Molecular targets of dietary polyphenols with anti-inflammatory properties

"Inflammation is the immunological defense mechanism by which the body fights infection or injury from bacteria, viruses and other pathogens.  The defining clinical features of inflammation are known in Latin as rubor (redness), calor (warmth), tumor (swelling) and dolor (pain)."

"In the early 1970's, aspirin and other non-steroidal anti-inflammatory drugs were found to inhibit cyclooxygenase (COX), which produces prostaglandins (PG's), a class of physiological and pathophysiological inflammatory mediators.  Since then, the biosynthetic cascade of arachadonic acid (AA) has been the subject of intense research.  This is because AA, having been previously liberated from phospholipids using various stimuli, can be metabolized by the COX pathway into PG's and thromboxane A2, or by the lipoxygenase pathways to hydroperoxyeicosateraenoic acids, (HpETEs), hydroxyeicosateraenoic acids (HETEs), and leukotrienes (LTs).  These proteins play a vital role in inflammation by controlling the intensitry and duration of pain, as well as the occurrence of fever, swelling and heat of an affected area."

“Given that certain polyphenols are known to affect more than one protein, it is necessary consider the possibility that any single com- pound may affect multiple mechanisms.”

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Cigarette smoking is associated with increased circulating proinflammatory and procoagulant markers in patients with chronic coronary artery disease; effects of aspirin treatment

"Smoking is associated with endothelial dysfunction.  Cytokines released by injured endothelium promote vascular interactions with leukocytes and platelets.  We investigated whether (a) cigarette smoking is linked to increased cytokine production, which may mediate platelet activation and thrombin generation in chronic coronary artery disease (CAD), and (b) aspirin treatment inhibits smoking-related changes on cytokines, platelets, and thrombin."

"After aspirin treatment, M-CSF, CRP, 11-dehydro-TXB2, and prothrombin fragments 1 + 2 remained higher in smokers compared with non smokers despite a significant reduction of these markers by aspirin."

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Reduced Blood Platelet Sensitivity to Aspirin in Coronary Artery Disease: Are Dyslipidaemia and Inflammatory States Possible factors Predisposing to Sub-optimal Platelet Response to Aspirin?

"Both environmental and genetic factors, including aspirin pharmacokinetics, inflammation, platelet COX-2, use of non-steroid anti-ainflammatory drugs and dyslipidaemia may determine variable platelet response to acetylsalicylic acid.”’ 

"However, CRP level was significantly associated with the extent of platelet refractoriness to acetylsalicylic acid in these patients, which points out that even subclinical inflammatory states may be considered possible candidates for suboptimal acetylsalicylic acid response."

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Role of thromboxane A2 in the induction of apoptosis of immature thymocytes by lipopolysaccharide

"Lipopolysaccharide (LPS) causes apoptotic deletion of CD4+ CD8* thymocytes, a phenomenon that has been linked to immune dysfunction and poor survival during sepsis.  Given the abundance of thromboxane-prostanoid (TP) receptors in CD4+ CD8* thymocytes and in vitro evidence that thromboxane A2 (TXA2) causes apoptosis of these cells, we tested whether enhanced generation of TXA2 plays a role in LPS-induced thymocyte apoptosis."

"These studies indicate that TXA(2) mediates a portion of apoptotic thymocyte death caused by LPS."

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Inhibition of the arachidonic acid metabolism blocks endothelial cell migration and induces apoptosis 2

"In highly migratory subpopulations of human glioma cells differential mRNA display identified human thromboxane synthase as a strongly overexpressed motility associated gene.  Subsequently, we demonstrated that this enzyme is expressed in gliomas in vitro and in vivo and that specific thromboxane synthase inhibitors block migration, which is paralleled by a decrease of thromboxane B2 formation.  These data implicate thromboxane synthase as an important regulator of glioma motility.  Interestingly, following thromboxane synthase inhibitor treatment the decrease of motillity rates is paralleled by increased caspase activity followed by intracellular DNA fragmentation and subsequent apoptotic cell death.  Prostanoid synthesis in general appears to be important in pathogenesis and progression of cancer because these metabolites influence cellular behaviour in several ways such as mitotic activity, cellular adhesion, invasion, angiogenesis and apoptosis."

"These data suggest that inhibitors of thromboxane synthase influence migration and apoptosis in both human glioma cells and human endothelial cells. An anti-invasive treatment strategy using this class of compounds may therefore not only sensitize glioma cells to conventional treatments inducing apoptosis but may also be supported by an anti-angiogenic effect.”

“We demonstrated that this enzyme is expressed in gliomas in vitro and in vivo and that specific thromboxane synthase inhibitors block migration, which is paralleled by a decrease of thromboxane B2."

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Differential Expression of Thromboxane Synthase in Prostate Carcinoma: Role in Tumor Cell Motility

"Arachidonic acid metabolism through cyclooxygenase, lipoxygenase, or P-450 epoxygenase pathways can generate a variety of eicosanoids.  Thromboxane synthase (TxS) metabolizes the cyclooxygenase product, prostanglandin H2, into thromboxane A2 (TXA2), which can cause vessel constriction, platelet activation, and aggregation.  Here we demonstrate that human prostate cancer (PCa) cells express enzymatically active TxS and that this enzyme is involved in cell motility.  In human PCa cell lines, PC-3, PC-3M, and ML-2 cells expressed higher levels of TxS than normal prostate epithelial cells or other established PCa cell lines such as DU145, LNCaP, or PPC-1.  We cloned and sequenced the full-length TxS cDNA from PC-3 cells and found two changes in the amino acid residues."

Immunohistochemical analysis of tumor specimens revealed that expression of TxS is weak or absent in normal differentiated luminal, or secretory cells, significantly elevated in less differentiated or advanced prostate tumors, and markedly increased in tumors with perineural invasion.  TxS expressed in PC-3 cells was enzymatically active and susceptible to carboxyheptal imidazole, an inhibitor of TxS.  The biosynthesis of TXA2 in PC-3 cells was dependent on COX-2, and to a lesser extent, COX-1.  Treatment of PC-3 cells with a COX-1 selective inhibitor, piroxicam, reduced TXA2 production by 80%. Inhibition of TxS activity or blockade of TXA2 function reduced PC-3 cell migration on fibronectin, while having minimal effects on cell cycle progression or survival.  Finally, increased expression of TxS in DU145 cells increased cell motility.  Our data suggest that human PCa cells express TxS and that this enzyme may contribute to PCa progression through modulating cell motility."

"The present study is the first report detailing the endogenous expression of TxS in human prostate cancer cells and its potential involvement in PCa cell motility and perineural invasion."

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Acute, short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus

“Compared with non-diabetics, patients with Type II diabetes mellitus (T2Dm) have a two-to four-fold increased risk of ischemic cardiovascular disease, a risk largely independent of concomitant hypertension, hypercholesterolemia, and smoking.”

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11-dehydro-thromboxane b2, a stable thromboxane metabolite, is a full agonist of chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2) in human eosinophils and basophils.

“In addition to TXA2, which is capable of causing bronchoconstriction, lasma extravasation, and chemokine expression, its stable metabolite 11-dehydro-TXB2 might also be directly involved in the recruitment of ecosinophils, basophils and presumably TH2 lymphocytes to sites of inflammation.”

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Opposite effects of nicotinic acid and pyridoxine on systemic prostacyclin, thromboxane and leukotriene production in man

"The results of this study suggest that nicotinic acid increases thromboxane and leukotriene synthesis which may not be beneficial for patients with cardiovascular diseases or asthma.  In contrast, the increase of prostacyclin production and the inhibition in thromboxane and leukotriene synthesis by pyriodoxine might be beneficial in disorders where the production of prostacyclin is decreased and the formation of thromboxane and cysteinyl leukotrienes is enhanced.

"The treatment with nicotinic acid increased 11-DHTXB2 excretion to 2.6 fold and leukotriene E4 excretion to twice the basal values."

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Platelet activation in obese Women. Role of inflammation and oxidant stress.

“Women with android obesity had higher levels of 8-iso PGF2alpha and 11-dehydro-TxB2 than nonobese women.” 

“Both 8-iso PGF2alpha and 11-dehydroTxB2 were higher in women with android obesity than women with gynoid obesity” 

“Of 20 women with android obesity, 11 achieved successful weight loss, which was associated with statistically significant reductions in C-reactive protein (median change 23%  p<.05), 8-iso PGF2alpha (median change 32%  p=.04) and 11-dehydro-TXB2 (median change 54% p=.005)." 

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