Resveratrol prevents dendritic cell maturation in response to advanced glycation end products.

Advanced glycation end products (AGEs), generated through nonenzymatic glycosylation of proteins, lipids, and nucleic acids, accumulate in the body by age thus being considered as biomarkers of senescence. Senescence is characterized by a breakdown of immunological self-tolerance, resulting in increased reactivity to self-antigens. Previous findings suggest that AGE and its receptor RAGE may be involved in the pathogenesis of autoimmune reactions through dendritic cell (DC) activation. The aim of this study was to investigate whether resveratrol, a polyphenolic antioxidant compound with tolerogenic effects on DCs, was able to counteract the mechanisms triggered by AGE/RAGE interaction on DCs. By immunochemical and cytofluorimetric assays, we demonstrated that in vitro pretreatment of human monocyte-derived DCs with resveratrol prevents DC activation in response to glucose-treated albumin (AGE-albumin). We found that resveratrol exerts an inhibitory effect on DC surface maturation marker and RAGE up-regulation in response to AGE-albumin. It also inhibited proinflammatory cytokine expression, allostimulatory ability upregulation, mitogen-activated protein (MAP) kinases, and NF-κB activation in AGE-albumin-stimulated DCs. We suggest that resveratrol, by dismantling AGE/RAGE signaling on DCs may prevent or reduce increased reactivity to self-molecules in aging.

Electrical field stimulation (EFS)-induced relaxations turn into contractions upon removal of extracellular calcium in rat mesenteric artery.

In the present study, we aimed to examine the effect of blockade of L-type Ca(2+) channels (LTCC) and in addition the removal of extracellular Ca(2+), on EFS-induced relaxations in rings of rat mesenteric artery. EFS applied to the tissues precontracted with phenylephrine caused relaxations which were markedly inhibited by nifedipine (10(-7)M) and tetraethylammonium (TEA) (1mM). Addition of LTCC opener BAY K 8644 (10(-7)M) failed to enhance the relaxations. Upon removal of Ca(2+), EFS with the same stimulation parameters produced frequency-dependent transient contractions. Tetrodotoxin (10(-6)M), capsaicin (10(-5)M) and removal of endothelium did not alter these contractions suggesting that they were not neural in origin and endothelium-derived contracting factors were unlikely to be involved. However, they were increased by nearly 40% in response to BAY K 8644 (10(-7)M) and were inhibited by nifedipine (10(-7)M), indicating that activation of the LTCCs was essential. Inositol triphosphate (InsP3) receptor antagonist 2-APB (10(-4)M) significantly reduced, and high concentration of caffeine (20mM) almost totally suppressed the contractions. These results suggest that in the absence of extracellular Ca(2+) EFS through membrane depolarization, evokes the opening of the LTCCs which subsequently leads to the release of Ca(2+) from internal stores via InsP3 receptors, a phenomenon known as Ca(2+) channel-induced Ca(2+) release (CCICR), to trigger vasoconstriction. That activation of LTCCs causes arterial relaxation or contraction depending on the Ca(2+) status apparently exemplifies how the same messenger fulfils opposing physiological functions in a given cell.

Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: novel non-steroidal anti-inflammatory agents with favorable gastrointestinal tolerance.

In an effort to establish new candidates with improved analgesic and anti-inflammatory activities and lower ulcerogenic risk, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one derivatives of ibuprofen were synthesized. All compounds were evaluated for their in vivo anti-inflammatory and analgesic activities in mice. Furthermore, the ulcerogenic risks of the compounds were determined. In general, none of the compounds represent a risk for developing stomach injury as much as observed in the reference drugs ibuprofen and indomethacin. The compounds carrying a 3-phenyl-2-propenylidene (1a), (biphenyl-4-yl)methylidene (1f) and (1-methylpyrrol-2-yl)methylidene (1n) at the 6th position of the fused ring have been evaluated as potential analgesic/anti-inflammatory agents without a gastrointestinal side effect. These new compounds, therefore, deserve further attention to develop new lead drugs.

Effects of atorvastatin and L-arginine treatments on electrical field stimulation-mediated relaxations in pulmonary arterial rings of monocrotaline-induced pulmonary hypertensive rats.

This study aimed to examine the effect of monocrotaline (MCT)-induced pulmonary hypertension on electrical field stimulation (EFS)-mediated relaxation in rings of rat main pulmonary artery and to see whether treatment with atorvastatin or L-arginine would prevent the action of MCT. Rats were killed 21 days after MCT injection (60 mg/kg), and the main pulmonary arteries were isolated. EFS (40 V, 0.2 milliseconds, 5 seconds, 10 Hz)-induced relaxations in vessels precontracted with phenylephrine (10(-6) to 3 × 10(-6) M) were abolished in MCT-injected group compared with control group. Treatment of MCT group with atorvastatin (10 mg/kg, orally) completely, whereas treatment with L-arginine (500 mg/kg, intraperitoneally) partially but significantly prevented the inhibition. Similarly, acetylcholine (10(-9) to 3 × 10(-5) M)-evoked relaxations that were markedly inhibited in MCT-group were also protected from inhibition after pretreatment with atorvastatin or L-arginine. Responses to endothelium-independent relaxants sodium nitroprusside (10(-9) to 10(-5) M), pinacidil (10(-10) to 10(-4) M), and papaverine (10(-8) to 10(-4) M) were unaltered in MCT-induced pulmonary hypertensive rats. The present findings suggest that MCT-induced pulmonary hypertension inhibits the EFS-mediated relaxation through suppression of endothelial NO production. Reversal of this inhibition by atorvastatin treatment presumably results from stimulation of endothelial nitric oxide synthase expression. Relatively weak protection elicited by L-arginine might be secondary to impaired endothelial nitric oxide synthase activity caused by MCT-induced pulmonary hypertension.