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Fayez SM, Elnahas OS, Fayez AM, El-Mancy SS. Coconut oil based self-nano emulsifying delivery systems mitigate ulcerogenic NSAIDs side effect and enhance drug dissolution: Formula optimization, in-vitro, and in-vivo assessments. Int J Pharm 2023; 634:122666. [PMID: 36736674 DOI: 10.1016/j.ijpharm.2023.122666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 02/04/2023]
Abstract
Gastric ulcer is a common gastrointestinal ailment that affects many people worldwide. NSAIDs induced ulcers are the second most common etiology of gastric ulcers. Coconut oil has well-known potential anti-ulcerogenic characteristics. This work aimed to develop and optimize diclofenac potassium (a highly used model drug of NSAIDs) as self-nanoemulsifying delivery system containing coconut oil (DFP-COSNEDS) to overcome its ulcerogenic effect. A mixture design was applied for formula optimization and investigation of the effect of different formulation factors on the droplet size (DS) and polydispersity index (PDI) of the prepared DFP-COSNEDS. The optimized formulae showed good self-emulsification characters and better drug dissolution compared with the drug suspension. The ulcer protection was assessed in-vivo using 7 groups of adult male Wistar rats. Oxidative stress parameters (MDA, GSH, and SOD), inflammatory mediators (PGE-2, TNF-α, and IL-6) and peroxisome proliferator-activated receptor-γ (PPAR-γ) gene expression were measured. The results revealed that pure coconut oil and DFP-COSNEDS containing 25 % of coconut oil showed close figures to normal group and better values than famotidine (FAM) group. In conclusion, coconut oil showed high potential for gastric-protection activity against DFP induced ulcer. DFP-COSNEDS offers dual benefits of improving DFP dissolution and alleviating its ulcerogenic effect.
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Affiliation(s)
- Sahar M Fayez
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, Giza, Egypt.
| | - Osama S Elnahas
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, Giza, Egypt.
| | - Ahmed M Fayez
- Department School of Life and Medical Sciences, University of Hert-fordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo, Egypt.
| | - Shereen S El-Mancy
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, October 6 University, Giza, Egypt.
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Visceral-to-subcutaneous fat ratio independently predicts the prognosis of locally advanced gastric cancer----- highlighting the role of adiponectin receptors and PPARα, β/ δ, ɤ. Eur J Surg Oncol 2021; 47:3064-3073. [PMID: 33941417 DOI: 10.1016/j.ejso.2021.04.028] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/23/2021] [Accepted: 04/20/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Results of computed tomography body composition (CTBC) predicting long-term outcomes of gastric cancer have been mixed and the plausible mechanism remains elusive. METHODS We retrospectively enrolled a cohort of stage III gastric cancer who had undergone curative-intent gastrectomy. Clinicopathological variables, preoperative CTBC including abdominal muscle, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and nutritional and inflammatory index were taken together to construct prognostic analysis. In vitro tests using co-culture system of gastric cancer cell lines and visceral adipocytes were conducted. RESULTS A total of 191 eligible patients were enrolled. By multivariate analysis, SAT and VAT/ SAT ratio were prognostic factors of disease-free survival, while sarcopenia was not. SAT remained as a prognostic factor of overall survival. SAT index was positively correlated with prognostic nutritional index, while VAT HU was positively correlated with platelet-to-lymphocyte ratio. Expression of adiponectin receptor 1 and 2 (AdipoR1, R2), and peroxisome proliferator-activated receptor (PPAR) α, β/δ, ɤ of patients with higher VAT/SAT ratio were decreased as compared to those with lower VAT/SAT ratio. Proliferation of gastric cancer cells co-cultured with adipocytes was increased by 50-100% and accompanied by down-regulation of mRNAs of AdipoR1, 2, PPARα, β/δ, ɤ, and pro-apoptotic genes, as compared to their controls. CONCLUSION SAT and VAT played exactly opposite prognostic roles of locally advanced gastric cancers, which might work through modulation of AdipoR1, 2 and PPARα, β/δ, ɤ. Preoperative CTBC, supplementary to classic TNM system, helps clinicians tailor individualized adjuvant therapy and/or nutritional support.
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Guo X, Cheng L, Yang S, Che H. Pro-inflammatory immunological effects of adipose tissue and risk of food allergy in obesity: Focus on immunological mechanisms. Allergol Immunopathol (Madr) 2020; 48:306-312. [PMID: 31477390 DOI: 10.1016/j.aller.2019.06.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/21/2019] [Accepted: 06/03/2019] [Indexed: 12/12/2022]
Abstract
Over the past three decades, the number of obese people has risen steadily. The chronic low-grade inflammatory state and the non-specific activation of the immune system have contributed greatly to the development of obesity-related immunology. Food allergy as a kind of inflammatory disease with abnormal immune response may be associated with obesity. This review begins with the pro-inflammatory immunological effects of adipose tissue in obesity, and explains the possible effects of obesity on food allergy. In short, obesity not only directly causes imbalance of allergic-related immune cells in adipose tissue, but also indirectly causes this consequence through affecting expression of adipocytokines and peroxisome proliferator-activated receptor gamma (PPARγ) in adipose tissue. As a result, circulating levels of pro-inflammatory factors which are partly derived from adipose tissue increase, which might cause intestinal barrier injury. Therefore, obesity may increase the risk of food allergy.
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Affiliation(s)
- X Guo
- College of Food Science and Nutritional Engineering, China Agricultural University, China; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, China
| | - L Cheng
- College of Food Science and Nutritional Engineering, China Agricultural University, China; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, China
| | - S Yang
- College of Food Science and Nutritional Engineering, China Agricultural University, China; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, China
| | - H Che
- College of Food Science and Nutritional Engineering, China Agricultural University, China; Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, China.
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Kim SH, Lim JW, Kim H. Astaxanthin Inhibits Mitochondrial Dysfunction and Interleukin-8 Expression in Helicobacter pylori-Infected Gastric Epithelial Cells. Nutrients 2018; 10:E1320. [PMID: 30231525 PMCID: PMC6164770 DOI: 10.3390/nu10091320] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 09/10/2018] [Accepted: 09/17/2018] [Indexed: 02/06/2023] Open
Abstract
Helicobacter pylori (H. pylori) infection leads to gastric inflammation, peptic ulcer and gastric carcinoma. H. pylori activates NADPH oxidase and increases reactive oxygen species (ROS), which induce NF-κB activation and IL-8 expression in gastric epithelial cells. Dysfunctional mitochondria trigger inflammatory cytokine production. Peroxisome proliferator-activated receptors-γ (PPAR-γ) regulate inflammatory response. Astaxanthin is a powerful antioxidant that protects cells against oxidative stress. The present study was aimed at determining whether astaxanthin inhibits H. pylori-induced mitochondrial dysfunction, NF-κB activation, and IL-8 expression via PPAR-γ activation in gastric epithelial cells. Gastric epithelial AGS cells were treated with astaxanthin, NADPH oxidase inhibitor apocynin and PPAR-γ antagonist GW9662, and infected with H. pylori. As a result, H. pylori caused an increase in intracellular and mitochondrial ROS, NF-κB activation and IL-8 expression, but decreased mitochondrial membrane potential and ATP level. Astaxanthin inhibited H. pylori-induced alterations (increased ROS, mitochondrial dysfunction, NF-κB activation, and IL-8 expression). Astaxanthin activated PPAR-γ and its target gene catalase in H. pylori-infected cells. Apocynin reduced ROS and inhibited IL-8 expression while astaxanthin did not affect NADPH oxidase activity. Inhibitory effects of astaxanthin on ROS levels and IL-8 expression were suppressed by addition of GW9662. In conclusion, astaxanthin inhibits H. pylori-induced mitochondrial dysfunction and ROS-mediated IL-8 expression by activating PPAR-γ and catalase in gastric epithelial cells. Astaxanthin may be beneficial for preventing oxidative stress-mediated gastric inflammation-associated H. pylori infection.
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Affiliation(s)
- Suhn Hyung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Joo Weon Lim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
| | - Hyeyoung Kim
- Department of Food and Nutrition, Brain Korea 21 PLUS Project, College of Human Ecology, Yonsei University, Seoul 03722, Korea.
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Abd-Elhakim YM, Hashem MM, Anwar A, El-Metwally AE, Abo-El-Sooud K, Moustafa GG, Mouneir SM, Ali HA. Effects of the food additives sodium acid pyrophosphate, sodium acetate, and citric acid on hemato-immunological pathological biomarkers in rats: Relation to PPAR-α, PPAR-γ and tnfα signaling pathway. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2018; 62:98-106. [PMID: 29986283 DOI: 10.1016/j.etap.2018.07.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 06/28/2018] [Accepted: 07/02/2018] [Indexed: 06/08/2023]
Abstract
The food additives sodium acid pyrophosphate (SAPP), sodium acetate (SA), and citric acid (CA) were evaluated for their hemato-immunotoxic effects. Forty adult Sprague-Dawley rats were distributed into four groups and were orally administered water, SAPP (12.6 mg/kg), CA (180 mg/kg), or SA (13.5 mg /kg) daily for 90 days. Erythrogram and leukogram profiles were evaluated. The levels of lysozyme, nitric oxide, immunoglobulin, and phagocytic activity were measured. Histologic and immunohistochemical evaluations of splenic tissues were performed. Changes in the mRNA expression levels of peroxisome proliferator-activated receptor α and γ (PPAR-α and PPAR-γ), and tumor necrosis factor α (TNF-α) genes were assessed. A significant leukopenic condition was observed with SAPP, while CA induced marked leukocytosis, and SA showed a lymphocytosis condition. Both the innate and humoral parameters were significantly depressed. Various pathological lesions were observed, including diffuse hyperplasia of the red pulp, depletion of the white pulp, and capsular and parenchymal fibrosis. A marked decrease in CD3 T-lymphocyte and CD20 B-lymphocyte immunolabeling in rats treated with SAPP and SA was evident. Marked downregulation of PPAR-α and PPAR-γ together with upregulation of TNF-α was recorded. These results indicate that high doses of SAPP, SA and CA exert hematotoxic and immunotoxic effects with long-term exposure.
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Affiliation(s)
| | - Mohamed M Hashem
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Abeer Anwar
- Immunology Unit, Animal Reproduction Research Institute (ARRI), Gizza, Egypt
| | - Abeer E El-Metwally
- Pathology Department, Animal Reproduction Research Institute (A.R.R.I.), Giza, Egypt
| | - Khaled Abo-El-Sooud
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Gihan G Moustafa
- Department of Forensic Medicine and Toxicology, Zagazig University, Zagazig, Egypt
| | - Samar M Mouneir
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Haytham A Ali
- Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt; Department of Biochemistry, Faculty of science, University of Jeddah, Saudi Arabia
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Mohseni Moghadam Z, Mahmoodzadeh Hosseini H, Amin M, Behzadi E, Imani Fooladi AA. Microbial metabolite effects on TLR to develop autoimmune diseases. TOXIN REV 2018. [DOI: 10.1080/15569543.2018.1469512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Affiliation(s)
- Zeinab Mohseni Moghadam
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Hamideh Mahmoodzadeh Hosseini
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mohsen Amin
- Department of Drug and Food Control, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Elham Behzadi
- Department of Microbiology, College of Basic Sciences, Islamic Azad University, Shahr-e-Qods Branch, Tehran, Iran
| | - Abbas Ali Imani Fooladi
- Applied Microbiology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Lysophospholipid-Related Diseases and PPARγ Signaling Pathway. Int J Mol Sci 2017; 18:ijms18122730. [PMID: 29258184 PMCID: PMC5751331 DOI: 10.3390/ijms18122730] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Revised: 12/14/2017] [Accepted: 12/15/2017] [Indexed: 02/04/2023] Open
Abstract
The nuclear receptor superfamily includes ligand-inducible transcription factors that play diverse roles in cell metabolism and are associated with pathologies such as cardiovascular diseases. Lysophosphatidic acid (LPA) belongs to a family of lipid mediators. LPA and its naturally occurring analogues interact with G protein-coupled receptors on the cell surface and an intracellular nuclear hormone receptor. In addition, several enzymes that utilize LPA as a substrate or generate it as a product are under its regulatory control. Recent studies have demonstrated that the endogenously produced peroxisome proliferator-activated receptor gamma (PPARγ) antagonist cyclic phosphatidic acid (cPA), which is structurally similar to LPA, inhibits cancer cell invasion and metastasis in vitro and in vivo. We recently observed that cPA negatively regulates PPARγ function by stabilizing the binding of the co-repressor protein, a silencing mediator of retinoic acid, and the thyroid hormone receptor. We also showed that cPA prevents neointima formation, adipocyte differentiation, lipid accumulation, and upregulation of PPARγ target gene transcription. The present review discusses the arbitrary aspects of the physiological and pathophysiological actions of lysophospholipids in vascular and nervous system biology.
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Yoon H, Kim SG, Kim BK, Shin E, Kim N, Lee HJ, Kang GH, Jung HC. Helicobacter pylori Eradication Downregulates Cellular Inhibitor of Apoptosis Protein 2 in Gastric Carcinogenesis. Gut Liver 2017; 11:79-86. [PMID: 27282269 PMCID: PMC5221864 DOI: 10.5009/gnl15585] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Revised: 01/03/2016] [Accepted: 01/03/2016] [Indexed: 12/13/2022] Open
Abstract
Background/Aims To evaluate the expression of cellular inhibitor of apoptosis protein 2 (cIAP2) during gastric carcinogenesis after Helicobacter pylori (HP) infection and after HP eradication. Methods We divided non-cancer patients into four groups according to the status of HP infection and atrophic gastritis (AG)/intestinal metaplasia (IM). We compared cIAP2 mRNA expression among these four groups and patients with HP-positive early gastric cancer (EGC) by using real-time polymerase chain reaction (PCR). We evaluated the expression of cIAP2 messenger RNA (mRNA)/protein by using real-time PCR/immunohistochemistry and the degree of apoptosis with a terminal deoxynucleotidyl transferase-mediated nick end labeling assay before and 12 months after endoscopic submucosal dissection (ESD) in HP-positive EGC patients, regardless of whether they had undergone eradication therapy. Results The expression of cIAP2 mRNA was significantly higher in the groups with HP(+), AG/IM(+), and HP-positive EGC than in the control, HP(+), and AG/IM(−) groups (p<0.005). In the HP eradication group, the expression of cIAP2 mRNA/protein significantly decreased (p=0.006) and apoptosis increased at the 12-month follow-up after ESD. In the HP noneradication group, the aforementioned changes were not found during the same follow-up period. Conclusions The expression of cIAP2 increased during gastric carcinogenesis after HP infection; HP eradication in the patients who had undergone ESD for EGC reversed overexpression of cIAP2 and suppressed cell apoptosis.
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Affiliation(s)
- Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sang Gyun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Bo Kyoung Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Shin
- Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.,Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyuk-Joon Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Chae Jung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Dhar P, Ng GZ, Sutton P. How host regulation of Helicobacter pylori-induced gastritis protects against peptic ulcer disease and gastric cancer. Am J Physiol Gastrointest Liver Physiol 2016; 311:G514-20. [PMID: 27469367 DOI: 10.1152/ajpgi.00146.2016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 07/26/2016] [Indexed: 01/31/2023]
Abstract
The bacterial pathogen Helicobacter pylori is the etiological agent of a range of gastrointestinal pathologies including peptic ulcer disease and the major killer, gastric adenocarcinoma. Infection with this bacterium induces a chronic inflammatory response in the gastric mucosa (gastritis). It is this gastritis that, over decades, eventually drives the development of H. pylori-associated disease in some individuals. The majority of studies investigating H. pylori pathogenesis have focused on factors that promote disease development in infected individuals. However, an estimated 85% of those infected with H. pylori remain completely asymptomatic, despite the presence of pathogenic bacteria that drive a chronic gastritis that lasts many decades. This indicates the presence of highly effective regulatory processes in the host that, in most cases, keeps a check on inflammation and protect against disease. In this minireview we discuss such known host factors and how they prevent the development of H. pylori-associated pathologies.
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Affiliation(s)
- Poshmaal Dhar
- Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; Centre for Animal Biotechnology, School of Veterinary and Agricultural Science, University of Melbourne, Parkville, Victoria, Australia; and
| | - Garrett Z Ng
- Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; Centre for Animal Biotechnology, School of Veterinary and Agricultural Science, University of Melbourne, Parkville, Victoria, Australia; and
| | - Philip Sutton
- Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia; Centre for Animal Biotechnology, School of Veterinary and Agricultural Science, University of Melbourne, Parkville, Victoria, Australia; and Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
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Ramakrishna YG, Savithri K, Kist M, Devaraj SN. Aegle marmelos fruit extract attenuates Helicobacter pylori Lipopolysaccharide induced oxidative stress in Sprague Dawley rats. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 15:375. [PMID: 26482072 PMCID: PMC4615325 DOI: 10.1186/s12906-015-0915-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/02/2015] [Accepted: 10/13/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Bael (Aegle marmelos (L.) Corr.) has been widely used in indigenous systems of Indian medicine to exploit its medicinal properties including astringent, antidiarrheal, antidysenteric, demulcent, antipyretic, antiulcer, anti-inflammatory and anti cancer activities. The present study aims to evaluate the antioxidative and antiulcer effect of methanolic extract of unripe fruit of Aegle marmelos (MEAM) against Helicobacter pylori-Lipopolysaccharide (HP-LPS) induced gastric ulcer in Sprague Dawley (SD) rats. METHODS Dose and duration of HP-LPS and MEAM were fixed based on ulcer index of gastric tissue of experimental animals. Various gastric secretory parameters such as volume of gastric juice, free and total acidity, acid output, pepsin concentration were analyzed. The activities of enzymatic antioxidants (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione transferase), non-enzymatic antioxidants (reduced glutathione, vitamin C and vitamin E) and the levels of lipid peroxidation products were measured. Histological analysis was performed to evaluate the effect of Aegle marmelos on HP-LPS induced gastric ulcer. RESULTS Oral administration of HP-LPS (50 μg per animal) for four consecutive days resulted in induction of ulcer with the increase in gastric secretory parameters such as volume of gastric juice, free and total acidity, acid output, pepsin concentration. Oral administration of methanolic extract of Aegle marmelos fruit (MEAM) (25, 50, 100, 250 and 500 mg/kg) reduced the gastric ulcer by 2.8 %, 52.4 %, 73 %, 93 % and 93.98 %, respectively, compared to 89.2 % reduction by sucralfate (100 mg/kg). MEAM treatment significantly (p < 0.05) inhibited the increase in gastric secretory parameters in ulcerated rats, and it also prevented the reduction of enzymatic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione transferase) and non-enzymatic antioxidants (reduced glutathione, vitamin C and vitamin E) after HP-LPS induction. In addition, lipid peroxidation was inhibited by MEAM in HP-LPS induced rats. Results of histological analysis correlated well with biochemical parameters. CONCLUSION These observations explored the antioxidant properties of MEAM contributing to the gastroprotective effect in HP-LPS induced gastric ulcer model.
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Affiliation(s)
| | - Kumarasamy Savithri
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai, 600025, India.
| | - Manfred Kist
- Institut fur Medizinische, Mekrobiologie und Hygiene, Freiburg, Germany.
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Zhao J, Zhi Z, Song G, Wang J, Wang C, Ma H, Yu X, Sui A, Zhang H. Peroxisome Proliferator-Activated Receptor-Gamma Pro12Ala Polymorphism Could be a Risk Factor for Gastric Cancer. Asian Pac J Cancer Prev 2015; 16:2333-40. [DOI: 10.7314/apjcp.2015.16.6.2333] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Cho SJ, Kook MC, Lee JH, Shin JY, Park J, Bae YK, Choi IJ, Ryu KW, Kim YW. Peroxisome proliferator-activated receptor γ upregulates galectin-9 and predicts prognosis in intestinal-type gastric cancer. Int J Cancer 2014; 136:810-20. [PMID: 24976296 DOI: 10.1002/ijc.29056] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 06/13/2014] [Indexed: 12/23/2022]
Abstract
The importance of PPARγ (peroxisome proliferator-activated receptor γ) in gastric cancer (GC) is unclear. We investigated the role of PPARγ in GC cell lines and an animal model, and its prognostic significance of PPARγ in GC patients. We controlled PPARγ and galectin-9 expression by using siRNAs and lentiviral constructs. Interaction between PPARγ and galectin-9 was evaluated using luciferase and chromatin immunoprecipitation assays. PPARγ expression in GCs was determined by immunohistochemical staining of tissue microarrays and survival analysis was done. Overexpression of PPARγ was accompanied by increased galectin-9. Enhanced PPARγ or galectin-9 expression increased E-cadherin expression; decreased expression of N-cadherin, fibronectin, snail, twist and slug and reduced cell invasion and migration. PPARγ bound to the galectin-9 promoter region. Galectin-9 activity increased in PPARγ-overexpressing cells but decreased in PPARγ siRNA-treated cells. In a zebrafish xenograft model, the number of migrated cancer cells and number of fish with AGS cells in the tail vein were reduced in PPARγ-overexpressing GC cells. PPARγ was expressed in 462 of the 688 patients (69.2%) with GC. In 306 patients with intestinal-type GC, those with PPARγ-positive tumors had lower overall and cancer-specific mortalities than those with PPARγ-negative tumors. PPARγ expression was an independent prognostic factor for overall and GC-specific mortality in patients with intestinal-type GC (adjusted hazard ratio, 0.42; 95% CI, 0.22-0.81). PPARγ inhibits cell invasion, migration and epithelial-mesenchymal transition through upregulation of galectin-9 in vitro and in vivo.
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Affiliation(s)
- Soo-Jeong Cho
- Center for Gastric Cancer, National Cancer Center, Gyeonggi, Republic of Korea
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Chang SS, Hu HY. Association of thiazolidinediones with gastric cancer in type 2 diabetes mellitus: a population-based case-control study. BMC Cancer 2013; 13:420. [PMID: 24041200 PMCID: PMC3850900 DOI: 10.1186/1471-2407-13-420] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2012] [Accepted: 09/10/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND It has been shown that peroxisome proliferator-activated receptors (PPAR) have physiological and pharmacological ligands. The objective is to assess the association between thiazolidinediones (TZDs) and the occurrence of gastric cancer. METHODS We conducted a population-based nested case-control study. Data were retrospectively collected from the National Health Insurance Research Database (NHIRD). The cases consisted of all diabetes mellitus (DM) patients aged 30 to 99 years, and who had a first time diagnosis of gastric cancer in the study cohort. The controls were matched to cases by age, sex, and index date. The adjusted odds ratio (OR) and 95% confidence interval (CI) were estimated by using multiple logistic regression. RESULTS Records from 357 gastric cancer and 1,428 selected matched controls were included in the analyses of gastric cancer risk. A total of 7% or 9.5% of the cases and 10.8% or 14.8% of the controls had used any quantity of at least 2 prescriptions for pioglitazone or rosiglitazone, respectively. After adjusting for possible confounders, pioglitazone (OR = 0.93, P > 0.05) and rosiglitazone (OR = 1.21, P > 0.05), had no significant association of decreasing gastric cancer. After adjusting for possible confounders, pioglitazone (OR = 0.70, P > 0.05) or rosiglitazone (OR = 0.79, P > 0.05), had no significant trend toward decreasing gastric cancer risk with increasing cumulative doses ≥ 260 defined daily doses (DDDs), respectively. Moreover, adjusting for possible confounders pioglitazone (OR = 0.68, P > 0.05) or rosiglitazone (OR = 0.74, P > 0.05) had no significant trend toward decreasing gastric cancer risk with increasing cumulative doses ≥ 1 year, respectively. CONCLUSIONS Our results did not show evidence to support that TZD derivatives in DM patients reduces gastric cancer occurrence.
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Affiliation(s)
- Shen-Shong Chang
- Institute of Public Health & Department of Public Health, National Yang-Ming University, Taipei, Taiwan.
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Lu Y, Zhou Q, Zhong F, Guo S, Hao X, Li C, Wang W, Chen N. 15-Deoxy-Δ(12,14)-prostaglandin J(2) modulates lipopolysaccharide-induced chemokine expression by blocking nuclear factor-κB activation via peroxisome proliferator activated receptor-γ-independent mechanism in renal tubular epithelial cells. Nephron Clin Pract 2013; 123:1-10. [PMID: 23887394 DOI: 10.1159/000353232] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Accepted: 07/25/2013] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND/AIMS Inflammation is an unavoidable milieu for renal tubular cells during the development of renal tubulointerstitial fibrosis. It has been demonstrated that chemokines including monocyte chemoattractant protein-1 (MCP-1) and IL-8 are related to tubulointerstitial lesions. 15d-PGJ2 may modulate renal tubulointerstitial fibrosis progression via anti-inflammatory effects. However, no information is known about the effects of 15d-PGJ2 on chemokine expression in human proximal renal tubular cells (HPTECs) under inflammation. METHODS In the present study, HPTECs (HK-2 cells) were stimulated with lipopolysaccharide (LPS) only, or preincubated with 15d-PGJ2. IL-8 and MCP-1 expressions were determined by real-time PCR and ELISA. Nuclear factor-κB (NF-κB) location was detected by immunofluorescence analysis. The p-IKK, p-IκBα and p65/p50 were analyzed by immunoblotting. To investigate the mechanism of inhibitory effects of 15d-PGJ2, the PPAR-γ gene was effectively silenced in HK-2 cells using specific siRNA. RESULTS The results showed that application of LPS significantly increased IL-8 and MCP-1 production. Phosphorylation of IκBα, IKK and nucleus translocation of NF-κB significantly increased in LPS-stimulated HK-2 cells. 15d-PGJ2 downregulated LPS-induced IL-8 and MCP-1 production. Interestingly, in PPAR-γ-deficient HK-2 cells, 15d-PGJ2 was still capable of inhibiting chemokines expression and attenuating phosphorylation of IκBα and nucleus translocation of NF-κB. CONCLUSION Collectively, these results suggest that 15d-PGJ2 exerts anti-inflammatory actions on HK-2 cells by attenuating chemokines expression. 15d-PGJ2 inhibits chemokines expression via a PPAR-γ-independent way, which is related to block NF-κB pathway. Since NF-κB is an important regulator of the response of HPTECs to injury, PPAR-γ agonists may represent a key pharmacological target for ameliorating inflammation-associated tubulointerstitial fibrosis.
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Affiliation(s)
- Ying Lu
- Department of Nephrology, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, PR China
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15
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Pimentel-Nunes P, Gonçalves N, Boal-Carvalho I, Afonso L, Lopes P, Roncon-Albuquerque R, Henrique R, Moreira-Dias L, Leite-Moreira AF, Dinis-Ribeiro M. Helicobacter pylori induces increased expression of Toll-like receptors and decreased Toll-interacting protein in gastric mucosa that persists throughout gastric carcinogenesis. Helicobacter 2013; 18:22-32. [PMID: 23061653 DOI: 10.1111/hel.12008] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Toll-like receptors (TLR) are essential for Helicobacter pylori (HP) recognition. Their role in the progression of gastric lesions leading to cancer is not established. AIM To evaluate for the first time in humans the expression of TLR2, TLR4, and TLR5, as well as the expression of other related molecules in the entire sequence of gastric lesions. METHODS Biopsy samples (n = 80, 48% HP+) from normal mucosa, HP gastritis, metaplasia, dysplasia or adenocarcinoma were obtained from 44 patients. mRNA quantification of TLR2, TLR4, TLR5, Toll-interacting protein (TOLLIP), PPAR-γ, NF-κB, TNF-α, COX-1, COX-2, and CDX-2 was performed by real-time RT-PCR. TLR2, TLR4, and TLR5 protein expression was quantified by immunohistochemistry. RESULTS When compared to normal mucosa (1.0 arbitrary unit (AU)), HP gastritis presented higher expression of TLR2 (2.23 ± 0.36 AU), TLR4 (1.92 ± 0.40 AU) and TNF-α (2.14 ± 0.50 AU) and lower TOLLIP and PPARγ expression (0.72 ± 0.12 AU, p < .05 all genes). Metaplasia and dysplasia/carcinoma presented higher expression of TLR2 (1.66 ± 0.46 and 1.48 ± 0.20 AU, respectively, p < .05), lower expression of TOLLIP (0.66 ± 0.09 and 0.52 ± 0.04 AU, p < .05) and PPARγ (0.73 ± 0.12 and 0.63 ± 0.10 AU, p < .05). The significant trend for decrease in TOLLIP and PPARγ was associated with increasing levels of CDX-2 from normal mucosa to carcinoma (p < .05), translating that in diffuse and higher TLRs protein expression (p < .05). CONCLUSION Gastric carcinogenesis is associated with decreasing levels of TLRs inhibitors and elevated TLRs levels throughout all the spectrum of lesions. Future studies should investigate if modulation of these receptors activity may influence gastric carcinogenesis and tumor progression.
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Affiliation(s)
- Pedro Pimentel-Nunes
- Department of Physiology and Cardiothoracic Surgery, University of Porto, Porto, Portugal.
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Lee JM, Kim SS, Cho YS. The Role of PPARγ in Helicobacter pylori Infection and Gastric Carcinogenesis. PPAR Res 2012; 2012:687570. [PMID: 22936949 PMCID: PMC3425866 DOI: 10.1155/2012/687570] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Accepted: 07/16/2012] [Indexed: 11/17/2022] Open
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is important in many physiological and pathological processes, such as lipid metabolism, insulin sensitivity, inflammation, cell proliferation, and carcinogenesis. Several studies have shown that PPARγ plays an important role in gastric mucosal injury due to Helicobacter pylori (H. pylori). As H. pylori infection is the main etiologic factor in chronic gastritis and gastric cancer, understanding of the potential roles of PPARγ in H. pylori infection may lead to the development of a therapeutic target. In this paper, the authors discuss the current knowledge on the role of PPARγ in H. pylori infection and its related gastric carcinogenesis.
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Affiliation(s)
- Jong-Min Lee
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 480717, Republic of Korea
| | - Sung Soo Kim
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 480717, Republic of Korea
| | - Young-Seok Cho
- Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu 480717, Republic of Korea
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Ohta M, Kawano H, Notsu T, Naba H, Imada K. Eicosapentaenoic acid attenuates statin-induced ER stress and toxicity in myoblast. Biochem Biophys Res Commun 2012; 424:301-7. [DOI: 10.1016/j.bbrc.2012.06.111] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 06/21/2012] [Indexed: 11/29/2022]
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The Ras inhibitors caveolin-1 and docking protein 1 activate peroxisome proliferator-activated receptor γ through spatial relocalization at helix 7 of its ligand-binding domain. Mol Cell Biol 2011; 31:3497-510. [PMID: 21690289 DOI: 10.1128/mcb.01421-10] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that promotes differentiation and cell survival in the stomach. PPARγ upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPARγ is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPARγ signaling. We show here that loss of Cav1 accelerated proliferation of normal stomach and GC cells in vitro and in vivo. Downregulation of Cav1 increased Ras/MAPK-dependent phosphorylation of serine 84 in PPARγ and enhanced nuclear translocation and ligand-independent transcription of PPARγ target genes. In contrast, Cav1 overexpression sequestered PPARγ in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPARγ's ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPARγ and to inhibit cell proliferation. Ligand-activated PPARγ also reduced tumor growth and upregulated the Ras/MAPK inhibitors Cav1 and Dok1 in a murine model of GC. These results suggest a novel mechanism of PPARγ regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPARγ to ligands, limiting proliferation of gastric epithelial cells.
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19
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Chu SH, Lim JW, Kim DG, Lee ES, Kim KH, Kim H. Down-regulation of Bcl-2 is mediated by NF-κB activation in Helicobacter pylori-induced apoptosis of gastric epithelial cells. Scand J Gastroenterol 2011; 46:148-55. [PMID: 20969490 DOI: 10.3109/00365521.2010.525255] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Bcl-2 family is involved in the regulation of apoptosis. NF-κB activation is associated with either the expression of Bcl-2 or down-regulation of Bcl-2 depending on cell types and stimuli. Previously, we showed NF-κB activation, decrease in the level of Bcl-2, and apoptosis in Helicobacter pylori (H. pylori)-infected gastric epithelial cells. The present study aims to investigate the relation of Bcl-2 expression and NF-κB activation in H. pylori-induced apoptotic cell death of AGS (gastric adenocarcinoma) cells. MATERIAL AND METHODS AGS cells were transfected with mutant IκBα to suppress NF-κB activation or Bcl-2 gene to induce overexpression of Bcl-2. mRNA expression of Bcl-2, p53 and Bax, DNA fragmentation, cell viability, and the numbers of apoptotic cells were determined. RESULTS H. pylori induced decrease in Bcl-2, but increase in p53 and Bax at the levels of mRNA and protein in AGS cells. H. pylori-induced increment of apoptotic cells and decrease in Bcl-2 level were inhibited in the cells transfected with mutant IκBα gene as compared with the cells transfected with control vector. H. pylori-induced apoptosis determined by apoptotic cells, DNA fragmentation, and cell viability was inhibited in the cells transfected with Bcl-2 gene. CONCLUSION Down-regulation of Bcl-2 is mediated by NF-κB activation, which may be the underlying mechanism of apoptosis in H. pylori-infected gastric epithelial cells.
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Affiliation(s)
- Sang Hui Chu
- Nursing Policy and Research Institute, Biobehavioral Research Center, Yonsei University College of Nursing, Seoul, Korea
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20
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Slomiany BL, Slomiany A. Ghrelin suppression of Helicobacter pylori-induced S-nitrosylation-dependent Akt inactivation exerts modulatory influence on gastric mucin synthesis. Inflammopharmacology 2011; 19:89-97. [PMID: 21279549 DOI: 10.1007/s10787-011-0078-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Accepted: 01/06/2011] [Indexed: 01/27/2023]
Abstract
Loss of mucus coat integrity and the impairment in its mucin component as well as the disturbance in nitric oxide (NO) generation are well-recognized features of gastric disease associated with H. pylori infection. As ghrelin plays a major role in the regulation of nitric oxide synthase system, we investigated the influence of this hormone on H. pylori LPS-induced interference with gastric mucin synthesis. The results revealed that the LPS-induced impairment in mucin synthesis and accompanied induction in inducible nitric oxide synthase (iNOS) expression, were associated with the suppression in Akt kinase activity and the impairment in constitutive nitric oxide synthase (cNOS) phosphorylation. The LPS effect on Akt inactivation was manifested in the kinase protein S-nitrosylation and a decrease in its phosphorylation at Ser(473). Further, we show that the countering effect of ghrelin, on the LPS-induced impairment in mucin synthesis was reflected in the suppression of iNOS and the increase in Akt activation, associated with the loss in S-nitrosylation and the increase in phosphorylation, as well as cNOS activation through phosphorylation. Our findings demonstrate that up-regulation in iNOS with H. pylori infection and subsequent Akt kinase inactivation through S-nitrosylation exerts the detrimental effect on the processes dependent on Akt activation, including that of cNOS activation and mucin synthesis. We also show that ghrelin protection against H. pylori-induced impairment in mucin synthesis is intimately linked to the events of Akt activation and reflected in a decrease in the kinase S-nitrosylation and the increase in its phosphorylation.
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Affiliation(s)
- B L Slomiany
- Research Center, UMDNJ-NJ Dental School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103-2400, USA.
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21
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Slomiany BL, Slomiany A. Role of constitutive nitric oxide synthase in regulation of <i>Helicobacter pylori</i>-induced gastric mucosal cyclooxygenase-2 ac-tivation through S-nitrosylation: mechanism of ghrelin action. ACTA ACUST UNITED AC 2011. [DOI: 10.4236/ojgas.2011.12003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Hirano E, Sugita N, Kikuchi A, Shimada Y, Sasahara J, Iwanaga R, Tanaka K, Yoshie H. Peroxisome proliferator-activated receptor gamma polymorphism and periodontitis in pregnant Japanese women. J Periodontol 2010; 81:897-906. [PMID: 20450366 DOI: 10.1902/jop.2010.090669] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Recent studies suggest an association between maternal periodontitis and preterm birth, although the association remains controversial. It was suggested that mechanisms such as a genetic predisposition for a hyperinflammatory response cause periodontitis and preterm births. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear hormone receptor and ligand-dependent transcription factor. PPARgamma inhibits the transcriptional activity of the genes that produce proinflammatory mediators and repress periodontitis. Recently, a common polymorphism, proline(PRO)-to-alanine(ALA) mutation at codon12 in exonB (Pro12Ala: rs 1801282) PPARgamma, was reported to reduce the ability to transactivate responsive promoters. In this study, we tested whether the PPARgammaPro12Ala polymorphism was associated with maternal periodontitis and/or preterm birth. METHODS Genomic DNA was isolated from the venous blood of pregnant Japanese women (term birth: n = 72; preterm birth: n = 58). The PPARgammaPro12Ala genotype was determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism. Within 5 days after labor, clinical periodontal parameters were evaluated, and periodontopathic bacteria from the subgingival plaque were detected by species-specific PCR. RESULTS The mean clinical attachment level (P = 0.012), mean probing depth (P = 0.031), mean gingival index (P = 0.037), and percentages of sites with bleeding on probing (P = 0.041) in women with the PPARgammaPro12Ala genotype were significantly higher than in women with the PPARgammaPro12Pro genotype. However, there was no association between preterm birth and periodontitis. CONCLUSION We suggest that the PPARgammaPro12Ala polymorphism may represent a genetic susceptibility factor for the clinical measurements of periodontitis in a limited number of pregnant Japanese women, but it probably cannot influence the relationship between periodontitis and preterm birth.
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Affiliation(s)
- Emi Hirano
- Division of Periodontology, Department of Oral Biological Science, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8514, Japan
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Role of constitutive nitric oxide synthase S-nitrosylation in Helicobacter pylori-induced gastric mucosal cell apoptosis: effect of ghrelin. Inflammopharmacology 2010; 18:233-40. [PMID: 20596895 DOI: 10.1007/s10787-010-0051-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2010] [Accepted: 06/14/2010] [Indexed: 01/01/2023]
Abstract
Infection with H. pylori is a primary factor in the etiology of gastric disease, and the excessive NO generation and a massive rise in apoptosis are well recognized features that characterize the mucosal inflammatory responses to the bacterium and its lipopolysaccharide (LPS). Here, we report that H. pylori LPS-induced enhancement in gastric mucosal cell apoptosis and NO generation was associated with the suppression in constitutive nitric oxide synthase (cNOS) activity and a marked up-regulation in the activity of inducible nitric oxide synthase (iNOS). Further, we demonstrate that the detrimental effect of the LPS on cNOS was manifested in the enzyme protein S-nitrosylation, that was susceptible to suppression by iNOS inhibitor, 1400W. Moreover, we show that the countering effect of peptide hormone, ghrelin, on the LPS-induced changes in apoptosis and cNOS activity was reflected in the loss in cNOS S-nitrosylation and the increase in the enzyme phosphorylation. These findings demonstrate that the disturbances in gastric mucosal NO generation system caused by H. pylori result from the iNOS-derived NO suppression of cNOS activation through S-nitrosylation. We also report that ghrelin protection against H. pylori-induced gastric mucosal proapoptotic events involves cNOS activation manifested by the increase in enzyme protein phosphorylation and a decrease in its S-nitrosylation.
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Chen Q, Zhou J, Jiang C, Chen J. Reversal of P-glycoprotein-mediated multidrug resistance in SGC7901/VCR cells by PPARγ activation by troglitazone. ACTA ACUST UNITED AC 2010; 30:326-31. [DOI: 10.1007/s11596-010-0351-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2009] [Indexed: 11/29/2022]
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Pimentel-Nunes P, Soares JB, Roncon-Albuquerque R, Dinis-Ribeiro M, Leite-Moreira AF. Toll-like receptors as therapeutic targets in gastrointestinal diseases. Expert Opin Ther Targets 2010; 14:347-68. [PMID: 20146632 DOI: 10.1517/14728221003642027] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
IMPORTANCE OF THE FIELD Toll-like receptors (TLRs) are innate immunity receptors that recognize several different antigens, initiating immunological/inflammatory responses. Recent evidence associates numerous pathophysiological processes and diseases with dysregulated activation of these receptors, conferring a potential therapeutic value to their modulation. AREAS COVERED IN THIS REVIEW The aim of this systematic review that covers literature from the past 10 years is to address the role of TLRs in the pathophysiology of gastrointestinal (GI) diseases as well as the therapeutic potential of modulating TLRs' signaling pathways in GI pathology. WHAT THE READER WILL GAIN This review shows that TLRs play an important role in the pathophysiology of several GI diseases and that modulating TLRs signaling pathways may have an enormous therapeutic potential. Different methods for modulation of TLRs' activity in GI tract, with direct agonists/antagonists but also with non-specific substances, like antibiotics or probiotics, are presented. TAKE HOME MESSAGE Even though TLRs modulators have been used for therapy in some GI diseases, further research, particularly in humans, is needed in order to establish the precise role of the different TLRs in the diverse GI diseases and to motivate clinical trials that consider TLRs as therapeutic targets in GI pathology.
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Affiliation(s)
- Pedro Pimentel-Nunes
- Department of Physiology, Cardiovascular Research & Development Unit, University of Porto, Al. Prof. Hernâni Monteiro, 4200-319, Portugal.
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Kim SS, Cho YS, Kim HK, Shin OR, Chae HS, Choi MG, Chung IS. [The effect of rosiglitazone on the cell proliferation and the expressions of p27 and skp2 in helicobacter pylori infected human gastric epithelial cells]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2010; 55:225-231. [PMID: 20389175 DOI: 10.4166/kjg.2010.55.4.225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIMS Ligands for peroxisome proliferator-activated receptorgamma (PPARgamma), a member of the ligand-activated nuclear receptor superfamily, exhibit anti-tumoral effects and are associated with de novo synthesis of proteins involved in regulating the cell cycle and cell survival/death. Helicobacter pylori (H. pylori) is an etiologic agent for gastric adenocarcinoma, and raises the cell turnover of gastric epithelium. The aim of this study was to investigate the effect of PPARgamma ligand rosiglitazone on the cell proliferation and the expressions of p27 and Skp2 protein in H. pylori infected gastric epithelial cells. METHODS We examined the expression of PPARgamma by Western blot in H. pylori infected AGS human gastric epithelial cells. The effect of rosiglitazone on the survival of H. pylori infected AGS cells was assessed by cell viability assay. After the treatment of rosiglitazone in H. pylori infected AGS cells, the expressions of p27 and Skp2 were assessed by Western blot. RESULTS The expression of PPARgamma protein was increased in H. pylori infected AGS cells. Cell growth was inhibited and decreased in dose- and time- dependent manner in H. pylori infected AGS cells treated with rosiglitazone. A decrease in Skp2 expression and a reciprocal increase in p27 expression were found in dose- and time-dependent manner in H. pylori infected AGS cells treated with rosiglitazone. CONCLUSIONS Rosiglitazone inhibited the growth of H. pylori infected AGS cells. Rosiglitazone attenuated Skp2 expression, thereby promoting p27 accumulation in H. pylori infected human gastric epithelial cells. Further studies will be needed to find the effects of accumulation on cell turnover in H. pylori infection and the role in the H. pylori-associated gastric carcinogenesis.
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Affiliation(s)
- Sung Soo Kim
- Departments of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
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Devi RS, Kist M, Vani G, Devi CSS. Effect of methanolic extract of Terminalia arjuna against Helicobacter pylori 26695 lipopolysaccharide-induced gastric ulcer in rats. J Pharm Pharmacol 2010; 60:505-14. [DOI: 10.1211/jpp.60.4.0014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Abstract
Helicobacter pylori lipopolysaccharide (HP-LPS) is a potent virulence factor in the causation of gastric ulcer and gastritis. H. pylori-induced gastric pathology is prevalent throughout the world. Herbal medicines are attracting attention because of their traditional values, popularity and belief, as well as for their advantages such as less toxicity, affordability and medicinal value. The present study aimed to evaluate the anti-ulcer effect of a methanolic extract of Terminalia arjuna (TA) against HP-LPS-induced gastric damage in rats. Ulcers were induced with HP-LPS (50 μg per animal) administered orally daily for 3 days. The efficacy of TA on gastric secretory parameters such as volume of gastric juice, pH, free and total acidity, pepsin concentration, and the cytoprotective parameters such as protein-bound carbohydrate complexes in gastric juice and gastric mucosa was assessed. The protective effect of TA was also confirmed by histopathological examination of gastric mucosa. HP-LPS-induced alterations in gastric secretory parameters were altered favourably in rats treated with TA, suggesting that TA has an anti-secretory role. Furthermore, HP-LPS-induced impairments in gastric defence factors were also prevented by treatment with TA. These results suggest that the severe cellular damage and pathological changes caused by HP-LPS are mitigated by TA; these effects are comparable with those of sucralfate. The anti-ulcer effect of TA may reflect its ability to combat factors that damage the gastric mucosa, and to protect the mucosal defensive factors.
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Affiliation(s)
- Rethinam Sundaresan Devi
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India
| | - Manfred Kist
- Institut für Medizinische Mikrobiologie und Hygiene, Freiburg, Germany
| | - Ganapathy Vani
- Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu, India
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Malfertheiner P, Bornschein J, Selgrad M. Role of Helicobacter pylori infection in gastric cancer pathogenesis: a chance for prevention. J Dig Dis 2010; 11:2-11. [PMID: 20132425 DOI: 10.1111/j.1751-2980.2009.00408.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Gastric cancer in the absence of strategies implemented for early detection continues to have a dismal prognosis. There are limited options for a curative therapy once patients present with clinical manifestations of this malignant disease. Helicobacter pylori (H. pylori) infection plays a key role in gastric carcinogenesis, supported by epidemiological, preclinical and clinical studies. The recognition of H. pylori infection as a critical risk factor in the development of gastric cancer opens the chance for new venues in prevention strategies.
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Affiliation(s)
- Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Leipziger, Magdeburg, Germany.
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Warfel JM, D'Agnillo F. Anthrax lethal toxin enhances IkappaB kinase activation and differentially regulates pro-inflammatory genes in human endothelium. J Biol Chem 2009; 284:25761-71. [PMID: 19620708 DOI: 10.1074/jbc.m109.036970] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Anthrax lethal toxin (LT) was previously shown to enhance transcriptional activity of NF-kappaB in tumor necrosis factor-alpha-activated primary human endothelial cells. Here we show that this LT-mediated increase in NF-kappaB activation is associated with the enhanced degradation of the inhibitory proteins IkappaBalpha and IkappaBbeta but not IkappaBepsilon. Moreover, this was accompanied by enhanced activation of the IkappaB kinase complex (IKK), which is responsible for targeting IkappaB proteins for degradation. Importantly, LT enhancement of IkappaBalpha degradation was completely blocked by a selective IKKbeta inhibitor, whereas IkappaBbeta degradation was attenuated, suggesting a mechanistic link. Consistent with the above data, LT-cotreated cells show elevated phosphorylation of two IKK substrates, IkappaBalpha and p65, both of which were blocked by incubation with the IKKbeta inhibitor. Consistent with NF-kappaB activation, LT increased transcription of the NF-kappaB regulated gene CD40. Conversely, LT inhibited transcription of another NF-kappaB-regulated gene, CCL2. This inhibition was linked to the LT-mediated suppression of another CCL2-regulating transcription factor, AP-1 (activator protein-1). These data suggest that LT-mediated enhancement of NF-kappaB is IKK-dependent, but importantly, the net effect of LT on the transcription of proinflammatory genes is driven by the cumulative effect of LT on the particular set of transcription factors that regulate a given promoter. Together, these findings provide new mechanistic insight on how LT may disrupt the host response to anthrax.
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Affiliation(s)
- Jason M Warfel
- Laboratory of Biochemistry and Vascular Biology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA
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Seppet E, Gruno M, Peetsalu A, Gizatullina Z, Nguyen HP, Vielhaber S, Wussling MH, Trumbeckaite S, Arandarcikaite O, Jerzembeck D, Sonnabend M, Jegorov K, Zierz S, Striggow F, Gellerich FN. Mitochondria and energetic depression in cell pathophysiology. Int J Mol Sci 2009; 10:2252-2303. [PMID: 19564950 PMCID: PMC2695278 DOI: 10.3390/ijms10052252] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2009] [Revised: 04/25/2009] [Accepted: 05/14/2009] [Indexed: 12/21/2022] Open
Abstract
Mitochondrial dysfunction is a hallmark of almost all diseases. Acquired or inherited mutations of the mitochondrial genome DNA may give rise to mitochondrial diseases. Another class of disorders, in which mitochondrial impairments are initiated by extramitochondrial factors, includes neurodegenerative diseases and syndromes resulting from typical pathological processes, such as hypoxia/ischemia, inflammation, intoxications, and carcinogenesis. Both classes of diseases lead to cellular energetic depression (CED), which is characterized by decreased cytosolic phosphorylation potential that suppresses the cell's ability to do work and control the intracellular Ca(2+) homeostasis and its redox state. If progressing, CED leads to cell death, whose type is linked to the functional status of the mitochondria. In the case of limited deterioration, when some amounts of ATP can still be generated due to oxidative phosphorylation (OXPHOS), mitochondria launch the apoptotic cell death program by release of cytochrome c. Following pronounced CED, cytoplasmic ATP levels fall below the thresholds required for processing the ATP-dependent apoptotic cascade and the cell dies from necrosis. Both types of death can be grouped together as a mitochondrial cell death (MCD). However, there exist multiple adaptive reactions aimed at protecting cells against CED. In this context, a metabolic shift characterized by suppression of OXPHOS combined with activation of aerobic glycolysis as the main pathway for ATP synthesis (Warburg effect) is of central importance. Whereas this type of adaptation is sufficiently effective to avoid CED and to control the cellular redox state, thereby ensuring the cell survival, it also favors the avoidance of apoptotic cell death. This scenario may underlie uncontrolled cellular proliferation and growth, eventually resulting in carcinogenesis.
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Affiliation(s)
- Enn Seppet
- Department of Pathophysiology, University of Tartu, Tartu, Estonia; E-Mail:
(M.G.)
| | - Marju Gruno
- Department of Pathophysiology, University of Tartu, Tartu, Estonia; E-Mail:
(M.G.)
| | - Ants Peetsalu
- Department of Surgery, University of Tartu, Tartu, Estonia; E-Mail:
(A.P.)
| | - Zemfira Gizatullina
- KeyNeurotek AG, ZENIT-Technology Park Magdeburg, Magdeburg, Germany; E-Mails:
(Z.G.);
(D.J.);
(M.S.);
(K.J.);
(F.S.);
(F.N.G.)
| | - Huu Phuc Nguyen
- Department of Medical Genetics, University of Tübingen, Tübingen, Germany; E-Mail:
(H.P.N.)
| | - Stefan Vielhaber
- Department of Neurology, Otto von Guericke University, Magdeburg, Germany; E-Mail:
(S.V.)
| | - Manfred H.P. Wussling
- Bernstein Institute for Physiology, Martin-Luther-University Halle-Wittenberg, Germany; E-Mail:
(M.H.P.W.)
| | - Sonata Trumbeckaite
- Institute for Biomedical Research, Kaunas University of Medicine, Kaunas, Lithuania; E-Mails:
(S.T.);
(O.A.)
| | - Odeta Arandarcikaite
- Institute for Biomedical Research, Kaunas University of Medicine, Kaunas, Lithuania; E-Mails:
(S.T.);
(O.A.)
| | - Doreen Jerzembeck
- KeyNeurotek AG, ZENIT-Technology Park Magdeburg, Magdeburg, Germany; E-Mails:
(Z.G.);
(D.J.);
(M.S.);
(K.J.);
(F.S.);
(F.N.G.)
| | - Maria Sonnabend
- KeyNeurotek AG, ZENIT-Technology Park Magdeburg, Magdeburg, Germany; E-Mails:
(Z.G.);
(D.J.);
(M.S.);
(K.J.);
(F.S.);
(F.N.G.)
| | - Katharina Jegorov
- KeyNeurotek AG, ZENIT-Technology Park Magdeburg, Magdeburg, Germany; E-Mails:
(Z.G.);
(D.J.);
(M.S.);
(K.J.);
(F.S.);
(F.N.G.)
| | - Stephan Zierz
- Department of Neurology, Martin-Luther-University Halle-Wittenberg, Germany; E-Mail:
(S.Z.)
| | - Frank Striggow
- KeyNeurotek AG, ZENIT-Technology Park Magdeburg, Magdeburg, Germany; E-Mails:
(Z.G.);
(D.J.);
(M.S.);
(K.J.);
(F.S.);
(F.N.G.)
| | - Frank N. Gellerich
- KeyNeurotek AG, ZENIT-Technology Park Magdeburg, Magdeburg, Germany; E-Mails:
(Z.G.);
(D.J.);
(M.S.);
(K.J.);
(F.S.);
(F.N.G.)
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Yan F, Cao H, Chaturvedi R, Krishna U, Hobbs SS, Dempsey PJ, Peek RM, Cover TL, Washington MK, Wilson KT, Polk DB. Epidermal growth factor receptor activation protects gastric epithelial cells from Helicobacter pylori-induced apoptosis. Gastroenterology 2009; 136:1297-1307, e1-3. [PMID: 19250983 PMCID: PMC2878739 DOI: 10.1053/j.gastro.2008.12.059] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2008] [Revised: 12/15/2008] [Accepted: 12/29/2008] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Helicobacter pylori infection disrupts the balance between gastric epithelial cell proliferation and apoptosis, which is likely to lower the threshold for the development of gastric adenocarcinoma. H pylori infection is associated with epidermal growth factor (EGF) receptor (EGFR) activation through metalloproteinase-dependent release of EGFR ligands in gastric epithelial cells. Because EGFR signaling regulates cell survival, we investigated whether activation of EGFR following H pylori infection promotes gastric epithelial survival. METHODS Mouse conditionally immortalized stomach epithelial cells (ImSt) and a human gastric epithelial cell line, AGS cells, as well as wild-type and kinase-defective EGFR (EGFRwa2) mice, were infected with the H pylori cag+ strain 7.13. Apoptosis, caspase activity, EGFR activation (phosphorylation), and EGFR downstream targets were analyzed. RESULTS Inhibiting EGFR kinase activity or decreasing EGFR expression significantly increased H pylori-induced apoptosis in ImSt. Blocking H pylori-induced EGFR activation with a heparin-binding (HB)-EGF neutralizing antibody or abrogating a disintegrin and matrix metalloproteinase-17 (ADAM-17) expression increased apoptosis of H pylori-infected AGS and ImSt, respectively. Conversely, pretreatment of ImSt with HB-EGF completely blocked H pylori-induced apoptosis. H pylori infection stimulated gastric epithelial cell apoptosis in EGFRwa2 but not in wild-type mice. Furthermore, H pylori-induced EGFR phosphorylation stimulated phosphotidylinositol-3'-kinase-dependent activation of the antiapoptotic factor Akt, increased expression of the antiapoptotic factor Bcl-2, and decreased expression of the proapoptotic factor Bax. CONCLUSIONS EGFR activation by H pylori infection has an antiapoptotic effect in gastric epithelial cells that appears to involve Akt signaling and Bcl family members. These findings provide important insights into the mechanisms of H pylori-associated tumorigenesis.
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Affiliation(s)
- Fang Yan
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, TN
| | - Hanwei Cao
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, TN
| | - Rupesh Chaturvedi
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN
| | - Uma Krishna
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
| | - Stuart S. Hobbs
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, TN
| | - Peter J. Dempsey
- Departments of Pediatrics and Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI
| | - Richard M. Peek
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN
| | - Timothy L. Cover
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN
| | - M. Kay Washington
- Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN
| | - Keith T. Wilson
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN
| | - D. Brent Polk
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University School of Medicine, Nashville, TN, Department of Cell & Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN,To whom correspondence should be addressed: D. Brent Polk, M.D., Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 2215 Garland Avenue, MRB IV, Room: 1025, Nashville, TN 37232-0696, Telephone: 615-322-7449, Fax: 615-343-5323,
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Kuriki K, Wakai K, Matsuo K, Hiraki A, Suzuki T, Yamamura Y, Yamao K, Nakamura T, Tatematsu M, Tajima K. Gastric cancer risk and erythrocyte composition of docosahexaenoic acid with anti-inflammatory effects. Cancer Epidemiol Biomarkers Prev 2008; 16:2406-15. [PMID: 18006930 DOI: 10.1158/1055-9965.epi-07-0655] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Infection with Helicobacter pylori is linked to inflammation and is the main cause of peptic ulcer, gastritis, and gastric malignancies. To examine associations between gastric cancer risk and the erythrocyte composition of docosahexaenoic acid (DHA), a fatty acid with anti-inflammatory and apoptosis-inducing effects, here we conducted a case-control study of 179 incident gastric cancer cases and 357 noncancer controls (matched by age, sex, and season of sample collection). Dietary information and blood samples were collected from all subjects, and erythrocyte fatty acid levels were measured using accelerated solvent extraction and gas-liquid chromatography. Gastric cancer risk did not seem to be directly associated with dietary intake of fish and n-3 highly unsaturated fatty acids (HUFAs), such as DHA, derived from fish. However, risk was inversely associated with erythrocyte compositions of n-3 HUFAs [the highest to the lowest tertile, odds ratio (OR), 0.39; 95% confidence interval (95% CI), 0.23-0.68; P(trend)<0.005] and DHA (OR, 0.47; 95% CI, 0.28-0.79; P(trend)<0.01). Particularly strong associations were noted for well-differentiated type lesions and n-3 HUFAs (OR, 0.10; 95% CI, 0.03-0.35; P(trend)=0.0005) as well as DHA (OR, 0.20; 95% CI, 0.07-0.58; P(trend)<0.01) values. In conclusion, the erythrocyte composition of DHA was found to be negatively linked to risk of gastric cancer, especially of well-differentiated adenocarcinoma. Further studies are needed to investigate mechanisms of action of DHA relevant to antitumor effects in the stomach.
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Affiliation(s)
- Kiyonori Kuriki
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
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Prasad KN, Saxena A, Ghoshal UC, Bhagat MR, Krishnani N. Analysis of Pro12Ala PPAR gamma polymorphism and Helicobacter pylori infection in gastric adenocarcinoma and peptic ulcer disease. Ann Oncol 2008; 19:1299-1303. [PMID: 18372284 DOI: 10.1093/annonc/mdn055] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-dependent transcription factor involved in various disease processes including inflammation and carcinogenesis. We investigated the association of Pro12Ala PPARgamma polymorphism and Helicobacter pylori infection with gastric cancer and peptic ulcer disease (PUD). PATIENTS AND METHODS In total, 348 adult patients [62 gastric adenocarcinoma, 45 PUD and 241 nonulcer dyspepsia (NUD)] who underwent an upper gastrointestinal endoscopy were enrolled. PPARgamma polymorphism was analyzed by PCR-based restriction fragment length polymorphism. H. pylori infection was diagnosed by rapid urease test, culture, histopathology and PCR. RESULTS PPARgamma G carrier had significant association with gastric adenocarcinoma [P = 0.023, odds ratio (OR) = 2.136, 95% CI = 1.112-4.104] and PUD (P = 0.028, OR = 2.165, 95% CI = 1.008-4.306) when compared with NUD. Combination of G carrier and H. pylori infection further increased the risk of gastric adenocarcinoma (OR = 3.054, 95% CI = 1.195-7.807) and PUD (OR = 11.161, 95% CI = 3.495-35.644). PPARgamma polymorphism did not increase the risk of gastric adenocarcinoma and PUD in H. pylori-negative subjects. CONCLUSIONS The study suggests that Pro12Ala PPARgamma polymorphism is associated with gastric adenocarcinoma and PUD, and is a potential marker for genetic susceptibility to these two diseases in the presence of H. pylori infection.
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Affiliation(s)
| | | | | | - M R Bhagat
- Department of Gastroenterology, Central Command Hospital, Lucknow, India
| | - N Krishnani
- Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow
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Tahara T, Arisawa T, Shibata T, Nakamura M, Wang F, Maruyama N, Kamiya Y, Nakamura M, Fujita H, Nagasaka M, Iwata M, Takahama K, Watanabe M, Hirata I, Nakano H. Influence of peroxisome proliferator-activated receptor (PPAR)gamma Plo12Ala polymorphism as a shared risk marker for both gastric cancer and impaired fasting glucose (IFG) in Japanese. Dig Dis Sci 2008; 53:614-21. [PMID: 17763950 DOI: 10.1007/s10620-007-9944-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2007] [Accepted: 07/17/2007] [Indexed: 01/10/2023]
Abstract
Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) has been shown to inhibit the proliferation of gastric cancer cells. A common polymorphism at codon 12 of this gene (Pro12Ala) has been shown to confer protection against diabetes and colorectal cancer. We investigated the influence of PPARgamma gene Plo12Ala polymorphism on the risk of gastric cancer and on the severity of Helicobacter pylori-induced gastritis as well as impaired fasting glucose (IFG) in Japanese. About 215 patients with gastric cancer (GC) and 201 patients without GC enrolled in this study. Plo12Ala polymorphism of PPARgamma was investigated by PCR-RFLP in all of the subjects. The gastritis score of noncancerous antral mucosa was calculated by the updated Sydney system. The diagnosis of IFG was based on repeated evidence of serum fasting glucose (SFG) concentration of greater than or equal to 110 mg/dl. The Plo12Ala genotype of PPARgamma showed a significantly higher frequency in GC patients than in controls (OR = 2.43; 95%CI = 1.04-5.67). In contrast, the Plo12Ala genotype held a lower risk of IFG (OR = 0.33; 95%CI = 0.13-0.83). The same genotype was associated with an increased risk of non-cardiac gastric cancer (OR = 2.39; 95%CI = 1.02-5.65), lower third gastric cancer (OR = 3.56; 95%CI = 1.31-9.71), advanced cancer (OR = 2.93; 95%CI = 1.13-7.58), and Lauren's intestinal cancer (OR = 2.94; 95%CI = 1.13-7.66). Among 151 gastric cancer subjects, the atrophy and metaplasia scores of the antral mucosa adjacent to cancer showed a tendency to be higher in those with the 12Ala allele. Our study suggests that the PPARgamma Pro12Ala polymorphism may be a shared risk marker of both IFG and gastric cancer in Japanese.
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Affiliation(s)
- Tomomitsu Tahara
- Department of Gastroenterology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
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Sebens S, Arlt A, Schäfer H. NF-kappaB as a molecular target in the therapy of pancreatic carcinoma. Recent Results Cancer Res 2008; 177:151-164. [PMID: 18084957 DOI: 10.1007/978-3-540-71279-4_17] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
The constitutive activation of the transcription factor nuclear-factor kappa B (NF-kappaB) is a hallmark of many highly malignant tumours such as the pancreatic ductal adenocarcinoma and accounts for profound chemoresistance. Inhibition of NF-kappaB activation has been shown to be a useful strategy for increasing the sensitivity towards cytostatic drug treatment in vitro and in vivo. Moreover, various pharmacological substances (e.g. thalidomide, bortezomib, sulphasalazine) have already entered clinical studies partially showing promising results for certain types of cancer. Further studies will be needed, in particular for pancreatic ductal adenocarcinoma, to evaluate the therapeutic efficacy of appropriate combinations of a NF-kappaB inhibitor and cytostatic drugs.
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Affiliation(s)
- S Sebens
- Klinik für Allgemeine Innere Medizin, Labor für Molekulare Gastroenterologie & Hepatologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Germany
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Slomiany BL, Slomiany A. Cytosolic phospholipase A2 activation in Helicobacter pylori lipopolysaccharide-induced interference with gastric mucin synthesis. IUBMB Life 2006; 58:217-23. [PMID: 16754300 DOI: 10.1080/15216540600732021] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Release of arachidonic acid from membrane glycerophospholipids by cytosolic phospholipase A2 (cPLA2) is a key step in the generation of platelet-activating factor (PAF), recognized as the most proximal mediator of inflammatory events triggered by bacterial infection. Here, we report on the role of cPLA2 in the disturbances in gastric mucin synthesis evoked by the LPS of H. pylori, a bacterium identified as a primary cause of gastric disease. Using rat gastric mucosal cells, we show that H. pylori LPS detrimental effect on gastric mucin synthesis, associated with up-regulation in PAF and endothelin-1 (ET-1) generation, was subject to suppression by a specific inhibitor of cPLA2, MAFP. Moreover, the LPS-induced changes in mucin synthesis and ET-1 generation were countered by PAF receptor antagonist, BN52020. The impedance by PAF antagonist of the LPS-induced reduction in mucin synthesis was countered by wortmannin, an inhibitor of PI3K, as well as by ERK inhibitor, PD98059. The blockade of ERK caused also inhibition of the LPS-induced cPLA2 activation and amplification in the impedance capacity of PAF antagonist on the LPS-induced ET-1 generation, while the inhibitor of PI3K had no effect. Our findings are the first to demonstrate that the detrimental consequences of H. pylori LPS on gastric mucin synthesis involve ERK-dependent cPLA2 activation that leads to up-regulation in PAF generation and ET-1 production.
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Affiliation(s)
- Bronislaw L Slomiany
- Research Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA.
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37
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Gruno M, Peet N, Seppet E, Kadaja L, Paju K, Eimre M, Orlova E, Peetsalu M, Tein A, Soplepmann J, Schlattner U, Peetsalu A, Seppet EK. Oxidative phosphorylation and its coupling to mitochondrial creatine and adenylate kinases in human gastric mucosa. Am J Physiol Regul Integr Comp Physiol 2006; 291:R936-46. [PMID: 16741143 DOI: 10.1152/ajpregu.00162.2006] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Energy metabolism in gastrobiopsy specimens of the antral and corpus mucosa, treated with saponin to permeabilize the cells, was studied in patients with gastric diseases. The results show twice lower oxidative capacity in the antral mucosa than in the corpus mucosa and the relative deficiency of antral mitochondria in complex I. The mucosal cells expressed mitochondrial and cytosolic isoforms of creatine kinase and adenylate kinase (AK). Creatine (20 mM) and AMP (2 mM) markedly stimulated mitochondrial respiration in the presence of submaximal ADP or ATP concentrations, and creatine reduced apparent Km for ADP in stimulation of respiration, which indicates the functional coupling of mitochondrial kinases to oxidative phosphorylation. Addition of exogenous cytochrome c increased ADP-dependent respiration, and the large-scale cytochrome c effect (>or=20%) was associated with suppressed stimulation of respiration by creatine and AMP in the mucosal preparations. These results point to the impaired mitochondrial outer membrane, probably attributed to the pathogenic effects of Helicobacter pylori. Compared with the corpus mucosa, the antral mucosa exhibited greater sensitivity to such type of injury as the prevalence of the large-scale cytochrome c effect was twice higher among the latter specimens. Active chronic gastritis was associated with decreased respiratory capacity of the corpus mucosa but with its increase in the antral mucosa. In conclusion, human gastric mucosal cells express the mitochondrial and cytosolic isoforms of CK and AK participating in intracellular energy transfer systems. Gastric mucosa disease is associated with the altered functions of these systems and oxidative phosphorylation.
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Affiliation(s)
- Marju Gruno
- Department of Pathophysiology, Faculty of Medicine, Univ. of Tartu, 19 Ravila St., 50411 Tartu, Estonia
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Edelblum KL, Yan F, Yamaoka T, Polk DB. Regulation of apoptosis during homeostasis and disease in the intestinal epithelium. Inflamm Bowel Dis 2006; 12:413-24. [PMID: 16670531 DOI: 10.1097/01.mib.0000217334.30689.3e] [Citation(s) in RCA: 147] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
A single epithelial layer serves as the interface between the organism and the contents of the gastrointestinal tract, underlining the importance of regulating cellular viability despite an onslaught of pathogens, toxins, waste by-products, and cytokines. A balance between cellular proliferation and apoptosis is necessary to maintain this critical barrier. Recent findings have begun to explain the mechanisms by which intestinal epithelial cells are able to survive in such an environment and how loss of normal regulatory processes may lead to inflammatory bowel disease (IBD) and predispose to inflammation-associated neoplasia. This review focuses on the regulation of physiological apoptosis in development and homeostasis and on pathological apoptosis in intestinal disease, inflammation, and neoplasia, identifying remaining questions and areas of needed investigation.
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Affiliation(s)
- Karen L Edelblum
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0696, USA
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39
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Abstract
The human gastrointestinal (GI) tract is colonized by non-pathogenic commensal microflora and frequently exposed to many pathogenic organisms. For the maintenance of GI homeostasis, the host must discriminate between pathogenic and non-pathogenic organisms and initiate effective and appropriate immune and inflammatory responses. Mammalian toll-like receptors (TLRs) are members of the pattern-recognition receptor (PRR) family that plays a central role in the initiation of innate cellular immune responses and the subsequent adaptive immune responses to microbial pathogens. Recent studies have shown that gastrointestinal epithelial cells express almost all TLR subtypes characterized to date and that the expression and activation of TLRs in the GI tract are tightly and coordinately regulated. This review summarizes the current understanding of the crucial dual roles of TLRs in the development of host innate and adaptive immune responses to GI infections and the maintenance of the immune tolerance to commensal bacteria through down-regulation of surface expression of TLRs in intestinal epithelial cells.
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O'Brien DP, Israel DA, Krishna U, Romero-Gallo J, Nedrud J, Medof ME, Lin F, Redline R, Lublin DM, Nowicki BJ, Franco AT, Ogden S, Williams AD, Polk DB, Peek RM. The role of decay-accelerating factor as a receptor for Helicobacter pylori and a mediator of gastric inflammation. J Biol Chem 2006; 281:13317-13323. [PMID: 16543227 DOI: 10.1074/jbc.m601805200] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Persistent gastritis induced by Helicobacter pylori is the strongest known risk factor for peptic ulcer disease and distal gastric adenocarcinoma, a process for which adherence of H. pylori to gastric epithelial cells is critical. Decay-accelerating factor (DAF), a protein that protects epithelial cells from complement-mediated lysis, also functions as a receptor for several microbial pathogens. In this study, we investigated whether H. pylori utilizes DAF as a receptor and the role of DAF within H. pylori-infected gastric mucosa. In vitro studies showed that H. pylori adhered avidly to Chinese hamster ovary cells expressing human DAF but not to vector controls. In H. pylori, disruption of the virulence factors vacA, cagA, and cagE did not alter adherence, but deletion of DAF complement control protein (CCP) domains 1-4 or the heavily O-glycosylated serine-threonine-rich COOH-terminal domain reduced binding. In cultured gastric epithelial cells, H. pylori induced transcriptional up-regulation of DAF, and genetic deficiency of DAF attenuated the development of inflammation among H. pylori-infected mice. These results indicate that DAF may regulate H. pylori-epithelial cell interactions relevant to pathogenesis.
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Affiliation(s)
- Daniel P O'Brien
- Division of Gastroenterology, Departments of Medicine, Pediatrics, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279
| | - Dawn A Israel
- Division of Gastroenterology, Departments of Medicine, Pediatrics, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279
| | - Uma Krishna
- Division of Gastroenterology, Departments of Medicine, Pediatrics, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279
| | - Judith Romero-Gallo
- Division of Gastroenterology, Departments of Medicine, Pediatrics, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279
| | - John Nedrud
- Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - M Edward Medof
- Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Feng Lin
- Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Raymond Redline
- Institute of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106
| | - Douglas M Lublin
- Department of Pathology, Washington University School of Medicine, St. Louis, Missouri 63110
| | - Bogdan J Nowicki
- Departments of Obstetrics & Gynecology and Biomedical Sciences and Division of Microbial Pathogenesis and Immune Response, Meharry Medical Center, Nashville, Tennessee 37208
| | - Aime T Franco
- Division of Gastroenterology, Departments of Medicine, Pediatrics, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279
| | - Seth Ogden
- Division of Gastroenterology, Departments of Medicine, Pediatrics, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279
| | - Amanda D Williams
- Division of Gastroenterology, Departments of Medicine, Pediatrics, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279
| | - D Brent Polk
- Division of Gastroenterology, Departments of Medicine, Pediatrics, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279
| | - Richard M Peek
- Division of Gastroenterology, Departments of Medicine, Pediatrics, and Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2279; Department of Veterans Affairs Medical Center, Nashville, Tennessee 37212.
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Malfertheiner P, Fry LC, Mönkemüller K. Can gastric cancer be prevented by Helicobacter pylori eradication? Best Pract Res Clin Gastroenterol 2006; 20:709-19. [PMID: 16997155 DOI: 10.1016/j.bpg.2006.04.005] [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] [Indexed: 01/31/2023]
Abstract
Helicobacter pylori infection always causes chronic gastritis and triggers several gastroduodenal pathologies ranging from peptic ulcer disease to gastric cancer. It is well established that H. pylori eradication decreases the incidence of gastroduodenal ulcer and its recurrence. However, despite being accepted as the critical risk factor for gastric cancer, there is no conclusive evidence that H. pylori eradication decreases the incidence of gastric cancer. Bacterial virulence characteristics, as well as genetic predisposition of the host in conjunction with certain environmental conditions, are the major factors which influence the development of gastric cancer. Preclinical and clinical data suggest that reversibility of precancerous lesions (atrophic gastritis and intestinal metaplasia) is possible in some patients after H. pylori eradication. Since neoplastic lesions do not progress - or even regress in some cases - after H. pylori eradication, eradication therapy should be considered even in patients with precancerous lesions. Nonetheless, progression of atrophic gastritis and intestinal metaplasia into cancer has been also demonstrated in patients after H. pylori eradication, suggesting that there might be a point of no return where genetic changes have already happened and are irreversible despite elimination of the triggering carcinogen (H. pylori). At the present time the clinical decision to treat a patient is based on established risk profiles. A general screen-and-treat policy, although desirable, currently awaits a less complex treatment regimen.
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Affiliation(s)
- Peter Malfertheiner
- Division of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Universitätsklinikum Magdeburg, Leipziger Strasse 44, Magdeburg, Germany.
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Hofseth LJ, Ying L. Identifying and defusing weapons of mass inflammation in carcinogenesis. Biochim Biophys Acta Rev Cancer 2005; 1765:74-84. [PMID: 16169156 DOI: 10.1016/j.bbcan.2005.08.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2005] [Revised: 08/11/2005] [Accepted: 08/14/2005] [Indexed: 12/23/2022]
Abstract
The continued cancer risks associated with chronic inflammation necessitate the identification of inflammatory molecules and the cancer pathways they affect. Evidence indicates that there are multiple mechanisms linking inflammation to cancer and that there are multiple targets for chemoprevention. Here, we review some of the key factors and the cancer pathways they disturb as a necessary prerequisite to the identification of targets for chemoprevention.
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Affiliation(s)
- Lorne J Hofseth
- Department of Basic Pharmaceutical Sciences, College of Pharmacy, Coker Life Sciences, University of South Carolina, Columbia, SC 29208, USA.
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Malfertheiner P, Sipponen P, Naumann M, Moayyedi P, Mégraud F, Xiao SD, Sugano K, Nyrén O. Helicobacter pylori eradication has the potential to prevent gastric cancer: a state-of-the-art critique. Am J Gastroenterol 2005; 100:2100-15. [PMID: 16128957 DOI: 10.1111/j.1572-0241.2005.41688.x] [Citation(s) in RCA: 146] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Helicobacter pylori infection continues to play a key role in gastric diseases. Colonization of the gastric mucosa with the bacterium invariably results in the development of chronic gastritis and subsets of patients have a progression of the chronic gastritis to either ulcer or cancer. Epidemiological evidence indicates that the proportion of all gastric cancers attributable to H. pylori infection, and hence potentially preventable upon elimination of this risk factor, is somewhere in the range of 60% to 90%. This portends significant benefit in terms of morbidity and mortality, not least in populations with high prevalence of H. pylori infection coupled with high incidence of gastric cancer. The effect of prophylactic H. pylori eradication on gastric cancer incidence in humans remains unknown, however. Results from randomized trials are eagerly awaited, but availability of strong conclusive results may take many years. A growing number of studies show considerable variation in risk for gastric cancer development, depending on H. pylori strain type and the genetic predisposition of the host. There is also a remote possibility that elimination of the infection may have adverse health implications (e.g., antibiotic resistance), and therefore "simple" risk stratification and targeted chemoprevention is required. Based on "in depth" evidence presented at this workshop, the majority of the scientific task force favored a search-and-treat strategy in first-degree relatives of gastric cancer patients and an overwhelming majority felt that a more general screen-and-treat strategy should be focused in the first instance on a population with a high incidence of H. pylori-associated diseases.
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Affiliation(s)
- Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University, Magdeburg, Germany
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Slomiany BL, Slomiany A. Up-regulation in endothelin-1 by Helicobacter pylori lipopolysaccharide interferes with gastric mucin synthesis via epidermal growth factor receptor transactivation. Scand J Gastroenterol 2005; 40:921-28. [PMID: 16173126 DOI: 10.1080/00365520510015890] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Endothelin-1 (ET-1), a key mediator of inflammatory processes associated with bacterial infection, is a 21-amino acid peptide produced from a biologically inactive big ET-1 by the action of endothelin-converting enzyme-1 (ECE-1) that acts through G protein-coupled ET(A) and ET(B) receptors. Here we report on the role of ET-1 in the mediation of the detrimental influence of Helicobacter pylori on the synthesis of gastric mucin. MATERIAL AND METHODS Rat gastric mucosal cells were exposed to H. pylori key virulence factor, lipopolysaccharide (LPS). RESULTS The LPS inhibitory effect on gastric mucin synthesis was accompanied by a marked increase in ET-1 generation and enhancement in ECE-1 activity. Inhibition of ECE-1 with phosphoramidon not only led to the impedance of LPS-induced ET-1 generation, but also countered the detrimental effect of LPS on mucin synthesis. Moreover, the LPS inhibitory effect on mucin synthesis was blocked by ET(A) receptor antagonist BQ610, but not by ET(B) receptor antagonist BQ788. Furthermore, the LPS-induced suppression in gastric mucin synthesis was countered in a concentration-dependent fashion by PD153035 (81.7%), a specific inhibitor of epidermal growth factor receptor (EGFR) kinase as well as PP2 (69.8%), a selective inhibitor of tyrosine kinase Src responsible for ligand-independent EGFR transactivation. CONCLUSIONS Our findings are the first to show that the detrimental effect of H. pylori on gastric mucin synthesis is intimately linked to the events associated with ECE-1 up-regulation, enhancement in ET-1 production, and G protein-coupled ET(A) receptor activation that triggers the EGFR transactivation.
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Affiliation(s)
- Bronislaw L Slomiany
- Research Center, C875, UMDJN-NJ Dental School, 110 Bergen Street, P.O. Box 1709, Newark, NJ 07103-2400, USA.
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Wu CY, Wang CJ, Tseng CC, Chen HP, Wu MS, Lin JT, Inoue H, Chen GH. Helicobacter pylori promote gastric cancer cells invasion through a NF-kB and COX-2-mediated pathway. World J Gastroenterol 2005; 11:3197-203. [PMID: 15929167 PMCID: PMC4316048 DOI: 10.3748/wjg.v11.i21.3197] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [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 examine the effects of Helicobacter pylori (H pylori) infection on the invasiveness of gastric cancer cells, and to elucidate its mechanism.
METHODS: Gastric carcinoma cells, MKN-45, were incubated with CagA-positive H pylori, and cell invasion was determined by Matrigel analysis. The expression of matrix metallopr-oteinase-9 (MMP-9), vascular endothelial growth factor (VEGF), and cyclooxygenase-2 (COX-2) were assessed by Western-blot analysis, and transcriptional activation of the COX-2 promoter was examined by measuring luciferase and β-galactosidase activities. Lastly, the protein-DNA interaction was confirmed by an electrophoretic mobility shift assay.
RESULTS: The current studies showed that: (1) incubation of CagA-positive H pylori with MKN-45 cells significantly promotes gastric cancer cells invasion, and this effect is attenuated by pre-treatment with NS-398, a COX-2 inhibitor, or PDTC, a nuclear factor κB (NF-κB) inhibitor; (2) the induction of MKN-45 cells invasion by H pylori is associated with increases in COX-2, MMP-9, and VEGF protein expression, and co-incubation of NS-398 or PDTC significantly reduces these effects; (3) H pylori infection transactivates COX-2 promoter activity and increases the binding of NF-κB to this promoter.
CONCLUSION: Our data demonstrate that H pylori infection promotes gastric epithelial cells invasion by activating MMP-9 and VEGF expression. These effects appear to be mediated through a NF-κB and COX-2 mediated pathway, as COX-2 or NF-κB inhibitor significantly attenuate the invasiveness of gastric cancer cells and the expressions of MMP-9 and VEGF protein.
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Affiliation(s)
- Chun-Ying Wu
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taiwan, China
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Abstract
This brief review summarizes the current understanding of Toll-like receptor (TLRs) mediated intestinal epithelial mechanisms of commensal tolerance versus intolerance and provides an update on the downstream negative control of signaling responses through decreased surface expression, interregulation with NOD2, overexpression of Tollip, various inhibitors of NF-kappaB as well as soluble tolerizing mediators present in lumen and serum which all may maintain or--when dysregulated--impair mucosal homeostasis in health or disease, respectively.
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Affiliation(s)
- Elke Cario
- Divison of Gastroenterology & Hepatology, University Hospital of Essen, Institutsgruppe I, Virchowstr. 171, D-45147 Essen, Germany.
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Kohler JE, Zaborina O, Wu L, Wang Y, Bethel C, Chen Y, Shapiro J, Turner JR, Alverdy JC. Components of intestinal epithelial hypoxia activate the virulence circuitry of Pseudomonas. Am J Physiol Gastrointest Liver Physiol 2005; 288:G1048-54. [PMID: 15550562 DOI: 10.1152/ajpgi.00241.2004] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We have previously shown that a lethal virulence trait in Pseudomonas aeruginosa, the PA-I lectin, is expressed by bacteria within the intestinal lumen of surgically stressed mice. The aim of this study was to determine whether intestinal epithelial hypoxia, a common response to surgical stress, could activate PA-I expression. A fusion construct was generated to express green fluorescent protein downstream of the PA-I gene, serving as a stable reporter strain for PA-I expression in P. aeruginosa. Polarized Caco-2 monolayers were exposed to ambient hypoxia (0.1-0.3% O2) for 1 h, with or without a recovery period of normoxia (21% O2) for 2 h, and then inoculated with P. aeruginosa containing the PA-I reporter construct. Hypoxic Caco-2 monolayers caused a significant increase in PA-I promoter activity relative to normoxic monolayers (165% at 1 h; P < 0.001). Similar activation of PA-I was also induced by cell-free apical, but not basal, media from hypoxic Caco-2 monolayers. PA-I promoter activation was preferentially enhanced in bacterial cells that physically interacted with hypoxic epithelia. We conclude that the virulence circuitry of P. aeruginosa is activated by both soluble and contact-mediated elements of the intestinal epithelium during hypoxia and normoxic recovery.
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Affiliation(s)
- Jonathan E Kohler
- Department of Surgery, University of Chicago, Chicago, Illinois 60637, USA
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Yang CR, Hsieh SL, Ho FM, Lin WW. Decoy receptor 3 increases monocyte adhesion to endothelial cells via NF-kappa B-dependent up-regulation of intercellular adhesion molecule-1, VCAM-1, and IL-8 expression. THE JOURNAL OF IMMUNOLOGY 2005; 174:1647-56. [PMID: 15661928 DOI: 10.4049/jimmunol.174.3.1647] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Decoy receptor 3 (DcR3), a soluble receptor for FasL, LIGHT and TL1A, is highly expressed in cancer cells. We show that pretreatment of HUVECs with DcR3 enhances the adhesion of THP-1 and U937 cells and primary monocytes. A similar stimulatory effect of DcR3 on THP-1 adhesion was also observed in human microvascular endothelial cells (HMVECs). Flow cytometry and ELISA showed that DcR3-treated HUVECs exhibited significant increases in ICAM-1 and VCAM-1 expression. We also demonstrate the ability of DcR3 to stimulate the secretion of IL-8 by HUVECs. RT-PCR and reporter assays revealed that the expression of adhesion molecules and IL-8 are regulated at the level of gene transcription. Experiments with pyrrolidine dithiocarbamate indicated the involvement of an NF-kappaB signaling pathway. DcR3 was found to induce IkappaB kinase activation, IkappaB degradation, p65 nuclear translocation, and NF-kappaB DNA-binding activity. The enhancement by DcR3 of cell adhesion to HUVECs was not mimicked by the TL1A-Ab, which has been shown in our previous work to be a neutralizing Ab against TL1A, thereby inducing HUVECs angiogenesis. Moreover, DcR3-induced cell adhesion could be detected in human aortic endothelial cells (ECs) in which TL1A expression is lacking. Together, our data demonstrate that DcR3 increases monocyte adhesion to ECs via NF-kappaB activation, leading to the transcriptional up-regulation of adhesion molecules and IL-8 in ECs. This novel action appears not to be due to TL1A neutralization, but occurs through an as yet undefined target(s). This study implicates DcR3 in the relationship between inflammation and cancer development.
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Affiliation(s)
- Chia-Ron Yang
- Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
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Abstract
With the mapping of the human genome comes the ability to identify genes of interest in specific diseases and the pathways involved therein. Laboratory technology has evolved in parallel, providing us with the ability to assay thousands of these genes at once, a technique known as microarray analysis. The main #x003Fion that this type of technology raises is how we can apply this powerful technology to clinical medicine. Recently, advances in data analysis, as well as standardization of the technology, have allowed us to examine this #x003Fion, and indeed a few clinical trials currently being performed include microarrays as part of their protocol. In this review we outline the microarray technique and describe these types of studies in further detail.
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Affiliation(s)
- Ashani T. Weeraratna
- Clinical Immunology Section, Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, Nathan Shock Dr, Baltimore, Maryland
| | - James E. Nagel
- Clinical Immunology Section, Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, Nathan Shock Dr, Baltimore, Maryland
| | - Valeria de Mello-Coelho
- Clinical Immunology Section, Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, Nathan Shock Dr, Baltimore, Maryland
| | - Dennis D. Taub
- Clinical Immunology Section, Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, Nathan Shock Dr, Baltimore, Maryland
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Aggarwal BB, Takada Y. Pro-apototic and anti-apoptotic effects of tumor necrosis factor in tumor cells. Role of nuclear transcription factor NF-kappaB. Cancer Treat Res 2005; 126:103-27. [PMID: 16209064 DOI: 10.1007/0-387-24361-5_5] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Affiliation(s)
- Bharat B Aggarwal
- Cytokine Research Section, Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA
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