A Fragment of the LG3 Peptide of Endorepellin Is Present in the Urine of Physically Active Mining Workers: A Potential Marker of Physical Activity

Biomarker analysis has been implemented in sports research in an attempt to monitor the effects of exertion and fatigue in athletes. This study proposed that while such biomarkers may be useful for monitoring injury risk in workers, proteomic approaches might also be utilised to identify novel exertion or injury markers. We found that urinary urea and cortisol levels were significantly elevated in mining workers following a 12 hour overnight shift. These levels failed to return to baseline over 24 h in the more active maintenance crew compared to truck drivers (operators) suggesting a lack of recovery between shifts. Use of a SELDI-TOF MS approach to detect novel exertion or injury markers revealed a spectral feature which was associated with workers in both work categories who were engaged in higher levels of physical activity. This feature was identified as the LG3 peptide, a C-terminal fragment of the anti-angiogenic/anti-tumourigenic protein endorepellin. This finding suggests that urinary LG3 peptide may be a biomarker of physical activity. It is also possible that the activity mediated release of LG3/endorepellin into the circulation may represent a biological mechanism for the known inverse association between physical activity and cancer risk/survival

Effects of Aspirin on Endothelial Function and Hypertension

PURPOSE OF REVIEW: Endothelial dysfunction is intimately related to the development of various cardiovascular diseases, including hypertension, and is often used as a target for pharmacological treatment. The scope of this review is to assess effects of aspirin on endothelial function and their clinical implication in arterial hypertension. RECENT FINDINGS: Emerging data indicate the role of platelets in the development of vascular inflammation due to the release of proinflammatory mediators, for example, triggered largely by thromboxane. Vascular inflammation further promotes oxidative stress, diminished synthesis of vasodilators, proaggregatory and procoagulant state. These changes translate into vasoconstriction, impaired circulation and thrombotic complications. Aspirin inhibits thromboxane synthesis, abolishes platelets activation and acetylates enzymes switching them to the synthesis of anti-inflammatory substances. SUMMARY: Aspirin pleiotropic effects have not been fully elucidated yet. In secondary prevention studies, the decrease in cardiovascular events with aspirin outweighs bleeding risks, but this is not the case in primary prevention settings. Ongoing trials will provide more evidence on whether to expand the use of aspirin or stay within current recommendations

Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice

Contains fulltext : 108207.pdf (publisher's version ) (Open Access)Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced by acetaminophen (APAP). Mice were given a single intraperitoneal dose of APAP (0-350 mg/kg bw) followed by 24 h urine collection. Doses of >/=275 mg/kg bw APAP resulted in hepatic centrilobular necrosis and significantly elevated plasma alanine aminotransferase (ALT) values (p<0.0001). Proteomic profiling resulted in the identification of 12 differentially excreted proteins in urine of mice with acute liver injury (p<0.001), including superoxide dismutase 1 (SOD1), carbonic anhydrase 3 (CA3) and calmodulin (CaM), as novel biomarkers for APAP-induced liver injury. Urinary levels of SOD1 and CA3 increased with rising plasma ALT levels, but urinary CaM was already present in mice treated with high dose of APAP without elevated plasma ALT levels. Importantly, we showed in human urine after APAP intoxication the presence of SOD1 and CA3, whereas both proteins were absent in control urine samples. Urinary concentrations of CaM were significantly increased and correlated well with plasma APAP concentrations (r = 0.97; p<0.0001) in human APAP intoxicants, who did not present with elevated plasma ALT levels. In conclusion, using this urinary proteomics approach we demonstrate CA3, SOD1 and, most importantly, CaM as potential human biomarkers for APAP-induced liver injury

Relaxations induced by arachidonic acid in airway smooth muscle

link_to_subscribed_fulltex

Inhibition of airway smooth muscle tone by a phorbol ester in the guinea pig trachea: Role of epithelium and receptor reserve of the contractile agent

Bronchial hyperresponsiveness in patients with asthma may be associated with a damaged or dysfunctional epithelium. Also, changes in the activities of protein kinase C have been implicated in the pathogenesis of asthma. This study examined the role of protein kinase C in the modulation of airway smooth muscle tone and the influence of the epithelium on this function. Phorbol- 12,13-diacetate (PDA) (10-8 to 10-5 M) induced concentration- dependent and epithelium-independent relaxations of guinea pig tracheal rings. PDA (10-8 to 10-5 M) induced significantly greater relaxations of tracheal rings contracted with 5-hydroxytryptamine (10-5 M) than in tissues contracted to an equivalent degree with acetylcholine (10-6 M). In experiments using phenoxybenzamine (10-7 M and 10-5 M), the dissociation constant (K(A)) for acetylcholine was significantly greater than that for 5-hydroxytryptamine. The fraction of active receptors (q) calculated for acetylcholine was significantly smaller than that calculated for an equieffective concentration of 5-hydroxytryptamine. Relaxations to PDA in tissues contracted with acetylcholine (2 x 10-6 M) or 5-hydroxytryptamine (10-5 M) were significantly augmented by phenoxybenzamine (10-5 M and 10-7 M, respectively). PDA did not affect contractions to acetylcholine (10-8 to 10-3 M) in the presence of epithelium but caused a significant right-ward displacement of the acetylcholine concentration-contraction curve in the absence of epithelium. The concentration-contraction curves for 5-hydroxytryptamine (10-8 to 10-5 M) were significantly displaced to the right by PDA in the presence or absence of epithelium. This effect was greater in the absence of epithelium. These results demonstrate that the effect of stimulation of protein kinase C by PDA is epithelium-independent and may be influenced by the receptor reserve of the contractile agonist for its receptors.link_to_subscribed_fulltex

Stimulation of sodium pump by vasoactive intestinal peptide in guinea-pig isolated trachea: Potential contribution to mechanisms underlying relaxation of smooth muscle

1. Relaxation of airway smooth muscle induced by vasoactive intestinal peptide (VIP) is mediated by adenosine 3':5' cyclic monophosphate (cyclic AMP). An interaction between the synthesis of cyclic AMP and enzymic activity of the plasmalemmal sodium pump (Na+-K+-ATPase) exists in certain isolated cell systems. This study sought to determine the contribution of Na+-K+-ATPase activity to relaxation of airway smooth muscle evoked by VIP. 2. All experiments were performed on isolated strips of guinea-pig trachea from which the epithelium had been removed. VIP was a more potent relaxant in tissues that were contracted with carbachol than those contracted with an equi-effective depolarizing concentration of K+. 3. Ouabain (0.1 μM-10 μM) induced contraction of tracheal strips. Contraction to ouabain (5 μM) was abolished following incubation of tissues with K+-free, or Ca2+-free (+EGTA, 0.1 mM) physiological solutions. The contractile response to ouabain (5 μM) was not influenced significantly by exposure of the tissues to atropine (1 μM), phentolamine (5 μM) and diphenhydramine (1 μM) for 60 min. 4. Tissues were incubated with ouabain (5 μM; 60 min) or K+-free physiological solution (60 min) to inhibit Na+-K+-ATPase activity. These procedures reduced relaxation induced by VIP, peptide histidine isoleucine, forskolin, isoprenaline and sodium nitroprusside. 5. Relaxation to VIP was impaired significantly following exposure of tissues to a low Na+ solution (30 min) or amiloride (500 μM; 30 min). 6. Ouabain-sensitive uptake of 86Rb was measured in tracheal strips (devoid of epithelium and cartilage) as an index of Na+-K+-ATPase activity. VIP (1 μM; 2 min) caused a 4.7 fold stimulation of ouabain-sensitive uptake of 86Rb. This effect was impaired significantly by low Na+ solution. 7. The results suggest that (i) relaxation of tracheal smooth muscle to VIP is sensitive to procedures that inhibit activity of Na+-K+-ATPase and invoke a role for altered sodium pump function in the mechanisms that underlie cyclic AMP-dependent relaxation; and (ii) VIP stimulates ouabain-sensitive uptake of 86Rb in airway smooth muscle in a Na+-dependent manner.link_to_subscribed_fulltex

Airway epithelial cells in the pathophysiology of asthma

link_to_subscribed_fulltex

Mechanisms of hypoxic vasoconstriction in the canine isolated pulmonary artery: Role of endothelium and sodium pump

Contraction of canine pulmonary artery to hypoxia in vitro is both endothelium dependent and independent. The mechanisms which underlie this phenomenon were studied. Rings of canine pulmonary artery were suspended for isometric force recording in tissue baths containing modified Krebs-Ringer bicarbonate solution. Tissues were first contracted with norepinephrine [effective dose at 35% (ED35) concentration]. Subsequent exposure to hypoxia induced a triphasic response: an initial phasic transient contraction (phase 1), a transient reduction in force (phase 2), followed by a sustained tonic contraction (phase 3). In the absence of endothelium, all phases of the hypoxic response were reduced and phase 2 was reversed from a contraction to a relaxation (with endothelium: 0.68 ± 0.2 g; without endothelium: -0.34 ± 0.1 g). Similar data were obtained in the presence of nitro-L-arginine (3 x 10-5 M). In the absence of endothelium, indomethacin (10-5 M) abolished the phase 2 relaxation and converted phase 3 from a contraction to a relaxation (control: 0.99 ± 0.2 g; indomethacin: -0.44 ± 0.1 g); and ONO- 3708 (thromboxane A2/prostaglandin H2 receptor antagonist) diminished phase 3 (control: 0.99 ± 0.2 g; ONO-3708: 0.3 ± 0.04 g). In the absence of endothelium, but in the presence of indomethacin (10-5 M), K+-free solution diminished phase 1 (contraction) and converted phase 2 (relaxation) to a contraction (control: -0.74 ± 0.1 g; K+-free solution: 0.1 ± 0.06 g). Similar results were obtained with ouabain (4 x 10-7 M), and cooling of the bathing medium (20°C). The vascular endothelium, vasoactive prostanoids, and activity of the smooth muscle sodium pump may modulate the response to hypoxia in the canine isolated pulmonary artery.link_to_subscribed_fulltex

Hyperpolarization and relaxation of canine vascular smooth muscle to vasoactive intestinal polypeptide

This study was designed to determine the influence of the endothelium on the hyperpolarization induced by vasoactive intestinal polypeptide (VIP) in smooth muscle cells of canine blood vessels, and the potential contribution that these electrophysiologic changes may make to the relaxant effects of VIP. Membrane potential was measured in isolated canine coronary arteries and saphenous veins, using glass microelectrodes. Isometric force was recorded in a conventional organ chamber. All experiments were performed in the presence of indomethacin. VIP induced concentration-dependent and endothelium- independent hyperpolarization of the saphenous vein. This response was abolished by glibenclamide. VIP did not induce hyperpolarization of coronary arterial smooth muscle either in the presence or absence of the endothelium. VIP caused concentration-dependent and endothelium-independent relaxations of both arterial and venous rings. The relaxation of the saphenous vein to VIP was not influenced by glibenclamide. These data suggest that hyperpolarization of the cell membrane does not play a significant role in the relaxation of canine blood vessels to VIP.link_to_subscribed_fulltex

Differential effects of the antianginal drug nicorandil on canine arteries and veins

Nicorandil, a potent coronary vasorelaxant used in the treatment of angina, has differental effects on arteries and veins in vivo. To explain this phenomenon, experiments were designed to characterize the relaxant and inhibitory actions of this compound on canine isolated arteries and veins. Paired rings of canine coronary, femoral, and saphenous arteries and saphenous veins were suspended at optimal length for isometric tension recording in organ chambers containing physiologic salt solution at 37°C and gassed with 95% O2-5% CO2. In certain experiments, one ring of each pair was denuded of the endothelium. Removal of the endothelium did not affect nicorandil-induced relaxations of contracted blood vessels. Nicorandil exerted a differential relaxant effect on arteries and veins contracted with KCl (order of potency: saphenous vein > coronary artery > femoral artery). No difference in sensitivity to nicorandil was observed in arteries and veins contracted with prostaglandin F(2α). Contractions of saphenous arteries and veins to norepinephrine (NE) were equally sensitive to the inhibitory action of nicorandil. However, contractions of saphenous veins induced by sympathetic nerve stimulation were more sensitive to nicorandil than were contractions of saphenous arteries. Furthermore, nicorandil did not affect contractions to phenylephrine in saphenous veins, although contractions to B-HT 920 were virtually abolished by the compound. Saphenous veins contracted with St 587 were more sensitive to the relaxant action of nicorandil than when contracted with phenylephrine. These results suggest that nicorandil inhibits preferentially contractions of canine arteries and veins mediated by α2- rather than α1-adrenoceptors. This selectivity of action may be conferred by a differential receptor reserve and/or receptor coupling efficiency between the α-adrenoceptor subtypes for contractile agonists.link_to_subscribed_fulltex