Departments of Pediatrics and Biochemistry and Molecular Biology, The Saban Research Institute of Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California
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Yu S, Fang Y, Sharav T, Sharp GC, Braley-Mullen H. CD8+ T cells induce thyroid epithelial cell hyperplasia and fibrosis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2011; 186:2655-62. [PMID: 21220693 PMCID: PMC3280124 DOI: 10.4049/jimmunol.1002884] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CD8(+) T cells can be important effector cells in autoimmune inflammation, generally because they can damage target cells by cytotoxicity. This study shows that activated CD8(+) T cells induce thyroid epithelial cell hyperplasia and proliferation and fibrosis in IFN-γ(-/-) NOD.H-2h4 SCID mice in the absence of CD4(+) T cells. Because CD8(+) T cells induce proliferation rather than cytotoxicity of target cells, these results describe a novel function for CD8(+) T cells in autoimmune disease. In contrast to the ability of purified CD8(+) T cells to induce thyrocyte proliferation, CD4(+) T cells or CD8 T cell-depleted splenocytes induced only mild thyroid lesions in SCID recipients. T cells in both spleens and thyroids highly produce TNF-α. TNF-α promotes proliferation of thyrocytes in vitro, and anti-TNF-α inhibits development of thyroid epithelial cell hyperplasia and proliferation in SCID recipients of IFN-γ(-/-) splenocytes. This suggests that targeting CD8(+) T cells and/or TNF-α may be effective for treating epithelial cell hyperplasia and fibrosis.
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Affiliation(s)
- Shiguang Yu
- Department of Veterans Affairs Research Service, Columbia, Mo 65212
- Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Mo 65212
- Arkansas Biosciences Institute, Department of Biological Science, Arkansas State University, Jonesboro, AR 72467
| | - Yujiang Fang
- Department of Veterans Affairs Research Service, Columbia, Mo 65212
- Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Mo 65212
| | - Tumenjargal Sharav
- Department of Veterans Affairs Research Service, Columbia, Mo 65212
- Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Mo 65212
| | - Gordon C. Sharp
- Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Mo 65212
- Department of Pathology, University of Missouri School of Medicine, Columbia, Mo 65212
| | - Helen Braley-Mullen
- Department of Veterans Affairs Research Service, Columbia, Mo 65212
- Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Mo 65212
- Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, Mo 65212
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Abstract
Spices and herbal remedies have been used since ancient times to treat a variety of disorders. It has been experimentally demonstrated that spices, herbs, and their extracts possess antimicrobial, anti-inflammatory, antirheumatic, lipid-lowering, hepatoprotective, nephroprotective, antimutagenic and anticancer activities, besides their gastroprotective and anti-ulcer activities. Despite a number of reports on the toxicity of herbs and spices, they are generally accepted as safer alternatives to conventional therapy against gastric ulcers. To this end, it is also believed, that excessive consumption of spices may favor the pathogenesis of gastric and duodenal ulcer and some studies have substantiated this common perception. Based on various in vivo experiments and clinical studies, on the effects of spices and herbs on gastric ulcers, it has indeed been shown that certain spices do possess remarkable anti-ulcer properties mediated by antisecretory, cytoprotective, antioxidant, and anti-Helicobacter pylori effects and mechanisms regulated by nitric oxide, prostaglandins, non-protein sulfhydryl molecules and epidermal growth factor expression. Accordingly, their consumption may attenuate and help prevent peptic ulcer disease. In the present review, the beneficial effects of spices and herbal nutritive components on the gastric mucosa are discussed against the paradigm of their deleterious potential.
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Ng KM, Cho CH, Chang FY, Luo JC, Lin HC, Lin HY, Chi CW, Lee SD. Omeprazole promotes gastric epithelial cell migration. J Pharm Pharmacol 2010; 60:655-60. [DOI: 10.1211/jpp.60.5.0012] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Abstract
Proton pump inhibitors (PPIs) are effective at preventing non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcers. They are also superior to histamine H2-receptor antagonists and misoprostol in treating NSAID-induced gastric ulcer healing. This study explored whether omeprazole, a PPI, can modulate ulcer healing through epithelial cell proliferation and/or cell migration using a rat normal gastric epithelial cell line (RGM-1). Flow cytometry was used to determine cell proliferation and an artificial wound model was used to measure cell migration. Western blot analysis was performed to evaluate the possible mechanisms of action. Omeprazole treatment (10−8, 10−6 and 10−4M) for 12 and 24 h did not promote cell proliferation. However, similar doses of the drug (10−6 and 10−4 M) incubated for 24–48 h significantly promoted the basal cell migration of gastric epithelial cells. Further, the higher concentration of omeprazole (10−4M) reversed the inhibitory action of indometacin (10−5M) on cell migration. Western blot results showed that omeprazole did not increase cyclooxygenase-2 expression and did not activate signal transduction pathways, including extracellular signal-regulated kinase (ERK1/ERK2), P38 mitogenic-activated protein kinase, and phosphatidyl inositol 3-kinase. The results suggest that omeprazole is beneficial in basal ulcer healing and it reversed the adverse action of indometacin on ulcer repair under acid-independent conditions. These actions are likely to be mediated through the promotion of gastric epithelial cell migration but not cell proliferation.
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Affiliation(s)
- Ka-Man Ng
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chi-Hin Cho
- Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Full-Young Chang
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Jiing-Chyuan Luo
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Han-Chieh Lin
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Hsiao-Yi Lin
- Division of Allergy, Immunology, and Rheumatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Chin-Wen Chi
- Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan
- Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan
| | - Shou-Dong Lee
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei, Taiwan
- Department of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
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13
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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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14
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Luo JC, Cho CH, Ng KM, Hsiang KW, Lu CL, Chen TS, Chang FY, Lin HC, Perng CL, Lee SD. Dexamethasone inhibits tumor necrosis factor-alpha-stimulated gastric epithelial cell migration. J Chin Med Assoc 2009; 72:509-14. [PMID: 19837644 DOI: 10.1016/s1726-4901(09)70419-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Cell migration (restitution) occurs in the early phase of gastric ulcer healing. Tumor necrosis factor (TNF)-alpha is overexpressed at the ulcer margin and plays a physiologic role in gastric ulcer healing. Dexamethasone, which is a potent corticosteroid, delays rat gastric ulcer healing. We evaluated whether dexamethasone inhibited TNF-alpha-stimulated gastric epithelial cell migration using a rat normal gastric epithelial cell line (RGM-1). METHODS An artificial wound model was employed to measure cell migration. Western blot was performed to evaluate the possible mechanisms. Intracellular prostaglandin E2 level was measured using an enzyme-linked immunosorbent assay. RESULTS TNF-alpha treatment (10 ng/mL) for 12-48 hours significantly increased RGM-1 cell migration, and TNF-alpha treatment increased cyclooxygenase (COX)-2 protein expression 8 hours later and prostaglandin E2 (PGE2) synthesis 12 hours later compared with control (p < 0.05). Dexamethasone (10(-6) M) significantly inhibited the stimulatory effect of TNF-alpha on RGM-1 cell migration, which was associated with a significant decrease in COX-2 expression and PGE2 level in cells (p < 0.05). CONCLUSION TNF-alpha plays a regulatory role in rat gastric epithelial cell migration and dexamethasone inhibited TNF-alpha-stimulated cell migration, which was associated with a decrease in COX-2 expression and PGE2 formation.
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Affiliation(s)
- Jiing-Chyuan Luo
- Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC.
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15
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Cakarova L, Marsh LM, Wilhelm J, Mayer K, Grimminger F, Seeger W, Lohmeyer J, Herold S. Macrophage tumor necrosis factor-alpha induces epithelial expression of granulocyte-macrophage colony-stimulating factor: impact on alveolar epithelial repair. Am J Respir Crit Care Med 2009; 180:521-32. [PMID: 19590023 DOI: 10.1164/rccm.200812-1837oc] [Citation(s) in RCA: 101] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
RATIONALE Resident alveolar macrophages have been attributed a crucial role in host defense toward pulmonary infection. Their contribution to alveolar repair processes, however, remains elusive. OBJECTIVES We investigated whether activated resident alveolar macrophages contribute to alveolar epithelial repair on lipopolysaccharide (LPS) challenge in vitro and in vivo and analyzed the molecular interaction pathways involved. METHODS We evaluated macrophage-epithelial cross-talk mediators for epithelial cell proliferation in an in vitro coculture system and an in vivo model of LPS-induced acute lung injury comparing wild-type, granulocyte-macrophage colony-stimulating factor (GM-CSF)-deficient (GM(-/-)), and human SPC-GM mice (GM(-/-) mice expressing an SPC-promotor-regulated GM-CSF transgene). MEASUREMENTS AND MAIN RESULTS Using reverse transcription-polymerase chain reaction and ELISA we showed that LPS-activated alveolar macrophages stimulated alveolar epithelial cells (AEC) to express growth factors, particularly GM-CSF, in coculture. Antibody neutralization experiments revealed epithelial GM-CSF expression to be macrophage tumor necrosis factor (TNF)-alpha dependent. GM-CSF elicited proliferative signaling in AEC via autocrine stimulation. Notably, macrophage TNF-alpha induced epithelial proliferation in wild-type but not in GM-CSF-deficient AEC as shown by [(3)H]-thymidine incorporation and cell counting. Moreover, intraalveolar TNF-alpha neutralization impaired AEC proliferation in LPS-injured mice, as investigated by flow cytometric Ki-67 staining. Additionally, GM-CSF-deficient mice displayed reduced AEC proliferation and sustained alveolar barrier dysfunction on LPS treatment compared with wild-type mice. CONCLUSIONS Collectively, these findings indicate that TNF-alpha released from activated resident alveolar macrophages induces epithelial GM-CSF expression, which in turn initiates AEC proliferation and contributes to restoring alveolar barrier function.
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Affiliation(s)
- Lidija Cakarova
- University of Giessen Lung Center, Department of Internal Medicine II, Klinikstr. 36, D-35392 Giessen, Germany
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16
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Chen WT, Hung WC, Kang WY, Huang YC, Su YC, Yang CH, Chai CY. Overexpression of cyclooxygenase-2 in urothelial carcinoma in conjunction with tumor-associated-macrophage infiltration, hypoxia-inducible factor-1alpha expression, and tumor angiogenesis. APMIS 2009; 117:176-84. [PMID: 19245590 DOI: 10.1111/j.1600-0463.2008.00004.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
This study examines whether the expression of cyclooxgenase-2 (COX-2) in urothelial carcinoma (UC) is associated with macrophage infiltration, hypoxia-inducible factor-1alpha (HIF-1alpha) expression and angiogenesis. We investigated the expression of COX-2 associated with HIF-1alpha and performed double immunohistochemical analysis of 216 UCs for COX-2 expression and the correlation with tumor-associated-macrophage (TAM) density and microvessel density (MVD) in situ. A high expression of COX-2 was positively correlated with tumor invasiveness, histologic grade and HIF-1alpha expression in UC (p<0.0001, p=0.003, p<0.0001, respectively). Quantification of double staining of COX-2/CD34 and COX-2/CD68 showed that a higher MVD and TAM density was found in COX-2 high-expression than in COX-2 low-expression tumor fields (p<0.0001). Adjacent to the principal of COX-2 expression areas, MVD value and TAM density were significantly increased in HIF-1alpha high-expression specimens compared with HIF-1alpha low-expression ones (p<0.0001). Interestingly, our data revealed that high COX-2 expression (p=0.002), high HIF-1alpha expression (p<0.0001) and TAM density (p<0.0001) were all associated with high MVD value. Our results suggest that COX-2 may produce a cooperative effect in promoting tumor progression and may be involved in the process of angiogenesis through increasing TAM infiltration or HIF-1alpha regulation by hypoxia.
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Affiliation(s)
- Wan-Tzu Chen
- Department of Pathology, Kaohsiung Medical University, Chung-Ho Memorial Hospital, No. 100 Tzyou 1st Road, Kaohsiung City, Taiwan
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17
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Involvement of voltage-gated K+ and Na+ channels in gastric epithelial cell migration. Mol Cell Biochem 2007; 308:219-26. [PMID: 17978865 DOI: 10.1007/s11010-007-9631-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2007] [Accepted: 10/18/2007] [Indexed: 12/23/2022]
Abstract
Epithelial cell migration plays an important role in gastrointestinal mucosal repair. We previously reported that multiple functional ion channels, including a Ba(2+)-sensitive K(+) inward rectifier K(ir)1.2, 4-aminopyridine (4-AP)-sensitive voltage-gated K(+) channels K(v)1.1, K(v)1.6 and K(v)2.1, and a nifedipine-sensitive, tetrodotoxin (TTX)-insensitive voltage-gated Na(+) channel Na(v)1.5 were expressed in a non-transformed rat gastric epithelial cell line (RGM-1). In the present study, we further investigated whether these ion channels are involved in the modulation of gastric epithelial cell migration. Cell migration was determined by monolayer wound healing assay. Results showed that blockade of K(v) with 4-AP or Na(v)1.5 with nifedipine inhibited RGM-1 cell migration in the absence or presence of epidermal growth factor (EGF), which effectively stimulated RGM-1 cell migration. Moreover, high concentration of TTX mimicked the action of nifedipine, suggesting that the action of nifedipine was mediated through specific blockade of Na(v)1.5. In contrast, inhibition of K(ir)1.2 with Ba(2+), either in basal or EGF-stimulated condition, had no effect on RGM-1 cell migration. In conclusion, the present study demonstrates for the first time that voltage-gated K(+) and Na(+) channels are involved in the modulation of gastric epithelial cell migration.
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Zhang YM, Wei EQ, Li L, Qiao WL, Wang L, Zhang JF. Extracellular signal-regulated kinase pathways may mediate the protective effect of electrical stimulation of the paraventricular nucleus against ischaemia-reperfusion injury of the gastric mucosa. Clin Exp Pharmacol Physiol 2007; 34:742-52. [PMID: 17600551 DOI: 10.1111/j.1440-1681.2007.04652.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
1. The aim of the present study was to elucidate the role of the extracellular signal-regulated kinase (ERK) pathway in mediating the effects of electrical stimulation of the paraventricular nucleus (PVN) on apoptosis and proliferation induced by gastric ischaemia-reperfusion injury (GI/RI). 2. To investigate the effects of electrical stimulation of the hypothalamic PVN on gastric mucosal apoptosis and proliferation in response to ischaemia-reperfusion (I/R), we used a GI/RI model by clamping the coeliac artery for 30 min and then reperfusing the artery for 30 min or 1, 3 or 6 h. We used immunohistochemistry and western blotting to investigate the expression, activation and distribution of ERKs and the dynamic changes in their downstream cellular factors Bcl-2 and Bax at different times subsequent to electrical stimulation of the PVN in the I/R-injured gastric mucosa. 3. Electrical stimulation of the PVN markedly attenuated GI/RI at 30 min and 1 and 3 h after reperfusion. Electrical stimulation decreased gastric mucosal apoptosis, increased gastric mucosal proliferation and promoted the expression and activation of phosphorylated (p)-ERK1/2 30 min after reperfusion. Electrical stimulation increased the expression of Bcl-2 and decreased the expression of Bax at 30 min and 1 and 3 h after reperfusion. In contrast, inhibition of ERK1/2 activity by the specific upstream mitogen-activated protein kinase kinase inhibitor PD98059 produced similar effects at 1 h after reperfusion in rats subjected to I/R with or without electrical stimulation of the PVN. Administration of PD98059 aggravated gastric mucosal injury, increased apoptosis, decreased proliferation in gastric mucosal cells, decreased the expression and activity of p-ERK1/2 and Bcl-2 expression and increased Bax expression. 4. These results indicate that the PVN protects against GI/RI and that this protection is associated with the inhibition of cellular apoptosis and the promotion of proliferation in the gastric mucosa, probably by activating the ERK pathway.
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Affiliation(s)
- Yong-Mei Zhang
- Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China
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19
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Ogunwobi OO, Beales ILP. Cyclo-oxygenase-independent inhibition of apoptosis and stimulation of proliferation by leptin in human colon cancer cells. Dig Dis Sci 2007; 52:1934-45. [PMID: 17406816 DOI: 10.1007/s10620-007-9784-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2005] [Accepted: 01/18/2007] [Indexed: 01/08/2023]
Abstract
Obesity increases the risk of colon cancer. Hyperleptinemia is characteristic of obesity and leptin has been reported to be a colonic growth factor. We have examined the involvement of the cyclo-oxygenase (COX) pathways in the proliferation and anti-apoptotic effects of leptin. Leptin stimulated proliferation in HT-29 colon cancer cells: this was unaffected by inhibition of COX-1, COX-2, protein kinase C, or the epidermal growth factor receptor. Leptin did not increase COX-2 mRNA or COX-derived prostaglandin E2 production. Celecoxib induced apoptosis in a COX-independent manner. Leptin reduced both serum starvation- and celecoxib-induced apoptosis. Inhibition of ERK, p38 MAP kinase, and nuclear factor (NF)-kappaB abolished the growth-promoting and anti-apoptotic effects of leptin. Treatment of HT-29 cells with leptin stimulated phosphorylation of ERK and p38 MAP kinase and nuclear translocation of active NF-kappaB. We conclude that leptin stimulates colon cancer proliferation via COX-independent pathways and reduces celecoxib-induced apoptosis via ERK, p38 MAP kinase, and NF-kappaB pathways.
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Affiliation(s)
- Olorunseun Olatunji Ogunwobi
- Gastroenterology Research Unit, School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, NR4 7TJ, UK
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Wu WKK, Wu WKK, Law PTY, Law PTY, Wong HPS, Wong HPS, Lam EKY, Lam EKY, Tai EKK, Tai EKK, Shin VY, Shin VY, Cho CH, Cho CH. Shift of homeostasis from parenchymal regeneration to fibroblast proliferation induced by lipopolysaccharide-activated macrophages in gastric mucosal healing in vitro. Wound Repair Regen 2007; 15:221-6. [PMID: 17352754 DOI: 10.1111/j.1524-475x.2007.00208.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Wound healing in the gastrointestinal tract is an orderly process involving orchestrated responses of various cell types. Lipopolysaccharides (LPS) are major components of the outer membrane of Gram-negative bacteria, which are known to impair gastric ulcer healing in animals. The influence of LPS on intercellular communication in wound healing, however, is unknown. We examined the effects of LPS-induced macrophage activation on the proliferative response in cultured rat gastric epithelial cells (RGM-1) and fibroblasts JHU-25. Rat peritoneal resident macrophages were activated with increasing doses of LPS. The supernatant from the activated macrophage preparation, designated as macrophage-conditioned medium, was then used to treat RGM-1 or JHU-25 cells. Cell proliferation and migration were determined by [(3)H]-thymidine incorporation and a monolayer wound-healing assay, respectively. Macrophage-conditioned medium significantly suppressed RGM-1 cell proliferation but had no effect on cell migration. The same medium, however, increased JHU-25 cell proliferation. LPS treatment alone suppressed JHU-25 cell proliferation while it had no effect on RGM-1 cell proliferation, indicating that the differential effects of the macrophage-conditioned medium on cell proliferation were elicited by the factors derived from macrophages. In this regard, tumor necrosis factor (TNF)-alpha stimulated while interleukin (IL)-1beta suppressed RGM-1 cell proliferation, suggesting that IL-1beta but not TNF-alpha may play a part in the mediation of the antiproliferative effect of macrophage-conditioned medium on gastric epithelial cells. In contrast, IL-1beta suppressed while TNF-alpha had no effect on JHU-25 cell proliferation. Collectively, LPS-activated macrophages delay gastric mucosal regeneration but promote fibroblast proliferation in vitro. Such changes may partly elucidate the detrimental effect of bacterial infection on tissue repair in the stomach.
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Affiliation(s)
- William K K Wu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong
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Role of mitogen-activated protein kinases in the regulation of paraventricular nucleus to gastric ischemia-reperfusion injuries. Chin Med J (Engl) 2007. [DOI: 10.1097/00029330-200706020-00010] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Sooriakumaran P, Langley SEM, Laing RW, Coley HM. COX-2 inhibition: a possible role in the management of prostate cancer? J Chemother 2007; 19:21-32. [PMID: 17309847 DOI: 10.1179/joc.2007.19.1.21] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
There is mounting evidence to support a role for cyclooxygenase-2 (COX-2) inhibitors (coxibs) in the management of prostate cancer. This review considers the current evidence base for the use of coxibs in prostate cancer as well as their adverse event profile. A systematic literature review using the search terms 'cyclooxygenase', 'COX-2', 'coxibs', 'cardiovascular risk', and 'prostate cancer' was performed using Medline. Celecoxib appears safer in terms of cardiovascular toxicity than other coxibs, and this may relate to its lower selectivity for the COX-2 enzyme. This lower selectivity also provides rationale for its putative broader anti-cancer effects, via non-COX-2-dependent pathways that affect cell cycle regulation, angiogenesis, and hypoxic modulation. There are also interacting relationships between COX-2, chronic inflammation, and prostate cancer. There is much promise for the coxibs as anti-cancer agents. The future might be to pharmacologically adapt these agents to exert their COX-2 independent mechanisms of action while minimizing their COX-2-dependent adverse cardiovascular effects.
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23
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Li L, Zhang YM, Qiao WL, Wang L, Zhang JF. Effects of hypothalamic paraventricular nuclei on apoptosis and proliferation of gastric mucosal cells induced by ischemia/reperfusion in rats. World J Gastroenterol 2007; 13:874-81. [PMID: 17352016 PMCID: PMC4065922 DOI: 10.3748/wjg.v13.i6.874] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of electrical stimulation of hypothalamic paraventricular nuclei (PVN) on gastric mucosal cellular apoptosis and proliferation induced by gastric ischemia/reperfusion (I/R) injury.
METHODS: For different experimental purposes, stimulating electrode plantation or electrolytic destruction of the PVN was applied, then the animals’ GI/R injury model was established by clamping the celiac artery for 30 min and allowing reperfusing the artery for 30 min, 1 h, 3 h or 6 h respectively. Then histological, immunohistochemistry methods were used to assess the gastric mucosal damage index, the gastric mucosal cellular apoptosis and proliferation at different times.
RESULTS: The electrical stimulation of PVN significantly attenuated the GI/R injury at 30 min, 1 h and 3 h after reperfusion. The electrical stimulation of PVN decreased gastric mucosal apoptosis and increased gastric mucosal proliferation. The electrolytic destruction of the PVN could eliminate the protective effects of electrical stimulation of PVN on GI/R injury. These results indicated that the PVN participated in the regulation of GI/R injury as a specific area in the brain, exerting protective effects against the GI/R injury, and the protection was associated with the inhibition of cellular apoptosis and the promotion of gastric mucosal proliferation.
CONCLUSION: Stimulating PVN significantly inhibits the gastric mucosal cellular apoptosis and promots gastric mucosal cellular proliferation. This may explain the protective mechanisms of electrical stimulation of PVN against GI/R injury.
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Affiliation(s)
- Li Li
- Department of Pathophysiology, Xuzhou Medical College, Xuzhou 221002, Jiangsu Province, China
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Qiao WL, Wang L, Zhang YM, Zhang JF, Wang GM. Extracellular signal-regulated kinase 1- and 2-mediated gastric mucosal injury and repair in gastric ischemia-reperfusion of rats. J Gastroenterol 2006; 41:1158-68. [PMID: 17287895 DOI: 10.1007/s00535-006-1902-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2006] [Accepted: 08/27/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND The current study was undertaken to investigate the time course of gastric ischemia-reperfusion (GI-R)-induced gastric mucosal injury and repair and whether extracellular signal-regulated kinase 1/2 (ERK1/2) were involved in GI-R-induced gastric mucosal injury and repair. METHODS Immunohistochemistry and Western blot analyses were used. RESULTS Gastric mucosal injury induced by ischemia alone was mild. However, the injury worsened after reperfusion, reaching a maximum at 1 h, and was accompanied by increased apoptotic cells and decreased proliferative cells. Then, the gastric mucosal cells began to repair the injury by enhanced proliferation, which peaked at 24 h after reperfusion, and by 72 h the damaged gastric mucosa was mostly repaired. The ERK1/2 (nonactivated ERK1/2) protein expression level and distribution profile showed no significant changes during the entire reperfusion phase, but the p-ERK1/2 (activated ERK1/2) level changed dramatically. The p-ERK1/2 protein level was decreased at 0.5 h after reperfusion began, and then gradually increased, peaking after 3 h of reperfusion; these changes in p-ERK1/2 occurred simultaneously in the cytoplasm and nucleus. On the other hand, inhibition of the activation of ERK1/2, induced by PD98059, a specific ERK1/2 upstream inhibitor, aggravated the gastric mucosal injury, and apoptosis was increased and proliferation was reduced in the gastric mucosal cells after the same duration of reperfusion. CONCLUSIONS Serious gastric mucosal damage involving apoptotic cells occurred rapidly at an early stage of reperfusion and was closely related to the suppression of ERK1/2 activation. The activated ERK1/2 signaling transduction pathway played an important role. Activated ERK1/2 participated in the regulation of gastric mucosal injury and repair induced by GI-R, and might be mediated by the inhibition of apoptosis and the promotion of proliferation in gastric mucosal cells.
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Affiliation(s)
- Wei-Li Qiao
- Department of Physiology and Neurobiology, Xuzhou Medical College, 84 West Huai-hai Road, Xuzhou 221002, Jiangsu, China
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Wu WKK, Li GR, Wong HPS, Hui MKC, Tai EKK, Lam EKY, Shin VY, Ye YN, Li P, Yang YH, Luo JC, Cho CH. Involvement of Kv1.1 and Nav1.5 in proliferation of gastric epithelial cells. J Cell Physiol 2006; 207:437-44. [PMID: 16331678 DOI: 10.1002/jcp.20576] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
In the present study, patch clamp experiments demonstrated the expression of multiple ionic currents, including a Ba2+-sensitive inward rectifier K+ current (IKir), a 4-aminopyridine- (4-AP) sensitive delayed rectifier K+ current (IKDR), and a nifedipine-sensitive, tetrodotoxin-resistant inward Na+ current (INa.TTXR) in the non-transformed rat gastric epithelial cell line RGM-1. RT-PCR revealed molecular identities of mRNAs for the functional ionic currents, including Kir1.2 for IKir, Kv1.1, Kv1.6, and Kv2.1 for IKDR, and Nav1.5 for INa.TTXR. Pharmacologic blockade of Kv and Nav, but not Kir, suppressed RGM-1 cell proliferation. To further elucidate which subtypes of the ion channels were involved in cell proliferation, RNA interference was employed to knockdown specific gene expression. Downregulation of Kv1.1 or Nav1.5 by RNA interference suppressed RGM-1 cell proliferation. To conclude, our study is the first to delineate the expression of ion channels and their functions as growth modulators in gastric epithelial cells.
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Affiliation(s)
- William Ka Kei Wu
- Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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Wang W, Bergh A, Damber JE. Cyclooxygenase-2 expression correlates with local chronic inflammation and tumor neovascularization in human prostate cancer. Clin Cancer Res 2005; 11:3250-6. [PMID: 15867220 DOI: 10.1158/1078-0432.ccr-04-2405] [Citation(s) in RCA: 113] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Chronic inflammation is linked to the development of cancer in several organs, including the prostate. Up-regulated cyclooxygenase-2 (COX-2) may play a role in influencing cell proliferation, differentiation, apoptosis, or angiogenesis. This study aimed to derive data from human prostate cancer to investigate whether chronic inflammation and angiogenesis were correlated with the expression of COX-2. EXPERIMENTAL DESIGN In this study, we did double-immunohistochemical analysis of a set of 43 human prostate cancer for COX-2 expression and the correlation with T-lymphocyte and macrophage densities and CD31-marked microvessel density (MVD) in situ. RESULTS COX-2 positive staining was detected in 40/43 cancer samples with the very heterogeneous expression. Elevated COX-2 expression was associated with high Gleason score (P = 0.002). Foci of chronic inflammation were found in all 43 samples. COX-2-positive areas were noted with high T-lymphocyte and macrophage densities than COX-2-negative tumor areas (P < 0.0001 and P = 0.001, respectively). MVD were also found higher in COX-2-positive areas than in COX-2-negative tumor areas (P = 0.001). CONCLUSIONS This study shows a novel relationship between COX-2 expression and the local chronic inflammation within prostate cancer and the increased angiogenesis. It is likely that the proinflammatory cytokines, released by T-lymphocytes and macrophages, up-regulate COX-2 in adjacent tumor cells and stimulate the angiogenesis in stromal tissues. These findings suggest that COX-2 may be an effective therapeutic target in prostate cancer treatment.
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Affiliation(s)
- Wanzhong Wang
- Department of Urology, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden
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