Many epidemiological studies demonstrate that treatment with non-steroidal anti-inflammatory drugs （NSAIDs） reduce the incidence and mortality of certain malignancies, especially gastrointestinal cancer. The cycloox...Many epidemiological studies demonstrate that treatment with non-steroidal anti-inflammatory drugs （NSAIDs） reduce the incidence and mortality of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase （COX） enzymes are well-known targets of NSAIDs. However, conventional NSAIDs nonselectively inhibit both the constitutive form COX-1, and the inducible form COX-2. Recent evidence indicates that COX-2 is an important molecular target for anticancer therapies. Its expression is undetectable in most normal tissues, and is highly induced by proinflammatory cytokines, mitogens, tumor promoters and growth factors. It is now well-established that COX-2 is chronically overexpressed in many premalignant, malignant, and metastastic cancers, including hepatocellular carcinoma （HCC）. Overexpression of COX-2 in patients with HCC is generally higher in welldifferentiated HCCs compared with less-differentiated HCCs or histologically normal liver, suggesting that COX-2 may be involved in the early stages of hepatocarcinogenesis, and increased expression of COX-2 in noncancerous liver tissue has been significantly associated with shorter disease-free survival in patients with HCC. In tumors, overexpression of COX-2 leads to an increase in prostaglandin （PG） levels, which affect many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, stimulation of cell growth as well as the invasiveness and metastatic potential of tumor cells. The availability of novel agents that selectively inhibit COX-2 （COXIB）, has contributed to shedding light on the role of this molecule. Experimental studies on animal models of liver cancer have shown that NSAIDs, including both selective and non-selective COX-2 inhibitors, exert chemopreventive as well as therapeutic effects. However, the key mechanism by which COX-2 inhibitors affect HCC cell growth is as yet not fully understood. Increasing evidence suggests the involvement of molecular targets other than COX-2 in the antiprol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
目的探讨环氧合酶-1(COX-1)、环氧合酶-2(COX-2)基因多态性与阿司匹林抵抗相关性。方法将96例缺血性脑卒中患者分为阿司匹林敏感组87例和阿司匹林非敏感组9例。2组患者口服100 mg阿司匹林至少一周。用光比浊法对患者的血小板聚集度进行...目的探讨环氧合酶-1(COX-1)、环氧合酶-2(COX-2)基因多态性与阿司匹林抵抗相关性。方法将96例缺血性脑卒中患者分为阿司匹林敏感组87例和阿司匹林非敏感组9例。2组患者口服100 mg阿司匹林至少一周。用光比浊法对患者的血小板聚集度进行测定,用Sequenom Mass A RRAY i PLEX基因型分析技术进行COX-1、COX-2的基因型检测,分析COX-1、COX-2基因多态性与阿司匹林的相关性。结果阿司匹林非敏感组患者的既往卒中史比例66.7%(6/9)显著高于阿司匹林敏感组21.9%(19/87)(P<0.05)。2组患者的COX-1(rs1330344,rs3842788)基因型分布差异有统计学意义(P<0.05),但COX-1(rs5788)、COX-2(rs20417)基因型分布差异无统计学意义(P>0.05)。COX-1(rs5788,rs1330344,rs3842788)、COX-2(rs20417)等位基因及基因型频率4个单核苷酸基因多态性均符合Hardy-Weinberg平衡(P>0.05)。结论 COX-1(rs3842788,rs1330344)GG型与阿司匹林抵抗密切相关。展开更多
Objective：To investigate the expression of cyclooxygenase-2 and its pathological effect in the experimental nonalcoholic fatty liver of rats, and to explore its possible mechanism. Methods：The rat NAFLD model was es...Objective：To investigate the expression of cyclooxygenase-2 and its pathological effect in the experimental nonalcoholic fatty liver of rats, and to explore its possible mechanism. Methods：The rat NAFLD model was established by giving a fat-enriched diet. The blood samples were obtained form abdominal aorta and the levels of serum ALT, AST and IL-1, changes in the hepatic tissue 6-k-PGF1 α TXB2 were measured. The expression level of COX-2 in rats livers were assayed by immunohistochemistry, RT-PCR and Westernblot. Results： Light microscope analysis revealed that hepatocytes were injured in the model group and slightly in the treatment group. The levels of serum TXB2 and IL-1 in the fatty liver rats were increased. Compared with the model group, the IL-1 and TXB2 increased significantly（P〈 0.05）, on the contrary, compared with the normal group, the hepatic tissue 6-Keto-prostagland decreased significantly in the model group（P 〈 0.05）, the treatment group also increased but P 〉 0.05. There was no positive expression of COX-2 in hepatic tissue of normal rats. In the model group, there was positive expression of COX-2 antigen and the number of COX positive cells progressively increased at 4, 8, 12 wks. The intensity of expression of COX-2 had significantly increased（P 〈 0.05 ） and the intensity of COX-2 expression in the treated group decreased remarkably compared with the model group（P 〈 0.05）. The expression of COX-2 mRNA and the level of COX-2 protein were significantly stronger in the liver of model rats compared with normal rats, and significantly weaker in treated rats, than in 8W and 12W model rats（P 〈 0.05）. Conclusion：The increase of COX-2 expression in NAFLD is closely associated with the severity of liver inflammation and damage. COX-2 may play an important role in the progression of rat NAFLD, and the expression of COX-2 mRNA is downregulated by cyclooxygenase-2 inhibitor, which can depress the oxidative stress and control inflammatory response efficiently.展开更多
目的观察环氧合酶-2(COX-2)、hMLH1和hMSH2蛋白在胃癌组织中的表达,探讨其与微卫星不稳定(MSI)的关系。方法采用W estern b lot和PCR技术,检测30例胃癌及相应癌旁正常组织COX-2、hMLH1和hMSH2蛋白表达及5个位点的MSI状态。结果胃癌组织C...目的观察环氧合酶-2(COX-2)、hMLH1和hMSH2蛋白在胃癌组织中的表达,探讨其与微卫星不稳定(MSI)的关系。方法采用W estern b lot和PCR技术,检测30例胃癌及相应癌旁正常组织COX-2、hMLH1和hMSH2蛋白表达及5个位点的MSI状态。结果胃癌组织COX-2高表达率为66.7%,hMLH1、hMSH2低表达率分别为40.0%和33.3%,与癌旁正常组织差异均有统计学意义(P均<0.05)。30例胃癌组织中微卫星稳定(MSS)17例,MSI 13例,其中高频率MSI(MSI-H)9例,低频率MSI(MSI-L)4例。9例MSI-H中COX-2、hMLH1和hMSH2低表达者分别为6,8和5例,与MSS组差异均有统计学意义(P均<0.05)。结论散发性胃癌发生过程中可能存在MSI途径。MSI途径常伴有hMLH1、hMSH2蛋白表达缺陷,并可能伴有COX-2表达降低。展开更多
Objective: To investigate the effect of Red Peony 801 (propyl gallate,PrG) on cyclooxygenase (COX) activity in murine peritoneal macrophages. Methods: A screening model for COX inhibitors in vitro based on murine peri...Objective: To investigate the effect of Red Peony 801 (propyl gallate,PrG) on cyclooxygenase (COX) activity in murine peritoneal macrophages. Methods: A screening model for COX inhibitors in vitro based on murine peritoneal macrophages was used. COX-1 activity was reflected by the level of 6-ketoprostaglandin F1α(6-keto-PGF1α) in supernatants of cultured macrophages which were stimulated with calcium ionophore A23187 for a short-term, while COX-2 activity was reflected by the level of prostaglandin E2 (PGE2) in supernatants of cultured macrophages which were stimulated with lipopolysaccharide (LPS) for a long-term. Results: PrG did not affect A23187-induced, COX-1-derived 6-keto-PGF1α synthesis at the concentrations of 1×10-5, 5×10-6 mol/L (P>0.05), but enhanced 6-keto-PGF1α synthesis at the concentrations of 1×10-6, 5×10-7, 1×10-7 mol/L (P<0.01) in vitro, and showed a good dose-dependent manner. It inhibited LPS-induced, COX-2-derived PGE2 synthesis at the concentrations of 1×10-5,1×10-6 mol/L (P< 0. 05). Conclusion: Within the range of 1×10-5 to 1×10-7 mol/L, PrG activated COX-1 at lower concentrations and inhibited COX-2 at higher concentrations in murine peritoneal macrophages.展开更多
基金Supported by a grant from the Associazione Italiana per la Ricerca sul Cancro and from the Italian Ministero dell'Universitàedella Ricerca Scientifica (ex 60%, year 2003)
文摘Many epidemiological studies demonstrate that treatment with non-steroidal anti-inflammatory drugs （NSAIDs） reduce the incidence and mortality of certain malignancies, especially gastrointestinal cancer. The cyclooxygenase （COX） enzymes are well-known targets of NSAIDs. However, conventional NSAIDs nonselectively inhibit both the constitutive form COX-1, and the inducible form COX-2. Recent evidence indicates that COX-2 is an important molecular target for anticancer therapies. Its expression is undetectable in most normal tissues, and is highly induced by proinflammatory cytokines, mitogens, tumor promoters and growth factors. It is now well-established that COX-2 is chronically overexpressed in many premalignant, malignant, and metastastic cancers, including hepatocellular carcinoma （HCC）. Overexpression of COX-2 in patients with HCC is generally higher in welldifferentiated HCCs compared with less-differentiated HCCs or histologically normal liver, suggesting that COX-2 may be involved in the early stages of hepatocarcinogenesis, and increased expression of COX-2 in noncancerous liver tissue has been significantly associated with shorter disease-free survival in patients with HCC. In tumors, overexpression of COX-2 leads to an increase in prostaglandin （PG） levels, which affect many mechanisms involved in carcinogenesis, such as angiogenesis, inhibition of apoptosis, stimulation of cell growth as well as the invasiveness and metastatic potential of tumor cells. The availability of novel agents that selectively inhibit COX-2 （COXIB）, has contributed to shedding light on the role of this molecule. Experimental studies on animal models of liver cancer have shown that NSAIDs, including both selective and non-selective COX-2 inhibitors, exert chemopreventive as well as therapeutic effects. However, the key mechanism by which COX-2 inhibitors affect HCC cell growth is as yet not fully understood. Increasing evidence suggests the involvement of molecular targets other than COX-2 in the antiprol
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
文摘目的探讨环氧合酶-1(COX-1)、环氧合酶-2(COX-2)基因多态性与阿司匹林抵抗相关性。方法将96例缺血性脑卒中患者分为阿司匹林敏感组87例和阿司匹林非敏感组9例。2组患者口服100 mg阿司匹林至少一周。用光比浊法对患者的血小板聚集度进行测定,用Sequenom Mass A RRAY i PLEX基因型分析技术进行COX-1、COX-2的基因型检测,分析COX-1、COX-2基因多态性与阿司匹林的相关性。结果阿司匹林非敏感组患者的既往卒中史比例66.7%(6/9)显著高于阿司匹林敏感组21.9%(19/87)(P<0.05)。2组患者的COX-1(rs1330344,rs3842788)基因型分布差异有统计学意义(P<0.05),但COX-1(rs5788)、COX-2(rs20417)基因型分布差异无统计学意义(P>0.05)。COX-1(rs5788,rs1330344,rs3842788)、COX-2(rs20417)等位基因及基因型频率4个单核苷酸基因多态性均符合Hardy-Weinberg平衡(P>0.05)。结论 COX-1(rs3842788,rs1330344)GG型与阿司匹林抵抗密切相关。
文摘Objective：To investigate the expression of cyclooxygenase-2 and its pathological effect in the experimental nonalcoholic fatty liver of rats, and to explore its possible mechanism. Methods：The rat NAFLD model was established by giving a fat-enriched diet. The blood samples were obtained form abdominal aorta and the levels of serum ALT, AST and IL-1, changes in the hepatic tissue 6-k-PGF1 α TXB2 were measured. The expression level of COX-2 in rats livers were assayed by immunohistochemistry, RT-PCR and Westernblot. Results： Light microscope analysis revealed that hepatocytes were injured in the model group and slightly in the treatment group. The levels of serum TXB2 and IL-1 in the fatty liver rats were increased. Compared with the model group, the IL-1 and TXB2 increased significantly（P〈 0.05）, on the contrary, compared with the normal group, the hepatic tissue 6-Keto-prostagland decreased significantly in the model group（P 〈 0.05）, the treatment group also increased but P 〉 0.05. There was no positive expression of COX-2 in hepatic tissue of normal rats. In the model group, there was positive expression of COX-2 antigen and the number of COX positive cells progressively increased at 4, 8, 12 wks. The intensity of expression of COX-2 had significantly increased（P 〈 0.05 ） and the intensity of COX-2 expression in the treated group decreased remarkably compared with the model group（P 〈 0.05）. The expression of COX-2 mRNA and the level of COX-2 protein were significantly stronger in the liver of model rats compared with normal rats, and significantly weaker in treated rats, than in 8W and 12W model rats（P 〈 0.05）. Conclusion：The increase of COX-2 expression in NAFLD is closely associated with the severity of liver inflammation and damage. COX-2 may play an important role in the progression of rat NAFLD, and the expression of COX-2 mRNA is downregulated by cyclooxygenase-2 inhibitor, which can depress the oxidative stress and control inflammatory response efficiently.
文摘目的观察环氧合酶-2(COX-2)、hMLH1和hMSH2蛋白在胃癌组织中的表达,探讨其与微卫星不稳定(MSI)的关系。方法采用W estern b lot和PCR技术,检测30例胃癌及相应癌旁正常组织COX-2、hMLH1和hMSH2蛋白表达及5个位点的MSI状态。结果胃癌组织COX-2高表达率为66.7%,hMLH1、hMSH2低表达率分别为40.0%和33.3%,与癌旁正常组织差异均有统计学意义(P均<0.05)。30例胃癌组织中微卫星稳定(MSS)17例,MSI 13例,其中高频率MSI(MSI-H)9例,低频率MSI(MSI-L)4例。9例MSI-H中COX-2、hMLH1和hMSH2低表达者分别为6,8和5例,与MSS组差异均有统计学意义(P均<0.05)。结论散发性胃癌发生过程中可能存在MSI途径。MSI途径常伴有hMLH1、hMSH2蛋白表达缺陷,并可能伴有COX-2表达降低。
文摘Objective: To investigate the effect of Red Peony 801 (propyl gallate,PrG) on cyclooxygenase (COX) activity in murine peritoneal macrophages. Methods: A screening model for COX inhibitors in vitro based on murine peritoneal macrophages was used. COX-1 activity was reflected by the level of 6-ketoprostaglandin F1α(6-keto-PGF1α) in supernatants of cultured macrophages which were stimulated with calcium ionophore A23187 for a short-term, while COX-2 activity was reflected by the level of prostaglandin E2 (PGE2) in supernatants of cultured macrophages which were stimulated with lipopolysaccharide (LPS) for a long-term. Results: PrG did not affect A23187-induced, COX-1-derived 6-keto-PGF1α synthesis at the concentrations of 1×10-5, 5×10-6 mol/L (P>0.05), but enhanced 6-keto-PGF1α synthesis at the concentrations of 1×10-6, 5×10-7, 1×10-7 mol/L (P<0.01) in vitro, and showed a good dose-dependent manner. It inhibited LPS-induced, COX-2-derived PGE2 synthesis at the concentrations of 1×10-5,1×10-6 mol/L (P< 0. 05). Conclusion: Within the range of 1×10-5 to 1×10-7 mol/L, PrG activated COX-1 at lower concentrations and inhibited COX-2 at higher concentrations in murine peritoneal macrophages.
