Lung cancer is the most frequent cause of cancer-related mortality worldwide.Nitric oxide(NO),prostaglandins(PGs),thromboxanes(TXs),and endothelins(ETs)participate in numerous physiological processes.These agents play...Lung cancer is the most frequent cause of cancer-related mortality worldwide.Nitric oxide(NO),prostaglandins(PGs),thromboxanes(TXs),and endothelins(ETs)participate in numerous physiological processes.These agents play an important role in lung carcinogenesis by regulating cancer cell proliferation,apoptosis,invasion,and angiogenesis.NO is a gaseous free radical with tumo-ricidal and tumorigenic activities in lung cancer.Arachidonic acid-derived PGs,including PGD2,PGE2,8-iso-PGF2α,and PGI2,are related to the development of lung cancer.PGD2 and PGI2 act as tumor suppressors,while PGE2 and 8-iso-PGF2αpromote tumor progression.TXA2 catalyzed by cyclooxygenase induces prolif-eration as well as angiogenesis.Elevated levels of TXB2,an inactive metabolite of TXA2,are positively correlated with lung carcinoma stages.ET-1 and ET-2 are 21 amino acid polypeptides;their silencing hinders lung cancer cell proliferation and invasion.ET-2 depletion also triggers apoptotic death.This chapter review aims to provide a comprehensive overview of the role of NO,PGs,TXs,and ETs in lung cancer.展开更多
This editorial aimed to consolidate current evidence on the role of major endogenous modulators—nitric oxide(NO),prostaglandins(PGs),thromboxanes(TXs),and endothelins(ETs)in the lung carcinogenesis,their receptor-spe...This editorial aimed to consolidate current evidence on the role of major endogenous modulators—nitric oxide(NO),prostaglandins(PGs),thromboxanes(TXs),and endothelins(ETs)in the lung carcinogenesis,their receptor-specific actions,compensatory feedback mechanisms,and their role in tumor immune evasion and angiogenesis.We searched PubMed and Google Scholar with free-text and MeSH combinations of terms including"lung cancer","nitric oxide","inducible NOS","COX-2","prostaglandin E2","thromboxane A2","endothelin","angiogenesis",and"immunosuppression".We examined English-language publications for mechanistic data,preclinical models,and clinical correlates,and synthesized findings from both animal and human tissue studies.We highlight here the dual,concentration-dependent actions of NO,PG-E2's immunosup-pressive and pro-angiogenic actions via E-Prostanoid(EP2/EP4)receptors,thromboxane A2's pro-metastatic functions by thromboxane receptor signaling and interaction with platelet-tumor interaction,and the underappreciated roles of ETs.We also point to gaps in the existing literature on the differential roles of other prostanoid subtypes(e.g.,PGI2,PGD2),hypoxia-inducible factor-1α's role in regulation of inflammatory cascades,and clinical significance of compensatory upregulation of TX synthase following cycloxygenase-2 inhibition.These obse-rvations underscore the potential need for receptor-targeted therapies,biomarker-guided patient stratification,and improved translational models to inform the development of personalized anti-inflammatory interventions in lung cancer.展开更多
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
Objective: To explore the effects of ligustrazine on proteinuria, serumcreati-nine, urinary thromboxane A_2(TxA_2), metabolism of prostacyclinI_2(PGI_2)―6-keto-PGF_(1α), and renal pathological changes of SD rats wit...Objective: To explore the effects of ligustrazine on proteinuria, serumcreati-nine, urinary thromboxane A_2(TxA_2), metabolism of prostacyclinI_2(PGI_2)―6-keto-PGF_(1α), and renal pathological changes of SD rats with passive Hermannnephritis (PHN). Methods: The PHN model was induced by intravenous injection of rabbit anti-ratrenal tubular epithelial antigen (Tub―Ag) an-tiserum to SD rats. I. P. administration ofligustrazine to rats was given every 2 d for 1 to 5 weeks. The proteinuria, creatinine, TxA_2 and6-keto-PGF_(1α) were measured by sulfosaticylic acid, picric acid, and direct radioimmunoassayrespectively. The renal pathological changes were observed under light microscope, electronicmicroscope and by direct immunofluorescence staining rabbit and rat IgG. Results: The PHN ratstreated with ligustrazine had significantly less proteinuria, serum creatinine, urinary TxA_2 andpathological changes of kidney, and more urinary 6-keto-PGF_(1α) than those without administrationof ligustrazine. Conclusion: Ligustrazine decreases proteinuria, urinary TxA_2, and renal tissueinjury and increases urinary 6-keto-PGF_(1α). These data indicate that ligustrazine may modulatethe balance of TxA_2 and PG I_2 in rat PHN model and can be used for preventing and treatingmembranous glomerulonephritis.展开更多
Effects of berberine (Ber) on platelet aggregation and TXB2 and 6 keto PGF1a plasma levels were studied in rabbits with uncomplete cerebral ischemia. Ber inhibited uncomplete cerebral ischemic rabbit platelet aggreg...Effects of berberine (Ber) on platelet aggregation and TXB2 and 6 keto PGF1a plasma levels were studied in rabbits with uncomplete cerebral ischemia. Ber inhibited uncomplete cerebral ischemic rabbit platelet aggregation triggered by collagen, ADP, and arachidonic acid (AA) with the IC 50 of 0.15, 0.46, and 0.51 mg·ml 1 , respectively. In rabbits, Ber 25, or 50 mg·kg 1 iv 30 min after uncomplete cerebral ischemia, restrained the collagen ADP and AA induced platelet aggregation determined 90 min later. With radioimmunoassay, we measured the thromboxane B2 (TXB 2) and 6 ketoprostaglandin F 1α (6 keto PGF 1α ) contents in rabbit plasma. The results indicated that the TXB 2 level in rabbit 120 min after uncomplete cerebral ischemia (921±539 pg·ml 1 ) was higher than that (230±71 pg·ml 1 ) in normal rabbits ( P < 0.01), but 6 keto PGF 1α level after ischemia (73±23pg·ml 1 ) was lower than that (262±988pg·ml 1 ) in normal rabbit. Ber (5, 25 or 50 mg·kg 1 ) reduced obviously the plasma TXB 2 level in rabbit with uncomplete cerebral ischemia (504±196, 386±174, or 272±183 vs 921±539 pg·ml 1 , respectively, P < 0.01). We conclude that the decrease of TXB 2 content is one of the possible mechanisms of Ber anti cerebral ischemic effect.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
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
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
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
AIM： To investigate the perioperative changes of nitric oxide （NO） and endothelin （ET）, thromboxane A2 （TXA2） and prostaglandin （PGI2） during liver transplantation in end-stage liver disease patients. METHODS...AIM： To investigate the perioperative changes of nitric oxide （NO） and endothelin （ET）, thromboxane A2 （TXA2） and prostaglandin （PGI2） during liver transplantation in end-stage liver disease patients. METHODS： Twenty-seven patients with end-stage cirrhosis undergoing liver transplantation were enrolled in this prospective study. Blood samples were obtained from superior vena at five different surgical stages. Plasma concentrations of nitrate and nitrite were determined to reflect plasma NO levels. Plasma levels of ET-1, 6-keto-PGF1 alpha and thromboxane B2 （TXB2）, the latter two being stable metabolites of PGI2 and TXA2 respectively, were measured.RESULTS： The NO level decreased significantly after vascular cross-clamping and increased significantly at 30 rain after reperfusion. While the ET levels at 30 rain after clamping and after reperfusion were significantly elevated. The ratio of NO/ET decreased significantly at 30 rain after vascular cross-clamping and at the end of surgery. The PGI2 level and the TXA2 during liver transplantation were significantly higher than the baseline level, but the ratio of TXA2/PGI2 decreased significantly at 30 rain after clamping. CONCLUSION： NO/ET and TXA2/PGI2 change during liver transplantation. Although the precise mechanism remains unknown, they may play a role in the pathobiology of a variety of liver transplant-relevant processes.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
Aim To study the mechanism of protective effects of Danbiqing granule (DBQ) on experimental acute bacterial cholangitis in rabbits. Methods The acute bacterial cholangitis was induced by injecting 1 mL of 1×10...Aim To study the mechanism of protective effects of Danbiqing granule (DBQ) on experimental acute bacterial cholangitis in rabbits. Methods The acute bacterial cholangitis was induced by injecting 1 mL of 1×10 8 cfu·mL -1 Escherchia coli suspension into common bile duit. The serum nitrous oxide (NO) levels were measured using nitric acid reductase kit. Phospholipase A 2 (PLA 2) activity was assayed by a method of acid titration (microassay). Serum tumor necrcsis factor α(TNF α), inferleukin 6 (IL 6) and plasma thromboxane B 2 (TXB 2), 6 keto platelet growth factor 1 (PGF 1α ) were determined by radioimmunoassay. Results Compared with control group, serum NO, PLA 2, TNF α, IL 6 and plasma TXB 2 levels increased significantly in model group ( P <0.01) while those of DBQ groups decreased significantly( P <0 01). Conclusion DBQ dramatically inhibits the overproduction of pro inflammatory factor PLA 2 and inflammatory cytokine. Hence, the mechanism of DBQ underlying anti inflammatory and protective effect against acute bacterial cholangitis in rabbits has been revealed.展开更多
文摘Lung cancer is the most frequent cause of cancer-related mortality worldwide.Nitric oxide(NO),prostaglandins(PGs),thromboxanes(TXs),and endothelins(ETs)participate in numerous physiological processes.These agents play an important role in lung carcinogenesis by regulating cancer cell proliferation,apoptosis,invasion,and angiogenesis.NO is a gaseous free radical with tumo-ricidal and tumorigenic activities in lung cancer.Arachidonic acid-derived PGs,including PGD2,PGE2,8-iso-PGF2α,and PGI2,are related to the development of lung cancer.PGD2 and PGI2 act as tumor suppressors,while PGE2 and 8-iso-PGF2αpromote tumor progression.TXA2 catalyzed by cyclooxygenase induces prolif-eration as well as angiogenesis.Elevated levels of TXB2,an inactive metabolite of TXA2,are positively correlated with lung carcinoma stages.ET-1 and ET-2 are 21 amino acid polypeptides;their silencing hinders lung cancer cell proliferation and invasion.ET-2 depletion also triggers apoptotic death.This chapter review aims to provide a comprehensive overview of the role of NO,PGs,TXs,and ETs in lung cancer.
文摘This editorial aimed to consolidate current evidence on the role of major endogenous modulators—nitric oxide(NO),prostaglandins(PGs),thromboxanes(TXs),and endothelins(ETs)in the lung carcinogenesis,their receptor-specific actions,compensatory feedback mechanisms,and their role in tumor immune evasion and angiogenesis.We searched PubMed and Google Scholar with free-text and MeSH combinations of terms including"lung cancer","nitric oxide","inducible NOS","COX-2","prostaglandin E2","thromboxane A2","endothelin","angiogenesis",and"immunosuppression".We examined English-language publications for mechanistic data,preclinical models,and clinical correlates,and synthesized findings from both animal and human tissue studies.We highlight here the dual,concentration-dependent actions of NO,PG-E2's immunosup-pressive and pro-angiogenic actions via E-Prostanoid(EP2/EP4)receptors,thromboxane A2's pro-metastatic functions by thromboxane receptor signaling and interaction with platelet-tumor interaction,and the underappreciated roles of ETs.We also point to gaps in the existing literature on the differential roles of other prostanoid subtypes(e.g.,PGI2,PGD2),hypoxia-inducible factor-1α's role in regulation of inflammatory cascades,and clinical significance of compensatory upregulation of TX synthase following cycloxygenase-2 inhibition.These obse-rvations underscore the potential need for receptor-targeted therapies,biomarker-guided patient stratification,and improved translational models to inform the development of personalized anti-inflammatory interventions in lung cancer.
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Objective: To explore the effects of ligustrazine on proteinuria, serumcreati-nine, urinary thromboxane A_2(TxA_2), metabolism of prostacyclinI_2(PGI_2)―6-keto-PGF_(1α), and renal pathological changes of SD rats with passive Hermannnephritis (PHN). Methods: The PHN model was induced by intravenous injection of rabbit anti-ratrenal tubular epithelial antigen (Tub―Ag) an-tiserum to SD rats. I. P. administration ofligustrazine to rats was given every 2 d for 1 to 5 weeks. The proteinuria, creatinine, TxA_2 and6-keto-PGF_(1α) were measured by sulfosaticylic acid, picric acid, and direct radioimmunoassayrespectively. The renal pathological changes were observed under light microscope, electronicmicroscope and by direct immunofluorescence staining rabbit and rat IgG. Results: The PHN ratstreated with ligustrazine had significantly less proteinuria, serum creatinine, urinary TxA_2 andpathological changes of kidney, and more urinary 6-keto-PGF_(1α) than those without administrationof ligustrazine. Conclusion: Ligustrazine decreases proteinuria, urinary TxA_2, and renal tissueinjury and increases urinary 6-keto-PGF_(1α). These data indicate that ligustrazine may modulatethe balance of TxA_2 and PG I_2 in rat PHN model and can be used for preventing and treatingmembranous glomerulonephritis.
文摘Effects of berberine (Ber) on platelet aggregation and TXB2 and 6 keto PGF1a plasma levels were studied in rabbits with uncomplete cerebral ischemia. Ber inhibited uncomplete cerebral ischemic rabbit platelet aggregation triggered by collagen, ADP, and arachidonic acid (AA) with the IC 50 of 0.15, 0.46, and 0.51 mg·ml 1 , respectively. In rabbits, Ber 25, or 50 mg·kg 1 iv 30 min after uncomplete cerebral ischemia, restrained the collagen ADP and AA induced platelet aggregation determined 90 min later. With radioimmunoassay, we measured the thromboxane B2 (TXB 2) and 6 ketoprostaglandin F 1α (6 keto PGF 1α ) contents in rabbit plasma. The results indicated that the TXB 2 level in rabbit 120 min after uncomplete cerebral ischemia (921±539 pg·ml 1 ) was higher than that (230±71 pg·ml 1 ) in normal rabbits ( P < 0.01), but 6 keto PGF 1α level after ischemia (73±23pg·ml 1 ) was lower than that (262±988pg·ml 1 ) in normal rabbit. Ber (5, 25 or 50 mg·kg 1 ) reduced obviously the plasma TXB 2 level in rabbit with uncomplete cerebral ischemia (504±196, 386±174, or 272±183 vs 921±539 pg·ml 1 , respectively, P < 0.01). We conclude that the decrease of TXB 2 content is one of the possible mechanisms of Ber anti cerebral ischemic effect.
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.
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.
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）.
基金Supported by the National Natural Science Foundation of China,No. 30271254the Medical Development Foundation of Guangdong Province, No. 2004B35001005
文摘AIM： To investigate the perioperative changes of nitric oxide （NO） and endothelin （ET）, thromboxane A2 （TXA2） and prostaglandin （PGI2） during liver transplantation in end-stage liver disease patients. METHODS： Twenty-seven patients with end-stage cirrhosis undergoing liver transplantation were enrolled in this prospective study. Blood samples were obtained from superior vena at five different surgical stages. Plasma concentrations of nitrate and nitrite were determined to reflect plasma NO levels. Plasma levels of ET-1, 6-keto-PGF1 alpha and thromboxane B2 （TXB2）, the latter two being stable metabolites of PGI2 and TXA2 respectively, were measured.RESULTS： The NO level decreased significantly after vascular cross-clamping and increased significantly at 30 rain after reperfusion. While the ET levels at 30 rain after clamping and after reperfusion were significantly elevated. The ratio of NO/ET decreased significantly at 30 rain after vascular cross-clamping and at the end of surgery. The PGI2 level and the TXA2 during liver transplantation were significantly higher than the baseline level, but the ratio of TXA2/PGI2 decreased significantly at 30 rain after clamping. CONCLUSION： NO/ET and TXA2/PGI2 change during liver transplantation. Although the precise mechanism remains unknown, they may play a role in the pathobiology of a variety of liver transplant-relevant processes.
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.
基金SupportedbyTianjinNinth Five YearProject,No .983 113 411
文摘Aim To study the mechanism of protective effects of Danbiqing granule (DBQ) on experimental acute bacterial cholangitis in rabbits. Methods The acute bacterial cholangitis was induced by injecting 1 mL of 1×10 8 cfu·mL -1 Escherchia coli suspension into common bile duit. The serum nitrous oxide (NO) levels were measured using nitric acid reductase kit. Phospholipase A 2 (PLA 2) activity was assayed by a method of acid titration (microassay). Serum tumor necrcsis factor α(TNF α), inferleukin 6 (IL 6) and plasma thromboxane B 2 (TXB 2), 6 keto platelet growth factor 1 (PGF 1α ) were determined by radioimmunoassay. Results Compared with control group, serum NO, PLA 2, TNF α, IL 6 and plasma TXB 2 levels increased significantly in model group ( P <0.01) while those of DBQ groups decreased significantly( P <0 01). Conclusion DBQ dramatically inhibits the overproduction of pro inflammatory factor PLA 2 and inflammatory cytokine. Hence, the mechanism of DBQ underlying anti inflammatory and protective effect against acute bacterial cholangitis in rabbits has been revealed.
