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Circulation Research Feb 2018
Topics: Humans; Judgment; Kidney Transplantation; Phospholipases A2; Prostaglandins; Thromboxanes
PubMed: 29449357
DOI: 10.1161/CIRCRESAHA.118.312616 -
The Western Journal of Medicine Oct 1985Although prostaglandin research began about 50 years ago, many of the most important advances in understanding the biochemistry, physiology and pharmacology have taken... (Review)
Review
Although prostaglandin research began about 50 years ago, many of the most important advances in understanding the biochemistry, physiology and pharmacology have taken place within the past five to ten years. There is great potential for the extension of this research to the clinical practice of medicine. At this time, the most common interaction that clinicians have with the prostaglandin field is in administering nonsteroidal anti-inflammatory drugs, which function by inhibiting prostaglandins. The uses of these drugs include treating not only inflammation, but also dysmenorrhea, some renal disease, thrombotic diseases and some metabolic disorders. Prostaglandin analogs, with their potent effects on uterine contraction, are in common use in obstetrics. Other analogs, with gastric and duodenal cytoprotective effects are useful in treating peptic ulcer disease. Future benefits from prostaglandin and leukotriene research may include new therapy for inflammatory and hypersensitivity diseases such as asthma, inflammatory bowel diseases and dermatitis.
Topics: Animals; Anti-Inflammatory Agents; Cardiovascular Diseases; Chemical Phenomena; Chemistry; Digestive System; Digestive System Physiological Phenomena; Female; Humans; Immunity, Cellular; Inflammation; Kidney; Leukotriene B4; Lung; Lung Diseases; Male; Metabolic Diseases; Pregnancy; Prostaglandin Antagonists; Prostaglandins; Reproduction; SRS-A; Thromboxanes; Uterine Contraction
PubMed: 3004043
DOI: No ID Found -
European Heart Journal Apr 2024Thromboxane (TX) A2, released by activated platelets, plays an important role in atherothrombosis. Urinary 11-dehydro-TXB2 (U-TXM), a stable metabolite reflecting the...
BACKGROUND AND AIMS
Thromboxane (TX) A2, released by activated platelets, plays an important role in atherothrombosis. Urinary 11-dehydro-TXB2 (U-TXM), a stable metabolite reflecting the whole-body TXA2 biosynthesis, is reduced by ∼70% by daily low-dose aspirin. The U-TXM represents a non-invasive biomarker of in vivo platelet activation and is enhanced in patients with diabetes. This study assessed whether U-TXM is associated with the risk of future serious vascular events or revascularizations (SVE-R), major bleeding, or cancer in patients with diabetes.
METHODS
The U-TXM was measured pre-randomization to aspirin or placebo in 5948 people with type 1 or 2 diabetes and no cardiovascular disease, in the ASCEND trial. Associations between log U-TXM and SVE-R (n = 618), major bleed (n = 206), and cancer (n = 700) during 6.6 years of follow-up were investigated by Cox regression; comparisons of these associations with the effects of randomization to aspirin were made.
RESULTS
Higher U-TXM was associated with older age, female sex, current smoking, type 2 diabetes, higher body size, urinary albumin/creatinine ratio of ≥3 mg/mmol, and higher estimated glomerular filtration rate. After adjustment for these, U-TXM was marginally statistically significantly associated with SVE-R and major bleed but not cancer [hazard ratios per 1 SD higher log U-TXM (95% confidence interval): 1.09 (1.00-1.18), 1.16 (1.01-1.34), and 1.06 (0.98-1.14)]. The hazard ratio was similar to that implied by the clinical effects of randomization to aspirin for SVE-R but not for major bleed.
CONCLUSIONS
The U-TXM was log-linearly independently associated with SVE-R in diabetes. This is consistent with the involvement of platelet TXA2 in diabetic atherothrombosis.
Topics: Humans; Female; Thromboxanes; Diabetes Mellitus, Type 2; Aspirin; Thromboxane B2; Thromboxane A2; Thrombosis; Neoplasms
PubMed: 38385506
DOI: 10.1093/eurheartj/ehad868 -
Scientific Reports Sep 2019Cerebral malaria pathogenesis involves vascular dysfunction with low nitric oxide (NO) bioavailability, vasoconstriction and impaired vasodilation, leading to ischemia,...
Cerebral malaria pathogenesis involves vascular dysfunction with low nitric oxide (NO) bioavailability, vasoconstriction and impaired vasodilation, leading to ischemia, tissue hypoxia and ultimately death. Cerebral blood flow (CBF) involves NO and other pathways, including arachidonic acid (AA)-derived metabolites. Here we show that mice with experimental cerebral malaria (ECM) by P. berghei ANKA showed marked decreases in CBF (as assessed by laser speckle contrast imaging - LSCI) and that administration of L-arginine supplementation (50 mg/kg) and/or of the thromboxane synthase inhibitor Ozagrel (100 mg/kg) induced immediate increases in CBF. L-arginine in combination with artesunate (32 mg/kg) induced immediate reversal of brain ischemia in the short-term (1 hour), but the effect subsided after 3 and 6 hours. Neither L-arginine nor Ozagrel reversed blood brain barrier breakdown. Mice with ECM showed brain levels of selected AA-derived metabolites with a vasoconstrictor profile, with increased levels of 8-isoprostanes, 20-HETE and 14,15-DHET, whereas mice infected with a non-ECM-inducing strain of P. berghei (NK65) showed a vasodilator profile, with normal levels of 20-HETE and 14,15-DHET and increased levels of PGE2. L-arginine is capable of partially reversing cerebral ischemia and AA metabolites may play a role in the cerebrovascular dysfunction in ECM.
Topics: Animals; Arginine; Blood-Brain Barrier; Brain; Cerebrovascular Circulation; Dietary Supplements; Female; Malaria, Cerebral; Methacrylates; Mice; Mice, Inbred C57BL; Plasmodium berghei; Thromboxane-A Synthase; Thromboxanes; Vasoconstriction
PubMed: 31541129
DOI: 10.1038/s41598-019-49855-x -
The Journal of Investigative Dermatology Mar 2019α-CGRP is synthesized by sensory nerves in the dermis and its release can cause vasodilation and local inflammation. Its vasorelaxant effects are based on the direct...
α-CGRP is synthesized by sensory nerves in the dermis and its release can cause vasodilation and local inflammation. Its vasorelaxant effects are based on the direct activation of smooth muscle and endothelial cells, as well as the activation of mast cells causing the release of vasoactive and proinflammatory mediators. Here, we show that in the capsaicin model for neurogenic inflammation, capsaicin-induced edema formation is mediated by α-CGRP and mast cells, but is absent in thromboxane receptor-deficient mice. Capsaicin treatment of mice induced a thromboxane synthesis, which was mediated by α-CGRP and mast cells. Fittingly, α-CGRP induced thromboxane synthesis in mast cells and the thromboxane receptor agonist I-BOP caused edema formation independently of mast cells, suggesting that mast cells are the source of thromboxane. Most importantly, I-BOP-induced edema formation was mediated by α-CGRP and I-BOP was able to stimulate through calcineurin the α-CGRP release from peripheral neurons. Likewise, the signaling pathway, including α-CGRP, thromboxane receptor, and mast cells, also mediated capsaicin-induced mechanical hypersensitivity, a common symptom of capsaicin treatment. Taken together, the thromboxane-induced α-CGRP release from neurons forms a positive feedback loop causing prolonged α-CGRP release and edema formation during capsaicin-induced neurogenic inflammation.
Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Calcitonin Gene-Related Peptide; Capsaicin; Cells, Cultured; Fatty Acids, Unsaturated; Feedback, Physiological; Hypersensitivity; Male; Mast Cells; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurogenic Inflammation; Neurons; Peripheral Nervous System; Receptors, Thromboxane; Thromboxanes
PubMed: 30612974
DOI: 10.1016/j.jid.2018.10.011 -
Digestive Diseases and Sciences Mar 1988Neonatal necrotizing enterocolitis is the most common serious gastrointestinal disorder encountered in neonatal intensive care units. It is a major cause of morbidity... (Review)
Review
Neonatal necrotizing enterocolitis is the most common serious gastrointestinal disorder encountered in neonatal intensive care units. It is a major cause of morbidity and mortality in the newborn, particularly in premature infants. Consistent risk factors are birth weight and prematurity. Polycythemia and hyperviscosity altering blood flow and infectious agents are also implicated. Clinical findings include abdominal distention and diarrhea, and systemic symptoms such as apnea, acidosis, and lethargy. Pneumatosis intestinalis can be demonstrated radiographically. Mucosal ulcerations, hemorrhage, and thrombosis occur early, followed by inflammatory changes. Later still necrosis develops. Ischemia, infection, and enteral feedings are suspected to be involved in the pathophysiology. Eicosanoids, especially thromboxane, platelet-activating factor, and leukotrienes are likely mediators.
Topics: Alprostadil; Arachidonic Acid; Arachidonic Acids; Enterocolitis, Pseudomembranous; Humans; Infant, Newborn; Intestines; Ischemia; Risk Factors; Thromboxanes
PubMed: 3126029
DOI: 10.1007/BF01538135 -
British Medical Journal (Clinical... Oct 1981Concentrations of the stable antiaggregatory prostacyclin metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and of the proaggregatory thromboxane A2...
Concentrations of the stable antiaggregatory prostacyclin metabolite 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and of the proaggregatory thromboxane A2 metabolite thromboxane B2 were measured by radioimmunoassay in plasma from 53 diabetics. In 33 of these patients the ability of platelets to produce thromboxane B2 during spontaneous clotting was also studied. Plasma 6-keto-PGF1 alpha concentrations were higher (p less than 0.05) in the diabetics (mean 107.7 +/- SE 7.6 ng/l) than in non-diabetic controls matched for age and sex (87.5 +/- 4.7 ng/l), and diabetics with microangiography (n = 28) and higher (p less than 0.01) concentrations (124.3 +/- 10.8 ng/l) than those without microangiography (n = 25; 89.2 +/- 9.3 ng/l). Plasma thromboxane B2 concentrations were also higher (p less than 0.01) in the diabetics (mean 218.5 +/- SE 25.3 ng/l) than in the controls (127.7 +/- 9.8 ng/l), but this increase was not related to microangiography. The ability of platelets to generate thromboxane B2 did not differ between the diabetics (181.4 +/- 16.4 microgram/l) and controls (195.8 +/- 11.8 microgram/l). Platelets of diabetics with microangiopathy or taking oral hypoglycaemic agents (n = 19), however, produced decreased amounts of thromboxane B2 during clotting. Plasma concentrations of 6-keto-PGF1 alpha and thromboxane B2 were not related to concentrations of glucose, haemoglobin A1, high-density lipoprotein cholesterol, cholesterol, triglycerides, magnesium, or creatinine. These results suggest that in diabetics with microangiopathy a balance between prostacyclin and thromboxane A2 is shifted to dominance by prostacyclin.
Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Aged; Blood Coagulation; Blood Platelets; Diabetes Mellitus; Diabetic Angiopathies; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Thromboxane B2; Thromboxanes
PubMed: 6794795
DOI: 10.1136/bmj.283.6300.1148 -
Nutrients Mar 2021In the DEPOXIN project, we have found that a high ratio of omega-6/omega-3 fatty acids (FA) is associated with worsening of depressive symptoms in children and... (Randomized Controlled Trial)
Randomized Controlled Trial
The Effect of Omega-3 Fatty Acids on Thromboxane, Brain-Derived Neurotrophic Factor, Homocysteine, and Vitamin D in Depressive Children and Adolescents: Randomized Controlled Trial.
In the DEPOXIN project, we have found that a high ratio of omega-6/omega-3 fatty acids (FA) is associated with worsening of depressive symptoms in children and adolescents with depressive disorder (DD) and that the 12-week omega-3 FA supplementation modulates DD symptoms. Here we present our results of the secondary outcomes: the levels of thromboxane (TXB), brain-derived neurotrophic factor (BDNF), homocysteine (HCy) and vitamin D. Fifty-eight patients were randomized into two arms. One group received a fish oil emulsion enriched with omega-3 FA, and the other received a sunflower oil emulsion containing omega-6 FA, for 12 weeks. Depressive symptoms were evaluated, using the Child's Depressive Inventory (CDI). The patients with DD had elevated TXB levels and decreased vitamin D levels, as compared to healthy controls. Both CDI and omega-6/omega-3 ratio correlated positively with TXB and negatively with BDNF at baseline. Compared to the omega-6 FA group, the supplementation with omega-3 FA for 12 weeks significantly reduced plasma TXB ( = 0.024) and increased BDNF ( = 0.011) levels. No changes in HCy and vitamin D were observed. Our results demonstrate the possible role of TXB and BDNF in the pathophysiology of DD and the benefits of omega-3 FA supplementation. The study was registered with the ISRCTN registry (ISRCTN81655012).
Topics: Adolescent; Brain-Derived Neurotrophic Factor; Case-Control Studies; Child; Depressive Disorder; Dietary Supplements; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Fish Oils; Homocysteine; Humans; Male; Thromboxanes; Vitamin D
PubMed: 33801688
DOI: 10.3390/nu13041095 -
The Journal of Biological Chemistry Nov 2002Cyclooxygenase-2 (COX-2) action on the endocannabinoids, 2-arachidonylglycerol (2-AG) and anandamide (AEA), generates prostaglandin glycerol esters (PG-G) and...
Cyclooxygenase-2 (COX-2) action on the endocannabinoids, 2-arachidonylglycerol (2-AG) and anandamide (AEA), generates prostaglandin glycerol esters (PG-G) and ethanolamides (PG-EA), respectively. The diversity of PG-Gs and PG-EAs that can be formed enzymatically following COX-2 oxygenation of endocannabinoids was examined in cellular and subcellular systems. In cellular systems, glycerol esters and ethanolamides of PGE(2), PGD(2), and PGF(2alpha) were major products of the endocannabinoid-derived COX-2 products, PGH(2)-G and PGH(2)-EA. The sequential action of purified COX-2 and thromboxane synthase on AEA and 2-AG provided thromboxane A(2) ethanolamide and glycerol ester, respectively. Similarly, bovine prostacyclin synthase catalyzed the isomerization of the intermediate endoperoxides, PGH(2)-G and PGH(2)-EA, to the corresponding prostacyclin derivatives. Quantification of the efficiency of prostaglandin and thromboxane synthase-directed endoperoxide isomerization demonstrated that PGE, PGD, and PGI synthases catalyze the isomerization of PGH(2)-G at rates approaching those observed with PGH(2). In contrast, thromboxane synthase was far more efficient at catalyzing PGH(2) isomerization than at catalyzing the isomerization of PGH(2)-G. These results define the in vitro diversity of endocannabinoid-derived prostanoids and will permit focused investigations into their production and potential biological actions in vivo.
Topics: Animals; Aorta; Arachidonic Acids; Cannabinoid Receptor Modulators; Cannabinoids; Cattle; Cell Line; Cyclooxygenase 2; Endocannabinoids; Epoprostenol; Esters; Glycerides; Glycerol; Humans; Intramolecular Oxidoreductases; Isoenzymes; Lipocalins; Membrane Proteins; Mice; Molecular Structure; Neurotransmitter Agents; Polyunsaturated Alkamides; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Stereoisomerism; Thromboxane-A Synthase; Thromboxanes
PubMed: 12244105
DOI: 10.1074/jbc.M206788200 -
Nan Fang Yi Ke Da Xue Xue Bao = Journal... Mar 2021To explore the role of prostacyclin (PGI2) and thromboxane A2 (TXA2) in lung hyper-permeability induced by mechanical ventilation (MV) in rabbits.
OBJECTIVE
To explore the role of prostacyclin (PGI2) and thromboxane A2 (TXA2) in lung hyper-permeability induced by mechanical ventilation (MV) in rabbits.
OBJECTIVE
Forty-eight healthy Japanese white rabbits were randomly allocated to vehicle treatment group (group V), tranylcypromine (a PGI2 synthase inhibitor) treatment group (group T), dazoxiben (a TXA2 synthase inhibitor) treatment group (group D), vehicle-treated MV group (group VM), tranylcyprominetreated MV group (group TM) and dazoxiben-treated MV group (group DM). The contents of PGI2 and TXA2 in the lung tissues and TNF-α level in BALF and lung tissues were measured by ELISA. The lung wet/dry weight (W/D) ratio, lung permeability index and pulmonary expressions of myosin light chain kinase (MLCK) protein and mRNA were detected to evaluate the pulmonary permeability. The severities of lung injury were assessed by lung histological scores.
OBJECTIVE
The measured parameters did not differ significantly among the rabbits receiving different treatments without MV. In rabbits in group VM, the contents of PGI2 and TXA2 in the lungs, TNF-α in BALF and lung tissues, PGI2/TXA2 ratio, lung W/D ratio, lung permeability index, pulmonary expressions of MLCK protein and mRNA and histological scores of the lungs all increased significantly ( < 0.05) as compared with those in group V, group T and group D. In rabbits undergoing MV, inhibition of PGI2 production by tranylcypromine significantly decreased the PGI2/TXA2 ratio ( < 0.05), further enhanced the production of TNF-α in the BALF and lung tissue ( < 0.05), and worsened lung hyper-permeability and lung injury ( < 0.05), while treatment with dazoxiben significantly reduced TXA2 production in the lung tissue ( < 0.05), increased the PGI2/TXA2 ratio ( < 0.05) and decreased TNF-α production in the BALF and lung tissue ( < 0.05), thus resulting in alleviated lung hyperpermeability and lung injury ( < 0.05).
OBJECTIVE
PGI2 plays a protective role against MV-induced lung hyper-permeability and lung injury by downregulating TNF-α/MLCK signaling pathway, while TXA2 can exacerbate MV-induced lung hyperpermeability in rabbits by up-regulating TNF-α/ MLCK signaling pathway.
Topics: Animals; Epoprostenol; Lung; Permeability; Rabbits; Respiration, Artificial; Thromboxane A2
PubMed: 33849834
DOI: 10.12122/j.issn.1673-4254.2021.03.15