Paul Nicholls | PubMed Health

PubMed2004

Changes in pulmonary vascular function after acute methionine loading in normal men.

Elevated blood levels of Hcy (homocysteine) are associated with endothelial dysfunction in the systemic and coronary arterial beds. We wished to know if similar changes could be detected in the pulmonary circulation, using non-invasive tests. We studied ten normal young men aged 23-31 years, in whom acute hyperhomocysteinaemia was induced by oral ingestion of methionine. Cardiopulmonary exercise testing [including measurement of exhaled breath NO (nitric oxide)] was performed on two occasions, with and without methionine loading. In addition, blood samples for vWf (von Willebrand factor) and factor VIIIc were taken as markers of endothelial function. After oral methionine, plasma Hcy increased from 11.8 +/- 3.1 to 31.2 +/- 10.3 micromol/l (values are means +/- S.D.; P < 0.0001), whereas there was no increase after placebo. After exercise there was an increase in V(NO) (NO production) and circulating plasma levels of vWf and factor VIIIc, but these were similar in the two tests. Exercise time, HR (heart rate) and BP (blood pressure) responses and P V(O2) (peak achieved O2 uptake) were also similar in the two tests. V(E) (expiratory minute ventilation)/ V(CO2) (CO2 production) was similar in the two groups at rest (methionine, 31.9 +/- 3.9; placebo, 30.5 +/- 3.9; P = 0.11), but increased during exercise after methionine (at peak, 32.2 +/- 4.6 compared with 29.9 +/- 2.8; P = 0.016). P(ETCO2) (end-tidal partial pressure of CO2) was also similar in the two groups at rest (35.1 +/- 2.9 compared with 36.8 +/- 3.2; P = 0.11), but decreased throughout the methionine test (peak 34.1 +/- 4.4 compared with 36.7 +/- 3.5; P = 0.006). V(E) vs V(CO2) slope also increased in the methionine test (25.2 +/- 2.4 compared with 22.8 +/- 2.3; P = 0.003). In conclusion, small, but consistent and significant, changes in respiratory gas exchange were seen after methionine loading, compatible with a V / Q (ventilation/perfusion) mismatch due to pulmonary vascular endothelial dysfunction.

Adult↗

PubMed2002

Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer.

Fresh organically grown pomegranates (Punica granatum L.) of the Wonderful cultivar were processed into three components: fermented juice, aqueous pericarp extract and cold-pressed or supercritical CO2-extracted seed oil. Exposure to additional solvents yielded polyphenol-rich fractions ('polyphenols') from each of the three components. Their actions, and of the crude whole oil and crude fermented and unfermented juice concentrate, were assessed in vitro for possible chemopreventive or adjuvant therapeutic potential in human breast cancer. The ability to effect a blockade of endogenous active estrogen biosynthesis was shown by polyphenols from fermented juice, pericarp, and oil, which inhibited aromatase activity by 60-80%. Fermented juice and pericarp polyphenols, and whole seed oil, inhibited 17-beta-hydroxysteroid dehydrogenase Type 1 from 34 to 79%, at concentrations ranging from 100 to 1,000 microg/ml according to seed oil >> fermented juice polyphenols > pericarp polyphenols. In a yeast estrogen screen (YES) lyophilized fresh pomegranate juice effected a 55% inhibition of the estrogenic activity of 17-beta-estradiol; whereas the lyophilized juice by itself displayed only minimal estrogenic action. Inhibition of cell lines by fermented juice and pericarp polyphenols was according to estrogen-dependent (MCF-7) >> estrogen-independent (MB-MDA-231) > normal human breast epithelial cells (MCF-10A). In both MCF-7 and MB-MDA-231 cells, fermented pomegranate juice polyphenols consistently showed about twice the anti-proliferative effect as fresh pomegranate juice polyphenols. Pomegranate seed oil effected 90% inhibition of proliferation of MCF-7 at 100 microg/ml medium, 75% inhibition of invasion of MCF-7 across a Matrigel membrane at 10 microg/ml, and 54% apoptosis in MDA-MB-435 estrogen receptor negative metastatic human breast cancer cells at 50 microg/ml. In a murine mammary gland organ culture, fermented juice polyphenols effected 47% inhibition of cancerous lesion formation induced by the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). The findings suggest that clinical trials to further assess chemopreventive and adjuvant therapeutic applications of pomegranate in human breast cancer may be warranted.

17-Hydroxysteroid Dehydrogenases↗