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-...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展开更多
AIM:To evaluate human gastric submucosal vascular dysfunction and its mechanism during the aging process.METHODS:Twenty male patients undergoing subtotal gastrectomy were enrolled in this study.Young and elderly patie...AIM:To evaluate human gastric submucosal vascular dysfunction and its mechanism during the aging process.METHODS:Twenty male patients undergoing subtotal gastrectomy were enrolled in this study.Young and elderly patient groups aged 25-40 years and 60-85 years,respectively,were included.Inclusion criteria were:no clinical evidence of cardiovascular,renal or diabetic diseases.Conventional clinical examinations were carried out.After surgery,gastric submucosal arteries were immediately dissected free of fat and connective tissue.Vascular responses to acetylcholine(ACh)and sodium nitroprusside(SNP)were measured by isolated vascular perfusion.Morphological changes in the gastric mucosal vessels were observed by hematoxylin and eosin(HE)staining and Verhoeff van Gieson(EVG)staining.The expression of xanthine oxidase(XO)and manganese-superoxide dismutase(Mn-SOD)was assessed by Western blotting analysis.The malondialdehyde(MDA)and hydrogen peroxide(H2O2)content and the activities of superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px)were determined according to commercial kits.RESULTS:The overall structure of vessel walls was shown by HE and EVG staining,respectively.Disruption of the internal elastic lamina or neointimal layers was not observed in vessels from young or elderly patients;however,cell layer number in the vessel wall increased significantly in the elderly group.Compared with submucosal arteries in young patients,the amount of vascular collagen fibers,lumen diameter and media cross-sectional area were significantly increased in elderly patients.Ach-and SNP-induced vasodilatation in elderly arterioles was significantly decreased compared with that of gastric submucosal arterioles from young patients.Compared with the young group,the expression of XO and the contents of MDA and H2O2in gastric submucosal arterioles were increased in the elderly group.In addition,the expression of Mn-SOD and the activities of SOD and GSH-Px in the elderly group decreased significantly compared with those in the young gro展开更多
AIM: To demonstrated the combined effects of aging and carcinogen treatment on cancer stem/stem-like cells(CSCs) of gastric mucosa in an animal model. METHODS: In this study we investigated the effects of aging and He...AIM: To demonstrated the combined effects of aging and carcinogen treatment on cancer stem/stem-like cells(CSCs) of gastric mucosa in an animal model. METHODS: In this study we investigated the effects of aging and Helicobacter pylori(H. pylori) inflammation as a model for inflammation induced carcinogenesis in human and rat gastric mucosa samples. In aging studies, we compared 4-mo old(young) with 22 mo(aged) old Fischer-344 rats. For human studies, gastric biop-sies and resection specimens representing normal mucosa or different stages of H. pylori gastritis and gastric adenocarcinomas were used for determining the expression of stem cell markers CD166, ALDH1 and LGR5. In addition we performed immunofluorescent double labeling for B-catenin and Lgr5 in both rat and human gastric tissues to examine the status of Wnt signaling in these cells. RESULTS: CSC markers ALDH1, LGR5, and CD166 were expressed in very low levels in normal human gastric mucosa or young rat gastric mucosa. In contrast, level of expression for all three markers significantly increased in H. pylori gastritis and gastric adenocarcinomas as well as in normal gastric mucosa in aged rats. We also observed cytoplasmic B-catenin staining in both aged rat and human H. pylori inflamed gastric mucosa, which were found to be colocalized with Lgr5 immunoreactive cells. The increased number of ALDH1, CD166 and LGR5 positive cells in H. pylori gastritis indicates that increased number of stem-like cells in gastric mucosa is an early event, and may constitute an important step in the progression to neoplasia. CONCLUSION: Our observation of the age-related increase in cancer stem/stem-like cells in the gastric mucosa may explain the increased incidence of gastric cancer during aging. Combination of aging and H. pylori infection may have additive effects in progression to neoplasia.展开更多
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-thromb...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展开更多
基金Supported by VA Merit Review grant to Tarnawski AS
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
基金Supported by The Natural Science Foundation of Jiangsu Province,China,No.BK2009088the Natural Science Fund for Colleges and Universities in Jiangsu Province,No.10KJB310015
文摘AIM:To evaluate human gastric submucosal vascular dysfunction and its mechanism during the aging process.METHODS:Twenty male patients undergoing subtotal gastrectomy were enrolled in this study.Young and elderly patient groups aged 25-40 years and 60-85 years,respectively,were included.Inclusion criteria were:no clinical evidence of cardiovascular,renal or diabetic diseases.Conventional clinical examinations were carried out.After surgery,gastric submucosal arteries were immediately dissected free of fat and connective tissue.Vascular responses to acetylcholine(ACh)and sodium nitroprusside(SNP)were measured by isolated vascular perfusion.Morphological changes in the gastric mucosal vessels were observed by hematoxylin and eosin(HE)staining and Verhoeff van Gieson(EVG)staining.The expression of xanthine oxidase(XO)and manganese-superoxide dismutase(Mn-SOD)was assessed by Western blotting analysis.The malondialdehyde(MDA)and hydrogen peroxide(H2O2)content and the activities of superoxide dismutase(SOD)and glutathione peroxidase(GSH-Px)were determined according to commercial kits.RESULTS:The overall structure of vessel walls was shown by HE and EVG staining,respectively.Disruption of the internal elastic lamina or neointimal layers was not observed in vessels from young or elderly patients;however,cell layer number in the vessel wall increased significantly in the elderly group.Compared with submucosal arteries in young patients,the amount of vascular collagen fibers,lumen diameter and media cross-sectional area were significantly increased in elderly patients.Ach-and SNP-induced vasodilatation in elderly arterioles was significantly decreased compared with that of gastric submucosal arterioles from young patients.Compared with the young group,the expression of XO and the contents of MDA and H2O2in gastric submucosal arterioles were increased in the elderly group.In addition,the expression of Mn-SOD and the activities of SOD and GSH-Px in the elderly group decreased significantly compared with those in the young gro
基金Supported by Grants to Dr.Majumdar from NIH/NIA,No.AG014343the Department of Veterans Affairs(VA Merit Review)
文摘AIM: To demonstrated the combined effects of aging and carcinogen treatment on cancer stem/stem-like cells(CSCs) of gastric mucosa in an animal model. METHODS: In this study we investigated the effects of aging and Helicobacter pylori(H. pylori) inflammation as a model for inflammation induced carcinogenesis in human and rat gastric mucosa samples. In aging studies, we compared 4-mo old(young) with 22 mo(aged) old Fischer-344 rats. For human studies, gastric biop-sies and resection specimens representing normal mucosa or different stages of H. pylori gastritis and gastric adenocarcinomas were used for determining the expression of stem cell markers CD166, ALDH1 and LGR5. In addition we performed immunofluorescent double labeling for B-catenin and Lgr5 in both rat and human gastric tissues to examine the status of Wnt signaling in these cells. RESULTS: CSC markers ALDH1, LGR5, and CD166 were expressed in very low levels in normal human gastric mucosa or young rat gastric mucosa. In contrast, level of expression for all three markers significantly increased in H. pylori gastritis and gastric adenocarcinomas as well as in normal gastric mucosa in aged rats. We also observed cytoplasmic B-catenin staining in both aged rat and human H. pylori inflamed gastric mucosa, which were found to be colocalized with Lgr5 immunoreactive cells. The increased number of ALDH1, CD166 and LGR5 positive cells in H. pylori gastritis indicates that increased number of stem-like cells in gastric mucosa is an early event, and may constitute an important step in the progression to neoplasia. CONCLUSION: Our observation of the age-related increase in cancer stem/stem-like cells in the gastric mucosa may explain the increased incidence of gastric cancer during aging. Combination of aging and H. pylori infection may have additive effects in progression to neoplasia.
基金Merit Review Award from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service,No.I01 BX000626-05A2 to Tarnawski AS
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
