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| 1 | Increased susceptibility of aging gastric mucosa to injury:The mechanisms and clinical implications显示文摘This review updates the current views on aging gastric mucosa and the mechanisms of its increased susceptibility to injury.Experimental and clinical studies indicate that gastric mucosa of aging individuals-'aging gastropathy'-has prominent structural and functional abnormalities vs young gastric mucosa.Some of these abnormalities include a partial atrophy of gastric glands,impaired mucosal defense(reduced bicarbonate and prostaglandin generation,decreased sensory innervation),increased susceptibility to injury by a variety of damaging agents such as ethanol,aspirin and other non-steroidal anti-inflammatory drugs(NSAIDs),impaired healing of injury and reduced therapeutic efficacy of ulcer-healing drugs.Detailed analysis of the above changes indicates that the following events occur in aging gastric mucosa:reduced mucosal blood flow and impaired oxygen delivery cause hypoxia,which leads to activation of the early growth response-1(egr-1)transcription factor.Activation of egr-1,in turn,upregulates the dual specificity phosphatase,phosphatase and tensin homologue deleted on chromosome ten(PTEN)resulting in activation of pro-apoptotic caspase-3 and caspase-9 and reduced expression of the anti-apoptosis protein,survivin.The imbalance between pro-and anti-apoptosis mediators results in increased apoptosis and increased susceptibility to injury.This paradigm has human relevance since increased expression of PTEN and reduced expression of survivin were demonstrated in gastric mucosa of aging individuals.Other potential mechanisms operating in aging gastric mucosa include reduced telomerase activity,increase in replicative cellular senescence,and reduced expression of vascular endothelial growth factor and importin-α-a nuclear transport protein essential for transport of transcription factors to nucleus.Aging gastropathy is an important and clinically relevant issue because of:(1)an aging world population due to prolonged life span;(2)older patients have much greater risk of gastroduodenal ulcers and gastrointestinal complications(e.g.,NSAIDs-induced gastric injury)than younger patients;and(3)increased susceptibility of aging gastric mucosa to injury can be potentially reduced or reversed pharmacologically. | Andrzej S Tarnawski Amrita Ahluwalia Michael K Jones | 2014 | World Journal of Gastroenterology2014，20，16： | 16 |
| 2 | Identification of specific genes and pathways involved in NSAIDs-induced apoptosis of human colon cancer cells显示文摘AIM: To study whether indomethacin (IND), a nonselective cyclooxygenase (COX) inhibitor or NS-398 (NS), a COX-2-selective inhibitor, induces apoptosis in human colon cancer cells and which apoptosis-related genes and pathways are involved. METHODS: Human colon cancer Caco-2 cells were treated with either: placebo, IND (0.05-0.5 mmol/L) or NS (0.01-0.2 mmol/L) for 1, 5 and 18 h. We then studied: (1) Cell death by the TUNEL method, (2) mRNA expression of 96 apoptosis-related genes using DNA microarray, (3) expression of selected apoptosis related proteins by Western blotting. RESULTS: Both IND and NS induced apoptosis in 30%-50% of Caco-2 cells in a dose dependent manner. IND (0.1 mmol/L for 1 h) significantly up-regulated pro-apoptotic genes in four families: (1) TNF receptor and ligand, (2) Caspase, (3) Bcl-2 and (4) Caspase recruiting domain. NS treatment up-regulated similar pro-apoptotic genes as IND. In addition, IND also down-regulated anti-apoptotic genes of the IAP family. CONCLUSION: (1) Both non-selective and COX-2-selective NSAIDs induce apoptosis in colon cancer cells in a dose dependent manner. (2) Both NSAIDs induce apoptosis by activating two main apoptotic pathways: the death receptor pathway (involving TNF-R) and the mitochondrial pathway. (3) IND induces apoptosis by up-regulating pro-apoptotic genes and down-regulating anti-apoptotic genes, while NS only up-regulates pro-apoptotic genes. (4) Induction of apoptosis in coloncancer cells by NSAIDs may explain in part, their inhibitory action on colon cancer growth. | Richard H Huang Jianyuan Chai Andrzej S Tarnawski | 2006 | World Journal of Gastroenterology2006，12，40： | 11 |
| 3 | Increased susceptibility of aging gastric mucosa to injury and delayed healing:Clinical implications显示文摘In this editorial we comment on the article by Fukushi K et al published in the recent issue of the World Journal of Gastroenterology 2018; 24(34): 3908-3918. We focus specifically on the mechanisms of the anti-thrombotic action of aspirin, gastric mucosal injury and aging-related increased susceptibility of gastric mucosa to injury. Aspirin is widely used not only for the management of acute and chronic pain and arthritis, but also importantly for the primary and secondary prevention of cardiovascular events such as myocardial infarcts and strokes. Clinical trials have consistently shown that antiplatelet therapy with long term, low dose aspirin(LDA)-75 to 325 mg daily, dramatically reduces the risk of non-fatal myocardial infarcts, stroke and mortality in patients with established arterial diseases. However, such treatment considerably increases the risk of gastrointestinal(GI) ulcerations and serious bleeding by > 2-4 fold, especially in aging individuals. This risk is further increased in patients using LDA together with other antiplatelet agents, other nonsteroidal anti-inflammatory agents(NSAIDs) and/or alcohol, or in patients with Helicobacter pylori(H. pylori) infection. Previous studies by our group and others have demonstrated prominent structural and functional abnormalities in gastric mucosa of aging individuals(which we refer to as aging gastric mucosa or 'aging gastropathy') compared to the gastric mucosa of younger individuals. Aging gastric mucosa has impaired mucosal defense, increased susceptibility to injury by a variety of noxious agents such as aspirin, other NSAIDs and ethanol, and delayed and impaired healing of injury. The mechanism underlying these abnormalities of aging gastric mucosa include reduced mucosal blood flowcausing hypoxia, upregulation of PTEN, activation of proapoptotic caspase-3 and caspase-9, and reduced survivin(anti-apoptosis protein), importin-α(nuclear transport protein), vascular endothelial growth factor, and nerve growth factor. The decision regarding initiation of a long-term LDA therapy should be made after a careful consideration of both cardiovascular and GI risk factors. The latter include a previous history of GI bleeding and/or ulcers, age ≥ 70, male gender, concurrent use of other NSAIDs, alcohol consumption and H. pylori infection. Furthermore, the incidence of GI ulcers and bleeding can be reduced in patients on long term LDA treatment by several measures. Clinicians treating such patients should test for and eradicate H. pylori, instruct patients to avoid alcohol and non-aspirin NSAIDs, including cyclooxygenase-2-selective NSAIDs, and prescribe proton pump inhibitors in patients on LDA therapy. In the future, clinicians may be able to prescribe one of several potential new drugs, which include aspirin associated with phosphatidylcholine(PL2200), which retains all property of aspirin but reduces by approximately 50% LDA-induced GI ulcerations. | Andrzej S Tarnawski Amrita Ahluwalia | 2018 | World Journal of Gastroenterology2018，24，42： | 8 |
| 4 | The Mechanisms of Gastric Mucosal Injury: Focus on Microvascular Endothelium as a Key Target显示文摘 | A. S. Tarnawski A. Ahluwalia M. K. Jones | 2012 | Current Medicinal Chemistry2012，，1： | 3 |
| 5 | Cellular and Molecular Mechanisms of Gastrointestinal Ulcer Healing显示文摘 | Andrzej S. Tarnawski MD PhD DSc | 2005 | Digestive Diseases and Sciences2005，，1： | 3 |
| 6 | Quality of Gastric Ulcer Healing: A New, Emerging Concept显示文摘 | Andrzej Tarnawski Jerzy Stachura William J. Krause Thomas G. Douglass Hella Gergely | 1991 | Journal of Clinical Gastroenterology1991，，： | 2 |
| 7 | 'Healed' experimental gastric ulcers remain histologically and ultrastructurally abnormal显示文摘 | Tarnawski A Hollander D William JK | 1990 | J Clin gastroenterol1990，12，1： | 1 |
| 8 | PTEN regulatory functions in tumor suppression and cell biology 显示文摘 | Chu EC Tarnawski AS | 2004 | Med Sci Monit2004，10，10： | 1 |
| 9 | Prostaglandin protection of the gastric mucosa against alcohol injury-a dynamic time-related process显示文摘 | Tarnawski A Hollander D Stachura J | 1985 | Gastroenterology1985，88，： | 1 |
| 10 | Apoptosis-programmed cell death and its relevance to gastrointestinal epithelium: survival signal from the matrix 显示文摘 | Tarnawski AS Szabo I | 2001 | Gastroenterology2001，120，1： | 1 |
| 11 | Increased expression of epidermal growth factor receptor during ulcer healing in rats显示文摘 | TARNAWSKI A STACHURA J DURBIN T | 1992 | Gastroenterology1992，102，： | 1 |
| 12 | Simultaneous radiotherapy and radioimmunotherapy of malignant gliomas with anti-EGFR antibody labelled with iodine 125显示文摘 | Wygoda Z Tarnawski R Brady L | 2002 | Nucl Med Rev Cent East Eur2002，5，1： | 1 |
| 13 | Quality of gastric ulcer healing: a new emerging concept 显示文摘 | Tarnawski A Stachura J William JK | 1991 | J Clin Gastroenterrol1991，13，1： | 1 |
| 14 | Cytoprotect-ion of the gastric mucosa byantacids and sucralfate but not by the H2 blockers显示文摘 | Tarnawski A Holland D Krause WJ | 1988 | Dig Dis Sci1988，33，7： | 1 |
| 15 | Cellular and molecular mechanisms of gastrointestinal ulcer healing显示文摘 | Tarnawski A S | | 0，，1： | 1 |
| 16 | Distorted microangioarchitecture and impaired angiogenesis in gastric mucosa of portal hypertensive rats显示文摘 | Tarnawski A Sarfeh IJ | 1994 | Gastroenterology1994，106，3： | 1 |
| 17 | Survivin an anti-apoptosis protein:it s biological roles and implications for cancer and beyond显示文摘 | Chiou SK Jones MK Tarnawski AS | 2003 | Med Sci Monit2003，9，4： | 1 |
| 18 | Nephrotic origin hyperlipilernia, relative reduction of Vitamin E level and subsequent oxidative stress may promote atherosclerosis 显示文摘 | Bronislawa Skrzep-Poloczek Andrzej Tomasik Roman Tarnawski et al | 2001 | Nephron2001，89，： | 1 |
| 19 | Portal hypertension triggers local activation of inducible nitric oxide synthase gene in colonic mucosa显示文摘 | Ohta M Kaviani A Tarnawski AS | 1997 | Gastrointest Surg1997，1，： | 1 |
| 20 | Extension of soil thermal conductivity models to frozen meats with low and high fat content显示文摘 | Tarnawski V R Cleland D J Corasaniti S | 2005 | Int J Refrigeration2005，28，： | 1 |
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