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.

Urinary 11-dehydro-thromboxane B2 as a predictor of acute myocardial infarction outcomes: results of leukotriene and thromboxane in myocardial infarction (LTMI) study

"Urinary 11-dehydro-thromboxane (TX)B2 has been described as a potential predictive biomarker of major adverse cardiovascular events (MACEs) in high cardiac risk patients.”

“11-Dehydro-TXB2 predicts 1-year cumulative MACEs in AMI patients and provides prognostic information on the left ventricular performance."

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The Current and Future Landscape of Urinary Thromboxane Testing to Evaluate Atherothrombotic Risk

"Biomarker testing for efficacy of therapy is an accepted way for clinicians to individualize dosing to genetic and/or environmental factors that may be influencing a treatment regimen.  Aspirin is used by nearly 43 million Americans on a regular basis to reduce risks associated with various artherothrombotic diseases.  Despite its widespread use, many clinicians are unaware of the link between suboptimal response to aspirin therapy and increased risk for inferior clinical outcomes in several disease states, and biomarker testing for efficacy of aspirin therapy is not performed as routinely as efficacy testing in other therapeutic areas.  This article reviews the clinical and laboratory aspects of determining whole-body thromboxane production, particularly as it pertains to efficacy assessment of aspirin responsiveness."

"Aspirin use has been shown to cause a dose-dependent reduction in urinary levels of 11-dehydroTxB2."

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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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Inhibiting breast cancer by targeting the thromboxane A2 pathway

“Cyclooxygenases have been implicated in mammary tumorigenesis. We sought to identify the key prostaglandin responsible for the pro-neoplastic effect of cyclooxygenases and develop prostaglandin-targeted strategies for breast cancer chemoprevention or therapy."

“Clinically, the thromboxane A2 pathway might be associated with HER2- positive and axillary lymph node metastasis in human breast cancer. We found that the thromboxane A2 pathway was required for breast cancer cell growth, anchorage-independent growth and invasion capabilities."

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Is Depression an Inflammatory Disorder?

“Studies consistently report that groups of individuals with major depressive disorder (MDD) demonstrate increased levels of a variety of peripheral inflammatory biomarkers when compared with groups of nondepressed individuals."

 “Two randomized, placebo-controlled studies have reported that the addition of an inhibitor of the cyclooxygenase enzyme to a standard antidepressant enhances symptomatic improvement in medically healthy individuals with depression.  Similarly, preclinical and clinical data suggest that acetylsalicylic acid (aspirin) may hold promise as an augmenting strategy in patients who fail to respond to monotherapy with a serotonin reuptake inhibitor."

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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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Cyclooxygenase Pathway Activation in Sleep Apnea Syndrome

"Patients with obstructive sleep apnea syndrome (OSA) exhibit an early vascular remodelling and alterations of acid arachidonic pathway 2.  Thromboxane A2 (TXA2) is a cycloxygenase (COX)-derived metabolite of AA involved in vascular remodelling."

"Atherosclerosis is a chronic inflammatory disease characterized by the activation of some components of the cyclooxygenase pathway.  OSA is associated with activation of the thromboxane A(TXA2)-pathway, in which obesity seems to be a major confounding factor." 

"Urinary excretion of 11-dTXB2 did not differ between OSA patients free of cardiovascular complications and healthy volunteers but increased in OSA patients with cormobidities compared to OSA patients without 694.0 (425.9-1235.6) versus 616.0 (354.3-838.2) pg/mg creatinine respectively; p=0.007). Finally, urinary 11-dTXB2 was increased by 30% in OSA Patients with cartoid hypertrophy (IMT>compared to OSA patients without carotid hypertrophy (783.0 (582.8-938.0) versus 592.9 (278.9-782.5) pg/mg creatinine, respect p=0.02)."

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Impact of commonly prescribed exercise interventions on platelet activation in physically inactive and overweight men

"The exercise paradox infers that, despite the well-established cardioprotective effects of repeated episodic exercise (training), the risk of acute atherothrombotic events may  be transiently increased during and soon after an exercise bout.  However, the acute impact of different exercise modalities on platelet function has not previously been addressed.  We hypothesized that distinct modalities of exercise would have differing effects on in vivo platelet activation and reactivity to agonists which induce monocyte-platelet aggregate (MPA) formation."

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Effects of pomegranate juice and extract polyphenols on platelet function

"Several clinical and In Vitro studies showed that polyphenols are able to inhibit platelet activation, preventing cerebro- and cardiovascular disease.  The Mediterranean diet includes fruit and vegetables rich in polyphenols known as effective protective agents.  Fruits and vegetables contain polyphenols such as tannins found in red wine and phenolic acid, flavonones, anthoscyanin, flavonols, stilbenes, and lignans found in pomegranates as protective agents from the hot Meditarranean sunshine."

“We have shown that pomegranate juice reduces every step of platelet activation, such as platelet aggregation, calcium mobilization, hydrogen peroxide formation, and TxA2 production induced by collagen and arachidonic acid.”

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