Loss of susceptibility to anoikis signals is a crucial step in metastasis.Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management.In this study,we have conducted a rationa...Loss of susceptibility to anoikis signals is a crucial step in metastasis.Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management.In this study,we have conducted a rationalized screening to search for novel leading anoikis sensitizer from daily foods.Among 19 tested dietary phytochemicals,the best results were obtained with apigenin,a natural component of celery.Phenotypically,apigenin sensitized breast cancer cells to anoikis,lowered the number of circulating tumor cells,and protected against breast cancer metastasis to lung in mice.Mechanistically,we demonstrated that the thromboxane A_(2)(TXA_(2))-TXA_(2)receptor(TP)axis has a critical role in acquired anoikis resistance by activating PI3K-Akt signaling pathway.Blockage of TXA_(2)signaling up-regulated p53 as well as its target gene p21,caused a G1 phase arrest,and finally led to apoptosis in breast cancer cells.TXA_(2)level was positively correlated with breast cancer cell anoikis rate,and apigenin significantly inhibited TXA_(2)biosynthesis in vitro and in vivo.Collectively,we identified apigenin as a potent anoikis sensitizer with anti-metastatic properties in a mouse model of breast cancer,and these findings might provide a rationale for introducing apigenin supplementation to breast cancer patients.展开更多
The 2-series eicosanoids are structurally related lipid-soluble hormones synthesized by cyclooxygenase enzymes from arachidonic acid. These compounds have well-established roles in the inflammatory response and the co...The 2-series eicosanoids are structurally related lipid-soluble hormones synthesized by cyclooxygenase enzymes from arachidonic acid. These compounds have well-established roles in the inflammatory response and the coagulation cascade. More recently, the eicosanoids have garnered attention for their potential roles in cancers of the lung, colon, breast, and brain. In this paper, we review the contributions of the different cyclooxygenase metabolites (i.e. prostaglandins, prostacyclins and thromboxanes) to cancer development, progression and recurrence, with special attention paid to their relevance to glioma biology. Our review suggests that 2-series eicosanoids merit further study as possible targets for therapy in patients with glioma.展开更多
Aspirin(ASA) irreversibly inhibits platelet cyclooxygenase-1(COX-1) leading to decreased thromboxane-mediated platelet activation. The effect of ASA ingestion on thromboxane generation was evaluated in patients with d...Aspirin(ASA) irreversibly inhibits platelet cyclooxygenase-1(COX-1) leading to decreased thromboxane-mediated platelet activation. The effect of ASA ingestion on thromboxane generation was evaluated in patients with diabetes(DM) and cardiovascular disease. Thromboxane inhibition was assessed by measuring the urinary excretion of 11-dehydro-thromboxane B2(11dhTxB2), a stable metabolite of thromboxane A2. The mean baseline urinary 11dhTxB2 of DM was 69.6% higher than healthy controls(P = 0.024): female subjects(DM and controls) had 50.9% higher baseline 11dhTxB2 than males(P = 0.0004), while age or disease duration had no influence. Daily ASA ingestion inhibited urinary 11dhTxB2 in both DM(71.7%) and controls(75.1%, P < 0.0001). Using a pre-established cut-off of 1500 pg/mg of urinary 11dhTxB2, there were twice as many ASA poor responders(ASA "resistant") in DM than in controls(14.8% and 8.4%, respectively). The rate of ASA poor responders in two populations of acute coronary syndrome(ACS) patients was 28.6 and 28.7%, in spite of a significant(81.6%) inhibition of urinary 11dhTxB2(P < 0.0001). Both baseline 11dhTxB2 levels and rate of poor ASA responders were significantly higher in DM and ACS compared to controls. Underlying systemic oxidative inflammation may maintain platelet function in atherosclerotic cardiovascular disease irrespective of COX-1 pathway inhibition and/or increase systemic generation of thromboxane from non-platelet sources.展开更多
Brain microvascular endothelial cells form the interface between nervous tissue and circulating blood, and regulate central nervous system homeostasis. Brain microvascular endothelial cells differ from peripheral endo...Brain microvascular endothelial cells form the interface between nervous tissue and circulating blood, and regulate central nervous system homeostasis. Brain microvascular endothelial cells differ from peripheral endothelial cells with regards expression of specific ion transporters and receptors, and contain fewer fenestrations and pinocytotic vesicles. Brain microvascular endothelial cells also synthesize several factors that influence blood vessel function. This review describes the morphological characteristics and functions of brain microvascular endothelial cells, and summarizes current knowledge regarding changes in brain microvascular endothelial cells during stroke progression and therapies. Future studies should focus on identifying mechanisms underlying such changes and developing possible neuroprotective therapeutic interventions.展开更多
Based on the antiplatelet aggregation mechanism and the bioisosterism principle of the reference drug picotamide, thirteen novel derivatives of arylamide and arylsulfonamide were designed and prepared. The biological ...Based on the antiplatelet aggregation mechanism and the bioisosterism principle of the reference drug picotamide, thirteen novel derivatives of arylamide and arylsulfonamide were designed and prepared. The biological activities of these derivatives were investigated. The chemical structures of the target compounds were confirmed by ^1H NMR and IR. The in vitro activities of antiplatelet aggregation of the thirteen target compounds were assessed by Bore's method. Compounds 2b and 8h have significant antiplatelet aggregation activities, which are superior to the corresponding activity of Picotamide.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 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.展开更多
Thromboxane A synthase 1 (TBXAS1) catalyses the synthesis of thromboxane A2 (TXA2), which plays an important role in the pathogenesis of ischemic stroke. Thus, the TBXAS1 gene was investigated as a candidate gene ...Thromboxane A synthase 1 (TBXAS1) catalyses the synthesis of thromboxane A2 (TXA2), which plays an important role in the pathogenesis of ischemic stroke. Thus, the TBXAS1 gene was investigated as a candidate gene involved in the formation of atherosclerosis. This case-control study collected peripheral blood specimens and clinical data of 370 ischemic stroke patients and 340 healthy controls in the Northern Chinese Han population from October 2010 to May 2011. Two TBXAS1 single-nucleotide polymorphisms, rs2267682 and rs10487667, were analyzed using a SNaPshot Multiplex sequencing assay to explore the relationships between the single-nucleotide polymorphisms in TBXAS1 and ischemic stroke. The TT genotype frequency and T allele frequency of rs2267682 in the patients with ischemic stroke were significantly higher than those in the controls (P 〈 0.01 and P = 0.02). Furthermore, compared with the GG + GT genotype, the TT rs2267682 genotype was associated with increased risk of ischemic stroke (odds ratio (OR) = 1.80, 95% confidence interval (CI): 1.16–2.79, P 〈 0.01). Multivariate logistic analysis with adjustments for confounding factors revealed that rs2267682 was still associated with ischemic stroke (OR = 1.94,95% CI : 1.13–3.33, P = 0.02). The frequency of the T-G haplotype in the patients was significantly higher than that in the controls according haplotype analysis (OR = 1.49, 95% CI: 1.10–2.00, P 〈 0.01). These data reveal that the rs2267682 TBXAS1 polymorphism is associated with ischemic stroke. The TT genotype of TBXAS1 and T allele of rs2267682 increase susceptibility to ischemic stroke in this Northern Chinese Han population. The protocol has been registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-COC-17013559).展开更多
To evaluate the changes of 3', 5'-cyclic adenosine monophosphate (cAMP), thrombox-ane A2(TXA2) and prostacyclin (PGI2) in cerebrospinal fluid (CSF) in the asphyxiated newborn and explore their roles in hypoxic...To evaluate the changes of 3', 5'-cyclic adenosine monophosphate (cAMP), thrombox-ane A2(TXA2) and prostacyclin (PGI2) in cerebrospinal fluid (CSF) in the asphyxiated newborn and explore their roles in hypoxic-ischamic brain damage (HIBD). Thirty-six full term newborns were divided into 3 groups, including 12 with moderate-severe hypoxic-ischaemic encephalopathy (HIE), 13 with mild HIE, 11 without HIE (control group). The levels of cAMP, TXB2(TXA2 metabolite) and 6-keto-PGF1α(PGI2 metabolite) in CSF and plasma were measured 36-72 h after birth by RIA, and the concentrations were expressed as nM/L (cAMP), ng/L(TXB2 and 6-keto-PGF1α). The infants were followed-up at 6 and 12 month of age and Mental Development Index (MDI) and Psychomotor Development Index (FDD were measured using Bayley Scales of Infant Development (BSID). The CSF cAMP level in moderate-severe HIE group was 8. 60±2. 40, significantly lower than that of the mild HIE group (14. 83±2. 84) and the control group (24. 43±2. 39)(for both P<0. 01). The levels of TXB2 and 6-keto-PGF1α in CFS in the moderate-severe HIE group (206. 06±29. 74, 168. 47± 23. 02, respectively) were significantly higher than in the mild HIE group (83. 37±28. 57, 131. 42± 16. 57, respectively, P<0. 01) and the control group (41. 77±21. 58, 86. 23±13. 05, respectively, P<0. 01). The level changes of cAMP,TXB2 and 6-keto-PGF1α in plasma in all groups were similar to those in CSF, but no significant difference was found between mild HIE group and the control group (P>0. 05). The follow-up results showed that MDI and PDI of the moderate-severe HIE group were the lowest (84. 79±13. 34, 83. 50±13. 28, respectively), followed by mild HIE group (102.19±7. 02, 99. 94±9. 08, respectively) , with the control group being the highest (116. 63± 12.08, 116. 69±10. 87, respectively). Univariate analysis showed some significant difference (the moderate-severe HIE group vs. the mild HIE group or the control group, P<0. 01; the mild HIE group vs. the control group P<0. 05). The results suggested that the concentration of cAMP, TXA2 and T/K ratio in CSF after neonatal asphyxia might be sensitive markers in evaluating the severity of brain damage in early stage and predicting the future outcome.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
Fifty-seven bum patients were dosdy observed for 28 d postburn.In general,plasma levelof thromboxane B<sub>2</sub>(TXB<sub>2</sub>),6-keto-PGF<sub>lx</sub> and TXB<sub>2<...Fifty-seven bum patients were dosdy observed for 28 d postburn.In general,plasma levelof thromboxane B<sub>2</sub>(TXB<sub>2</sub>),6-keto-PGF<sub>lx</sub> and TXB<sub>2</sub>/6-keto-PGF<sub>lx</sub> ratio all rose up abruptly tothe peak in the first half day after burns and then declined gradually.However the patterns of theirchanges were different:6-keto-PGF<sub>lx</sub> returned to the control level in the 2nd day postburn,remained in a higher level than the control even in the 5th day postburn,and the increase ofTXB<sub>2</sub>/6-keto-PGF<sub>lα</sub> ratio was especially pronounced in the first 3 d postbum.It was also shownthat the changes of hemodynamics and hemorrheology occurred simultaneously with the imbalanceof thromboxane and prcstacyclin in the early postburn stage.The extent of the imbalance accordedwith the severity of hemodynamical and hemorrheological changes and was closely correlated withthe changes with the stroke volume,cardiac output,systemic vascular resistance,circulatory plateletaggregate ratio,platelet count and blood vinery.These findings suggest that the imbalance be-tween thromboxane and prostacyclin plays an important role in the changes of hemodynamics andhemorrheology in severe burn cases.展开更多
Fifty-seven severely burned patients were divided into 2 groups:16 withmultiple organ failure(MOF),and 41 without MOF.It was found that the levelof thromboxane B<sub>2</sub>(TXB<sub>2</sub>...Fifty-seven severely burned patients were divided into 2 groups:16 withmultiple organ failure(MOF),and 41 without MOF.It was found that the levelof thromboxane B<sub>2</sub>(TXB<sub>2</sub>)and the ratio between TXB<sub>2</sub> and 6-keto-prostaglandinF<sub>1α</sub>(TBX<sub>2</sub>/6-keto-PGF<sub>1α</sub>)in plasma and in visceral tissues were increased and re-mained significantly high in the first 5~7 d postburn in patients with MOF but notso in those without MOF.The circulatory platelet aggregate ratio(CPAR)wasmarkedly decreased in the same period in MOF group.Myocardial enzymes(CPK,LDH,and GOT)were markedly increased in the first 3d and remainedsignificantly high within 7 d postburn.Degeneration,structural destruction,edema,hemorrhage and thrombosis were revealed in cardiac,pulmonary,renal andhepatic tissues succumbing to functional failure.Thirteen out of the 16 cases de-veloped MOF during the 3rd to 7th day posthurn and 11 died in that period.These findings substantiate that persistent increase of thromboxane andthromboxane/prostacyclin ratio is closely related to the origin and development ofMOF after burn injury.展开更多
The puapose of this study was to evaluate the effects of cyclooxygenase inhibitor (Ibuprofen)and thromboxane synthetase inhibitor (OKY-046) on oxygen metabolism in acute respiratory failure.Intratracheal instillation ...The puapose of this study was to evaluate the effects of cyclooxygenase inhibitor (Ibuprofen)and thromboxane synthetase inhibitor (OKY-046) on oxygen metabolism in acute respiratory failure.Intratracheal instillation of hydrochloric acid was produced in 18 dogs, six dogs were pretreated with ibuprofen (IBU), six dogs with OKY-046 (OKY),and the remaindere used as control (CTR). After acid aspiration oxygen delivery (DO_2) fell in all groups as a results of decreased PaO_2 and cardiac output.However, oxygen consumption (VO_2)was maintained in all animals by the end of experiments except in CTR group. Arterial oxygen content maintained at baseline level throughout the experiments in IBU group. Meanwhile a significantly decreased mixed venous oxygen tension was found in OKY group after acid challenge. Liner regression of _vO_2 and DO_2 was confirmed in both CTR and OKY group. However,the dependent relationship between VO_2 and DO_2 was not identified in IBU group, which may indicate that the body oxygen metabolism was maintained rather well in acute rcspiratory failure dogs treated with ibuproten.展开更多
The correlation of secondary brain injury with thromboxane A<sub>2</sub>(TXA<sub>2</sub>) and prostacy-clin (PGI<sub>2</sub>) levels following head injury was studied in rats an...The correlation of secondary brain injury with thromboxane A<sub>2</sub>(TXA<sub>2</sub>) and prostacy-clin (PGI<sub>2</sub>) levels following head injury was studied in rats and patients.Thromboxane B<sub>2</sub>(TXB<sub>2</sub>) and 6-keto-PGF<sub>1α</sub> in rat brain homogenate and TXB<sub>2</sub> in cerebral spinal fluid (CSF) ofpatients with severe head injury were determined by RIA.The effects of ligustrazini hydrochlo-rioi were also tested.The results showed that the concentration of TXB<sub>2</sub> and 6-keto-PGF<sub>1α</sub> inrat brain was progressively increased within 3h after injury (P【0.01),and the ratio betweenTXB<sub>2</sub> and 6-keto-PGF<sub>1α</sub>(T/K value) increased during the early stage after injury,along withthe tissue damage aggravation.After the use of ligustrazini hydrochlorioi,TXB<sub>2</sub> content inbrain decreased sharply accompanied with a drop in T/K value.Moreover,TXB<sub>2</sub> content inCSF increased within 7 d after injury (P【0.01),and it reached its peak value on the 3rd day.This could indicate that the metabolic imbalance between TXA<sub>2</sub> and PGI<sub>2</sub> might be one of theimportant factors in the development of secondary brain injury,and ligustrazini hydrochlorioiproved to have a protective effect on the brain tissue by normalizing the metabolism of TXA<sub>2</sub>and PGI<sub>2</sub>.In addition,the metabolic disorders of TXA<sub>2</sub> in the brain tissue of head injured pa-tients have much to do with the outcome of the patients.展开更多
In order to understand the relation between TXA2- PGI2 and secondary trauma and the effect of intra-arachnoid perfusion of dexamethasone and verapamil on alteration of TXA,-PGI, following spinal cord injury, TXB2 and ...In order to understand the relation between TXA2- PGI2 and secondary trauma and the effect of intra-arachnoid perfusion of dexamethasone and verapamil on alteration of TXA,-PGI, following spinal cord injury, TXB2 and 6-keto-PGFconcentration and pathological changes in injured site 1, 2, 4 and 6 h after injury were studied using a rabbit spinal cord injury model by Allen's weight drop method.展开更多
基金supported by the National Natural Science Foundation of China (81773064,31972973,32021005)National Youth 1000 Talents Plan+2 种基金the Jiangsu Specially-Appointed Professor ProgramJiangsu Province Recruitment Plan for High-level,Innovative and Entrepreneurial Talents (Innovative Research Team)Collaborative Innovation Center of Food Safety and Quality Control in Jiangsu Province
文摘Loss of susceptibility to anoikis signals is a crucial step in metastasis.Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management.In this study,we have conducted a rationalized screening to search for novel leading anoikis sensitizer from daily foods.Among 19 tested dietary phytochemicals,the best results were obtained with apigenin,a natural component of celery.Phenotypically,apigenin sensitized breast cancer cells to anoikis,lowered the number of circulating tumor cells,and protected against breast cancer metastasis to lung in mice.Mechanistically,we demonstrated that the thromboxane A_(2)(TXA_(2))-TXA_(2)receptor(TP)axis has a critical role in acquired anoikis resistance by activating PI3K-Akt signaling pathway.Blockage of TXA_(2)signaling up-regulated p53 as well as its target gene p21,caused a G1 phase arrest,and finally led to apoptosis in breast cancer cells.TXA_(2)level was positively correlated with breast cancer cell anoikis rate,and apigenin significantly inhibited TXA_(2)biosynthesis in vitro and in vivo.Collectively,we identified apigenin as a potent anoikis sensitizer with anti-metastatic properties in a mouse model of breast cancer,and these findings might provide a rationale for introducing apigenin supplementation to breast cancer patients.
文摘The 2-series eicosanoids are structurally related lipid-soluble hormones synthesized by cyclooxygenase enzymes from arachidonic acid. These compounds have well-established roles in the inflammatory response and the coagulation cascade. More recently, the eicosanoids have garnered attention for their potential roles in cancers of the lung, colon, breast, and brain. In this paper, we review the contributions of the different cyclooxygenase metabolites (i.e. prostaglandins, prostacyclins and thromboxanes) to cancer development, progression and recurrence, with special attention paid to their relevance to glioma biology. Our review suggests that 2-series eicosanoids merit further study as possible targets for therapy in patients with glioma.
基金Supported by In part by the Senit Foundation,Scotland(United Kingdom)grant-in-aid for Scientific Research from the Ministry of Education,Culture,Sports,Science and Technology(Japan)
文摘Aspirin(ASA) irreversibly inhibits platelet cyclooxygenase-1(COX-1) leading to decreased thromboxane-mediated platelet activation. The effect of ASA ingestion on thromboxane generation was evaluated in patients with diabetes(DM) and cardiovascular disease. Thromboxane inhibition was assessed by measuring the urinary excretion of 11-dehydro-thromboxane B2(11dhTxB2), a stable metabolite of thromboxane A2. The mean baseline urinary 11dhTxB2 of DM was 69.6% higher than healthy controls(P = 0.024): female subjects(DM and controls) had 50.9% higher baseline 11dhTxB2 than males(P = 0.0004), while age or disease duration had no influence. Daily ASA ingestion inhibited urinary 11dhTxB2 in both DM(71.7%) and controls(75.1%, P < 0.0001). Using a pre-established cut-off of 1500 pg/mg of urinary 11dhTxB2, there were twice as many ASA poor responders(ASA "resistant") in DM than in controls(14.8% and 8.4%, respectively). The rate of ASA poor responders in two populations of acute coronary syndrome(ACS) patients was 28.6 and 28.7%, in spite of a significant(81.6%) inhibition of urinary 11dhTxB2(P < 0.0001). Both baseline 11dhTxB2 levels and rate of poor ASA responders were significantly higher in DM and ACS compared to controls. Underlying systemic oxidative inflammation may maintain platelet function in atherosclerotic cardiovascular disease irrespective of COX-1 pathway inhibition and/or increase systemic generation of thromboxane from non-platelet sources.
基金supported by grants from the National Natural Science Foundation of ChinaNo.8117111281371272 to MCL
文摘Brain microvascular endothelial cells form the interface between nervous tissue and circulating blood, and regulate central nervous system homeostasis. Brain microvascular endothelial cells differ from peripheral endothelial cells with regards expression of specific ion transporters and receptors, and contain fewer fenestrations and pinocytotic vesicles. Brain microvascular endothelial cells also synthesize several factors that influence blood vessel function. This review describes the morphological characteristics and functions of brain microvascular endothelial cells, and summarizes current knowledge regarding changes in brain microvascular endothelial cells during stroke progression and therapies. Future studies should focus on identifying mechanisms underlying such changes and developing possible neuroprotective therapeutic interventions.
文摘Based on the antiplatelet aggregation mechanism and the bioisosterism principle of the reference drug picotamide, thirteen novel derivatives of arylamide and arylsulfonamide were designed and prepared. The biological activities of these derivatives were investigated. The chemical structures of the target compounds were confirmed by ^1H NMR and IR. The in vitro activities of antiplatelet aggregation of the thirteen target compounds were assessed by Bore's method. Compounds 2b and 8h have significant antiplatelet aggregation activities, which are superior to the corresponding activity of Picotamide.
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 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.
基金supported by a grant from the National Natural Science Foundation of China,No.81070913
文摘Thromboxane A synthase 1 (TBXAS1) catalyses the synthesis of thromboxane A2 (TXA2), which plays an important role in the pathogenesis of ischemic stroke. Thus, the TBXAS1 gene was investigated as a candidate gene involved in the formation of atherosclerosis. This case-control study collected peripheral blood specimens and clinical data of 370 ischemic stroke patients and 340 healthy controls in the Northern Chinese Han population from October 2010 to May 2011. Two TBXAS1 single-nucleotide polymorphisms, rs2267682 and rs10487667, were analyzed using a SNaPshot Multiplex sequencing assay to explore the relationships between the single-nucleotide polymorphisms in TBXAS1 and ischemic stroke. The TT genotype frequency and T allele frequency of rs2267682 in the patients with ischemic stroke were significantly higher than those in the controls (P 〈 0.01 and P = 0.02). Furthermore, compared with the GG + GT genotype, the TT rs2267682 genotype was associated with increased risk of ischemic stroke (odds ratio (OR) = 1.80, 95% confidence interval (CI): 1.16–2.79, P 〈 0.01). Multivariate logistic analysis with adjustments for confounding factors revealed that rs2267682 was still associated with ischemic stroke (OR = 1.94,95% CI : 1.13–3.33, P = 0.02). The frequency of the T-G haplotype in the patients was significantly higher than that in the controls according haplotype analysis (OR = 1.49, 95% CI: 1.10–2.00, P 〈 0.01). These data reveal that the rs2267682 TBXAS1 polymorphism is associated with ischemic stroke. The TT genotype of TBXAS1 and T allele of rs2267682 increase susceptibility to ischemic stroke in this Northern Chinese Han population. The protocol has been registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-COC-17013559).
文摘To evaluate the changes of 3', 5'-cyclic adenosine monophosphate (cAMP), thrombox-ane A2(TXA2) and prostacyclin (PGI2) in cerebrospinal fluid (CSF) in the asphyxiated newborn and explore their roles in hypoxic-ischamic brain damage (HIBD). Thirty-six full term newborns were divided into 3 groups, including 12 with moderate-severe hypoxic-ischaemic encephalopathy (HIE), 13 with mild HIE, 11 without HIE (control group). The levels of cAMP, TXB2(TXA2 metabolite) and 6-keto-PGF1α(PGI2 metabolite) in CSF and plasma were measured 36-72 h after birth by RIA, and the concentrations were expressed as nM/L (cAMP), ng/L(TXB2 and 6-keto-PGF1α). The infants were followed-up at 6 and 12 month of age and Mental Development Index (MDI) and Psychomotor Development Index (FDD were measured using Bayley Scales of Infant Development (BSID). The CSF cAMP level in moderate-severe HIE group was 8. 60±2. 40, significantly lower than that of the mild HIE group (14. 83±2. 84) and the control group (24. 43±2. 39)(for both P<0. 01). The levels of TXB2 and 6-keto-PGF1α in CFS in the moderate-severe HIE group (206. 06±29. 74, 168. 47± 23. 02, respectively) were significantly higher than in the mild HIE group (83. 37±28. 57, 131. 42± 16. 57, respectively, P<0. 01) and the control group (41. 77±21. 58, 86. 23±13. 05, respectively, P<0. 01). The level changes of cAMP,TXB2 and 6-keto-PGF1α in plasma in all groups were similar to those in CSF, but no significant difference was found between mild HIE group and the control group (P>0. 05). The follow-up results showed that MDI and PDI of the moderate-severe HIE group were the lowest (84. 79±13. 34, 83. 50±13. 28, respectively), followed by mild HIE group (102.19±7. 02, 99. 94±9. 08, respectively) , with the control group being the highest (116. 63± 12.08, 116. 69±10. 87, respectively). Univariate analysis showed some significant difference (the moderate-severe HIE group vs. the mild HIE group or the control group, P<0. 01; the mild HIE group vs. the control group P<0. 05). The results suggested that the concentration of cAMP, TXA2 and T/K ratio in CSF after neonatal asphyxia might be sensitive markers in evaluating the severity of brain damage in early stage and predicting the future outcome.
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Fifty-seven bum patients were dosdy observed for 28 d postburn.In general,plasma levelof thromboxane B<sub>2</sub>(TXB<sub>2</sub>),6-keto-PGF<sub>lx</sub> and TXB<sub>2</sub>/6-keto-PGF<sub>lx</sub> ratio all rose up abruptly tothe peak in the first half day after burns and then declined gradually.However the patterns of theirchanges were different:6-keto-PGF<sub>lx</sub> returned to the control level in the 2nd day postburn,remained in a higher level than the control even in the 5th day postburn,and the increase ofTXB<sub>2</sub>/6-keto-PGF<sub>lα</sub> ratio was especially pronounced in the first 3 d postbum.It was also shownthat the changes of hemodynamics and hemorrheology occurred simultaneously with the imbalanceof thromboxane and prcstacyclin in the early postburn stage.The extent of the imbalance accordedwith the severity of hemodynamical and hemorrheological changes and was closely correlated withthe changes with the stroke volume,cardiac output,systemic vascular resistance,circulatory plateletaggregate ratio,platelet count and blood vinery.These findings suggest that the imbalance be-tween thromboxane and prostacyclin plays an important role in the changes of hemodynamics andhemorrheology in severe burn cases.
文摘Fifty-seven severely burned patients were divided into 2 groups:16 withmultiple organ failure(MOF),and 41 without MOF.It was found that the levelof thromboxane B<sub>2</sub>(TXB<sub>2</sub>)and the ratio between TXB<sub>2</sub> and 6-keto-prostaglandinF<sub>1α</sub>(TBX<sub>2</sub>/6-keto-PGF<sub>1α</sub>)in plasma and in visceral tissues were increased and re-mained significantly high in the first 5~7 d postburn in patients with MOF but notso in those without MOF.The circulatory platelet aggregate ratio(CPAR)wasmarkedly decreased in the same period in MOF group.Myocardial enzymes(CPK,LDH,and GOT)were markedly increased in the first 3d and remainedsignificantly high within 7 d postburn.Degeneration,structural destruction,edema,hemorrhage and thrombosis were revealed in cardiac,pulmonary,renal andhepatic tissues succumbing to functional failure.Thirteen out of the 16 cases de-veloped MOF during the 3rd to 7th day posthurn and 11 died in that period.These findings substantiate that persistent increase of thromboxane andthromboxane/prostacyclin ratio is closely related to the origin and development ofMOF after burn injury.
文摘The puapose of this study was to evaluate the effects of cyclooxygenase inhibitor (Ibuprofen)and thromboxane synthetase inhibitor (OKY-046) on oxygen metabolism in acute respiratory failure.Intratracheal instillation of hydrochloric acid was produced in 18 dogs, six dogs were pretreated with ibuprofen (IBU), six dogs with OKY-046 (OKY),and the remaindere used as control (CTR). After acid aspiration oxygen delivery (DO_2) fell in all groups as a results of decreased PaO_2 and cardiac output.However, oxygen consumption (VO_2)was maintained in all animals by the end of experiments except in CTR group. Arterial oxygen content maintained at baseline level throughout the experiments in IBU group. Meanwhile a significantly decreased mixed venous oxygen tension was found in OKY group after acid challenge. Liner regression of _vO_2 and DO_2 was confirmed in both CTR and OKY group. However,the dependent relationship between VO_2 and DO_2 was not identified in IBU group, which may indicate that the body oxygen metabolism was maintained rather well in acute rcspiratory failure dogs treated with ibuproten.
文摘The correlation of secondary brain injury with thromboxane A<sub>2</sub>(TXA<sub>2</sub>) and prostacy-clin (PGI<sub>2</sub>) levels following head injury was studied in rats and patients.Thromboxane B<sub>2</sub>(TXB<sub>2</sub>) and 6-keto-PGF<sub>1α</sub> in rat brain homogenate and TXB<sub>2</sub> in cerebral spinal fluid (CSF) ofpatients with severe head injury were determined by RIA.The effects of ligustrazini hydrochlo-rioi were also tested.The results showed that the concentration of TXB<sub>2</sub> and 6-keto-PGF<sub>1α</sub> inrat brain was progressively increased within 3h after injury (P【0.01),and the ratio betweenTXB<sub>2</sub> and 6-keto-PGF<sub>1α</sub>(T/K value) increased during the early stage after injury,along withthe tissue damage aggravation.After the use of ligustrazini hydrochlorioi,TXB<sub>2</sub> content inbrain decreased sharply accompanied with a drop in T/K value.Moreover,TXB<sub>2</sub> content inCSF increased within 7 d after injury (P【0.01),and it reached its peak value on the 3rd day.This could indicate that the metabolic imbalance between TXA<sub>2</sub> and PGI<sub>2</sub> might be one of theimportant factors in the development of secondary brain injury,and ligustrazini hydrochlorioiproved to have a protective effect on the brain tissue by normalizing the metabolism of TXA<sub>2</sub>and PGI<sub>2</sub>.In addition,the metabolic disorders of TXA<sub>2</sub> in the brain tissue of head injured pa-tients have much to do with the outcome of the patients.
文摘In order to understand the relation between TXA2- PGI2 and secondary trauma and the effect of intra-arachnoid perfusion of dexamethasone and verapamil on alteration of TXA,-PGI, following spinal cord injury, TXB2 and 6-keto-PGFconcentration and pathological changes in injured site 1, 2, 4 and 6 h after injury were studied using a rabbit spinal cord injury model by Allen's weight drop method.