Chronic Diseases

The thromboxane A2 pathway through its end product thromboxane A2 is implicated in the development and progression of many chronic diseases. There is clear clinical and/or experimental evidence platelet thromboxane A2 release is greatly enhanced in a number of chronic diseases. Frequently in these diseases, the balance between thromboxane A2 and prostacyclin is significantly altered, resulting in excessive vasoconstriction and disorders of hemostasis. Levels of urinary 11-dehydrothromboxane B2 reflect activity of components of the thromboxane A2 pathway resulting in thromboxane A2 generation.

2218-PUB: Increased Platelet Reactivity Is Associated with Inflammation and Arterial Stiffness in Subjects with Prediabetes

"We investigated markers of platelet reactivity and low-grade inflammation, and their association with early markers of vascular disease in subjects with prediabetes and new onset type 2 diabetes (NDOM)."

"Platelet reactivity was evaluated as 11-dehydrothromboxane B2 urinary levels (TXB2)"

"TXB2 urinary levels were independently associated with hs-CRP, fibrinogen and HbA1c in multiple regression analysis."

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Digoxin and Platelet Activation in Patients with Atrial Fibrillation: In Vivo and In Vitro Study

"Digoxin use was shown to be associated with an increased risk of cardiovascular events in atrial fibrillation (AF). We hypothesized that digoxin may affect cardiovascular risk by increasing platelet activation. Urinary excretion of 11-dehydro-thromboxane B2 (TxB2), a marker of platelet activation, and serum digoxin concentration (SDC) were measured. Patients in the upper tertile of SDC showed higher 11-dehydro-TxB2 compared with non-digoxin users. In vitro study showed an increased basal platelet activation in patients with AF compared with healthy subjects."

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Treatment of bipolar depression with minocycline and/or aspirin: an adaptive, 2×2 double-blind, randomized, placebo-controlled, phase IIA clinical trial

“Given evidence of chronic inflammation in bipolar disorder (BD), we tested the efficacy of aspirin and minocycline as augmentation therapy for bipolar depression.

"The absence of a significant interaction between the efficacy of aspirin treatment and baseline levels of CRP and/or IL-6 may reflect Type II error given the relatively small samples, but also may reflect the clinically non-significant anti-inflammatory effect of low-dose aspirin in autoimmune or other inflammatory disorders".

"In this regard, this first report of higher baseline 11-D-TXB2 levels in the BD sample relative to the control sample (Figure S2) is noteworthy as it suggests that the activity of the arachidonic acid pathway is elevated in a subset of individuals with BD, consistent with previous hypotheses".

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Role of Cox-2/PGE2 Mediated inflammation in Oral Squamous Cell Carcinoma

"Oral cancer include malignancy of the oral cavity and oropharynx, 90% of which are squamous cell carcinoma.  Oral and oropharyngeal squamous cell carcinoma (OSCCP) is a very aggressive neoplasm and is often diagnosed late in the disease.  Extensive research has demonstrated a relationship between chronic inflammation and a variety of cancer types, including OSCC."

"A significant amount of research indicates that the cyclooxygenase/prostaglandin E2 (PGE2) pathway of inflammation contributes to the development and progression of a variety of cancers, including squamous cell carcinoma of the oral cacity and oropharynx (OSCC). Although there have been promising results from studies examining the utility of anti-inflammatory drugs in the treatment of toxicities, this strategy has been met with only variable success and may make them inappropriate for some OSCC patients.  Improved inflammation-targeting therapies require continued study of the mechanisms linking inflammation and progression of OSCC.  In this review, a synopsis of OSCC biology will be provided, and recent insights into inflammation related mechanisms of OSCC pathobiology will be discussed  The roles of prostaglandin E2 and cluster of differentiation factor 147 (CD147) will be presented, and evidence for their interactions in OSCC will be explored.  Through continued investigation into the protumourigenic pathways of OSCC, more treatment modalities targeting inflammation-related pathways can be designed with the hope of slowing tumour progression and improving patient prognosis in patients with this aggressive form of cancer."

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Thromboxane-Dependent Platelet Activation in Obese Subjects with Prediabetes or Early Type 2 Diabetes: Effects of Liraglutide or Lifestyle Changes-Induced Weight Loss

"Thromboxane (TX)-dependent platelet activation and lipid peroxidation, as reflected in vivo by the urinary excretion of 11-dehydro-TXBand 8-iso-prostaglandin (PG)F2a, play a key role in atherothrombosis in obesity and type 2 diabetes mellitus (T2DM) since the earlier stages."

"After achievement of the weight loss target, a comparable reduction in U-11-dehydro-TXB2 (between-group = 0.679) and 8-iso-PGF-2a (p = 0.985) was observed in both arms in parallel with a comparable improvement in glycemic control, insulin sensitivity, SAT, high-sensativity C-reactive protein (hs-CRP)." 

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Significance of urinary 11-dehydro-thromboxane B2 in age-related diseases: Focus on atherothrombosis

"Although urinary11-dehydro-TXB2 levels are largely suppressed with low-dose aspirin, incomplete suppression by aspirin predicts the future risk of vascular events and death in high-risk patients and may identify individuals who might benefit from treatments that more effectively block in vivo TX production or activity. Several disease-modifying agents, including lifestyle intervention, antidiabetic drugs and antiplatelet agents besides aspirin have been shown to reduce TX biosynthesis."

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Perioperative Urinary Thromboxane Metabolites and Outcome of Coronary Artery Bypass Grafting: A Nested Case-Control Study

"As a marker of in vivo thromboxane generation, high-level urinary thromboxane metabolites (TXA-M) increase the occurance of cardiovascular events in high-risk patients. To investigate whether perioperative urinary TXA-M level is associated with major adverse cardiac and cerebrovascular events (MACCE) after coronary artery bypass graft (CABG) surgery, we designed a nested case-control study."

"Post-CABG 24 hours urinary TXA-M elevation is associated with an increase of 1 year adverse events after CABG."

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Oxidant Stress as a major determinant of platelet activation in invasive breast cancer

“Breast cancer (BC) is the most common female cancer and the second leading cause of cancer-related death in women, worldwide."  Recent data have clearly demonstrated that type 2 diabetes (T2D) and obesity are among the most important risk factors for postmenopausal estrogen-dependent BC, also suggesting that oxidative stress might represent a shared mechanism for BC initiation and/or progression.

 “The results obtained showed that presurgical urinary excretion of both biomarkers was enhanced in BC patients compared to controls and was associated with patients’ estrogen receptor (ER) expression, but not HER2 status or Ki67 proliferation index. Accordingly, both urinary biomarkers were increased in patients with luminal-like BC molecular subtypes compared with triple negative or HER2-enriched tumors. "The prognostic value of 11-dehydro-TXB2 was then evaluated showing a significant correlation with BC pathological response to neoadjuvant treatment. Furthermore, among relapsing patients, those with elevated urinary biomarker levels were more likely to develop distant metastasis rather than local recurrence."

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Prognostic value of urinary 11-dehydro-thromboxane B2 for mortality: A cohort study of stable coronary artery disease patients treated with aspirin

"There is a variable cardiovascular risk reduction attributable to aspirin because of individual differences in the suppression of thromboxane A2 and its downstream metabolite 11-dehydrothromboxane B2 (11dhTxB2). Our data indicates the optimal cut point for urine 11dhTxB2 is 1597.8 (pg/mg) for the risk prediction of mortality over five years in stable patients with CAD patients treated with aspirin."

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Differential Impact of Serial Measurement of Nonplatelet Thromboxane Generation on Long-Term Outcome After Cardiac Surgery

"Long-term nonplatelet thromboxane generation after coronary artery bypass graft surgery is a novel risk factor for 5-year adverse outcome, including death. In contrast, nonplatelet thromboxane generation in the early postoperative period appears to be dirven predominantly by inflammation and did not independently predict long-term clinical outcome."

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