Cigarette smoke is associated with up-regulation of inducible NOS and COX-2 protein expression and activity in granulosa cells of women undergoing in vitro fertilization.

Cigarette smoke exposure represents a well-established ovotoxic exogenous stress, but the molecular mechanisms underlying of this effect are still unclear. Cigarette smoke upregulates inflammatory genes in the female reproductive organs, therefore an abnormal inflammation response may contribute to the impairment of female fertility. In this study we investigated for the first time the effect of cigarette smoke exposure on NOS and COX expression and activity and on their transcription factors (CREB and NF-kB) in human GCs and on the release of NO and PGE2 in the FF in smoking and non-smoking patients undergoing IVF treatment. In addition, correlation analysis between AMH serum levels, an index of ovarian reserve, and smoking exposure or iNOS and COX-2 protein expression levels were performed using a Pearson correlation method. Cigarette smoke exposure resulted in a significant increase of iNOS and COX-2 protein expression together with an increase of iNOS activity and PGE2 levels. pNF-kB and pCREB protein expression were upregulated in the GCs of smokers compared to non-smokers. The habit of smoking was negatively correlated with serum AMH levels, and positively correlated with iNOS and COX-2 protein expression levels. The data presented in the current study revealed a novel molecular mechanism underlying the toxic effects of cigarette smoke on fertility. Additional pathways mediating the effects of cigarette smoke exposure in human GCs cannot be excluded and should be investigated in future studies.

The translational therapeutics of prostaglandin inhibition in atherothrombosis.

Prostaglandins, products of the cyclo-oxygenase (COX) enzymes, can both promote and restrain atherothrombosis. While non-steroidal anti-inflammatory drugs (NSAIDs) selective for inhibition of COX-2 predispose to myocardial infarction, heart failure, hypertension and stroke, suppression of products of COX-1, such as thromboxane (Tx) A2, underlie cardioprotection from low-dose aspirin. Data from clinical pharmacology, rodent models, human genetics, observational studies and randomized trials provide insight into the implications of inhibiting COX product synthesis or function. Many lines of evidence afford a mechanistic explanation for the cardiovascular (CV) hazard from NSAIDs. Elucidation of the biology of this pathway using diversified approaches is also relevant to understanding the implications of substrate rediversion following inhibition of enzymes downstream of COXs, such as the microsomal PGE synthase (mPGES)-1 and of combining D prostanoid antagonism with niacin to attenuate facial flushing.

Platelet activation in patients with colorectal cancer.

Aspirin may reduce the risk of colorectal neoplasia at doses similar to those recommended for the prevention of cardiovascular disease. Thus, we aimed to address whether enhanced platelet activation, as assessed by the measurement of the urinary excretion of 11-dehydro-TXB(2) (a major enzymatic metabolite of TXB(2)), occurs in patients with colorectal cancer. In 10 patients with colorectal cancer, the urinary excretion of 11-dehydro-TXB(2) was significantly higher than in 10 controls, matched for sex, age and cardiovascular risk factors [1001(205-5571) versus 409(113-984) pg/mg creatinine, respectively, median (range), P<0.05]. The administration of aspirin 50 mg daily for 5 consecutive days to colorectal cancer patients caused a cumulative inhibition of platelet cyclooxygenase (COX)-1 activity either ex vivo, as assessed by the measurement of serum TXB(2) levels, or in vivo, as assessed by urinary 11-dehydro-TXB(2) excretion. In conclusion, enhanced platelet activation occurs in colorectal cancer patients. Permanent inactivation of platelet COX-1 by low-dose aspirin might restore anti-tumor reactivity.

The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisol and synthetic glucocorticoids.

BACKGROUND: We studied the concentration dependence of the inhibitory effects of cortisol, 6-methylprednisolone, and dexamethasone on cyclooxygenase-2 (COX-2) expression and activity in human monocytes in response to lipopolysaccharide (LPS) in vitro. Moreover, we characterized the time and dose dependence of the inhibitory effects of 6-methylprednisolone, administered to healthy subjects, on LPS-inducible prostaglandin E2 (PGE2) biosynthesis in whole blood ex vivo. METHODS: Heparinized whole-blood samples obtained from healthy subjects and patients with rheumatoid arthritis were incubated with LPS (10 microg/ml) for 24 hours at 37 degrees C, and PGE2 was measured in plasma as an index of monocyte COX-2 activity. Comparative experiments were performed in LPS-stimulated isolated monocytes. The levels of COX-2-like immunoreactivity in monocyte lysates were measured by a specific Western blot technique. PGE2 was evaluated by radioimmunoassay. RESULTS: Nanomolar concentrations of cortisol, 6-methylprednisolone, and dexamethasone suppressed LPS-induced PGE2 biosynthesis both in whole blood and in isolated monocytes in vitro with relative potencies similar to those reported for their anti-inflammatory effects in vivo. The administration of single oral doses (4, 8, or 16 mg) of 6-methylprednisolone caused a dose- and time-dependent inhibition of whole-blood COX-2 activity. Whole-blood samples obtained from patients with rheumatoid arthritis treated with comparable maintenance doses of glucocorticoids produced significantly lower levels of LPS-inducible PGE2 than were found in untreated patients. CONCLUSIONS: Therapeutic plasma levels of synthetic glucocorticoids down-regulate inducible prostanoid biosynthesis in circulating monocytes. This effect may represent a readily measurable surrogate marker of their clinical efficacy for dose-finding studies.