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
目的:研究第10号染色体缺失的磷酸酶张力蛋白同源物基因(phosphatase and tensin homologue deleted on chromosome ten,PTEN)/磷脂酰肌醇3-激酶(phosphoinositide 3-kinase,PI3K)在肝缺血再灌注损伤中的调控作用及可能的机制.方法:夹闭...目的:研究第10号染色体缺失的磷酸酶张力蛋白同源物基因(phosphatase and tensin homologue deleted on chromosome ten,PTEN)/磷脂酰肌醇3-激酶(phosphoinositide 3-kinase,PI3K)在肝缺血再灌注损伤中的调控作用及可能的机制.方法:夹闭C57BL/6J小鼠的肝动脉和门静脉以阻断肝脏向头侧肝叶血供90 min,随后取下血管夹恢复血供,建立肝缺血再灌注损伤模型.实验分为四组:正常对照组(sham)、缺血再灌注模型组(IR)、PTEN抑制剂bpv(HOpic)干预组(BPV+IR)、PI3K抑制剂wortmannin干预组(WM+IR).检测小鼠血清ALT水平,行肝组织病理检查,以评估抑制PTEN/PI3K对肝脏IRI的影响.采用Western blot法检测p-AKT、p-GSK3β的表达,分析抑制PTEN/PI3K对其下游关键效应分子AKT/GSK3β磷酸化的调控.采用定量PCR法检测炎性因子IL-12p40、IL-10及TNF-α的基因表达,分析抑制PTEN/PI3K对TLR4介导的炎症反应的影响.结果:血清ALT及肝组织学改变均提示,抑制PTEN使IR诱导的肝损害明显减轻,相反,抑制PI3K则使IRI加剧.随着再灌注的发生,缺血期去磷酸化的AKT/GSK3β逐渐恢复其磷酸化活性.抑制PTEN增强了再灌注触发的AKT/GSK3β磷酸化,而阻断PI3K则使其明显削弱.阻断PTEN抑制了促炎基因IL-12p40、TNF-α的表达,并使IL-12/IL-10比值下调,该结果与抑制PI3K产生的效应完全相反.结论:PTEN/PI3K在肝缺血再灌注损伤中发挥重要的调控作用,PTEN抑制和/或PI3K活化可能通过上调p-AKT/p-GSK3β以及抑制炎症反应明显减轻肝缺血再灌注损伤.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
