Soluble complement receptor-1 protects heart, lung, and cardiac myofilament function from cardiopulmonary bypass damage.
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BACKGROUND: Host defense system activation occurs with cardiopulmonary bypass (CPB) and is thought to contribute to the pathophysiological consequences of CPB. Complement inhibition effects on the post-CPB syndrome were tested with soluble complement receptor-1 (sCR1). METHODS AND RESULTS: Twenty neonatal pigs (weight 1.8 to 2.8 kg) were randomized to control and sCR1-treated groups. LV pressure and volume, left atrial pressure, pulmonary artery pressure and flow, and respiratory system compliance and resistance were measured. Preload recruitable stroke work, isovolumic diastolic relaxation time constant (tau), and pulmonary vascular resistance were determined. Pre-CPB measures were not statistically significantly different between the 2 groups. After CPB, preload recruitable stroke work was significantly higher in the sCR1 group (n=5, 46.8+/-3.2x10(3) vs n=6, 34.3+/-3.7x10(3) erg/cm(3), P=0.042); tau was significantly lower in the sCR1 group (26.4+/-1.5, 42.4+/-6. 6 ms, P=0.003); pulmonary vascular resistance was significantly lower in the sCR1 group (5860+/-1360 vs 12 170+/-1200 dyn. s/cm(5), P=0.009); arterial PO(2) in 100% FIO(2) was significantly higher in the sCR1 group (406+/-63 vs 148+/-33 mm Hg, P=0.01); lung compliance and airway resistance did not differ significantly. The post-CPB Hill coefficient of atrial myocardium was higher in the sCR1 group (2.88+/-0.29 vs 1.88+/-0.16, P=0.023). CONCLUSIONS: sCR1 meaningfully moderates the post-CPB syndrome, supporting the hypothesis that complement activation contributes to this syndrome. (+info)
Chemoprevention of cancer: a controversial and instructive story.
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Increased intake of fruits and vegetables seems to be one of the simplest means of decreasing the risk for cancer. Cancer-preventive effects of fruits and vegetables have been observed in epidemiological studies, which could not, however, distinguish the effects of the various ingredients. Antioxidant defence has been proposed as a mechanism of chemoprevention, although inconclusive results have been obtained. The results of randomized intervention trials have shown that beta-carotene supplements are of limited value and may even be deleterious. Vitamins are a good marker of the ingestion of fruits and vegetables, and vitamin E (alpha-tocopherol) is a lipid-soluble antioxidant which can scavenge free radicals. It has no significant effect on the risk for lung cancer of long-term smokers in an intervention trial, but it decreased both the incidence of and mortality from prostate cancer; however, there was a 50% increase in the occurrence of cerebral haemorrhage among the men given vitamin E. Aspirin and aspirin-like drugs appear to decrease the risk for intestinal tumours; the mechanism of action appears to involve diminishing prostaglandin production due to inhibition of cyclooxygenases. Dietary fibre has been linked to a reduced risk for colorectal cancer in many observational studies, but opposite findings were reported recently. In order to resolve these paradoxes, we need to understand better the underlying biology, develop mechanistic hypotheses and test them in clinical trials in humans. Until that time, we should confine any premature enthusiasm for chemopreventive micronutrient supplementation. (+info)
Problems and approaches in investigating the role of micronutrients in the aetiology of cancer in humans.
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Observational studies have provided leads regarding a number of micronutrients which may account for the apparent protective effects of high intakes of vegetables and fruit against many types of cancer. In general, these leads have not been confirmed by randomised controlled trials. This apparent conflict raises issues about the timing and duration of a critical period or periods during which micronutrient intake may influence the development of cancer, the dose, possible interaction between high doses of micronutrients and exposures conferring a high risk of cancer and gene-micronutrient interactions. When gene-environmental interaction exists, failure to take both of these sets of factors into account leads to bias in the estimation of disease risk. As a result of recent advances, it is now possible to take measures of genetic susceptibility into account. Therefore, in future studies, the opportunity should be taken to obtain DNA samples to determine genotypes for polymorphisms potentially affecting micronutrient metabolism. (+info)
Intravenous ifosfamide/mesna is associated with depletion of plasma thiols without depletion of leukocyte glutathione.
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Depletion of cellular glutathione (GSH) enhances the efficacy of many anticancer agents in preclinical systems. Limited published data showing depletion of GSH in vitro and in patients by ifosfamide and/or mesna provided the rationale for a Phase I trial. Ifosfamide and mesna were infused over 24 and 36 h, respectively, at equal daily doses; carboplatin was given after ifosfamide to a target plasma area under the curve of 4 mg x min x ml(-1). Plasma and peripheral WBC thiols were quantitated by high-performance liquid chromatography. The dose of ifosfamide was escalated from 2 to 8 g/m2; the maximum tolerated dose was 6 g/m2. Significant depletion in plasma cysteine and homocysteine, precursors for GSH synthesis, was observed (maximum, 95% to >99% at 8 g/m2). Plasma mesna and cysteine/ homocysteine levels were inversely correlated; nadir levels of cysteine/homocysteine were maintained for several hours after ifosfamide infusion had stopped and while mesna infusion was continuing. In vitro coincubation experiments confirmed that mesna reduces these thiols from disulfides to sulfhydryls, which are readily cleared, as evidenced by the significantly increased rate of excretion of cysteine in urine. In contrast, ifosfamide/mesna treatment caused a moderate depletion of plasma GSH in only 60% of the patients, with a nadir at 24 h and recovery immediately after the end of ifosfamide infusion. The GSH depletion in these patients was not dose related. The profile of GSH recovery in plasma after ifosfamide and the fact that mesna could not reduce GSH disulfides in vitro suggest that the observed GSH depletion in plasma in 60% of the patients may be related to direct reactions of GSH with ifosfamide metabolites and/or mesna. Our results indicate that mesna is a modulator of GSH precursors and that a prolonged infusion of mesna may be required to achieve GSH precursor starvation and the consequent GSH depletion in cells. (+info)
Histamine H(3)-receptor antagonists inhibit gastroprotection by (R)-alpha-methylhistamine in the rat.
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(R)-alpha-methylhistamine, a selective agonist of histamine H(3) receptors, is capable of protecting the gastric mucosa against differently acting damaging agents. The objective of the present study was to determine whether H(3) receptors mediate its protective action in the rat. Gastric mucosal lesions were induced intragastrically (i.g.) by 0.6 N HCl, 1 ml rat(-1). (R)-alpha-methylhistamine, 100 mg kg(-1) i.g., substantially reduced the severity of macroscopically and histologically assessed damage caused by concentrated acid. Prior treatment with highly selective H(3)-receptor antagonists, ciproxifan (0.3, 1 and 3 mg kg(-1) i.g.) and clobenpropit (3, 10 and 30 mg kg(-1) i.g.), dose-dependently inhibited the protection exerted by (R)-alpha-methylhistamine up to a complete reversal. When given alone at high doses, both antagonists tended to worsen the HCl-induced histologic damage. During basal conditions, (R)-alpha-methylhistamine, 100 mg kg(-1) i. g., caused a significant increase in titratable acidity of the gastric juice. Prior treatment with ciproxifan (3 mg kg(-1) i.g.) and clobenpropit (30 mg kg(-1) i.g.) did not alter the secretory response to (R)-alpha-methylhistamine. Clobenpropit alone, but not ciproxifan, increased the volume of gastric juice, and both compounds alone had no effect on titratable acid. Present findings support evidence that H(3) receptors are actively involved in the maintenance of gastric mucosal integrity, with no apparent role in the regulation of basal gastric acid secretion. (+info)
p38 MAPK and NF-kappa B collaborate to induce interleukin-6 gene expression and release. Evidence for a cytoprotective autocrine signaling pathway in a cardiac myocyte model system.
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In cardiac myocytes, the stimulation of p38 MAPK by the MAPKK, MKK6, activates the transcription factor, NF-kappaB, and protects cells from apoptosis. In the present study in primary neonatal rat cardiac myocytes, constitutively active MKK6, MKK6(Glu), bound to IkappaB kinase (IKK)-beta and stimulated its abilities to phosphorylate IkappaB and to activate NF-kappaB. MKK6(Glu) induced NF-kappaB-dependent interleukin (IL)-6 transcription and IL-6 release in a p38-dependent manner. IL-6 protected myocardial cells against apoptosis. Like IL-6, TNF-alpha, which activates both NF-kappaB and p38, also induced p38-dependent IL-6 expression and release and protected myocytes from apoptotis. While TNF-alpha was relatively ineffective, IL-6 activated myocardial cell STAT3 by about 8-fold, indicating a probable role for this transcription factor in IL-6-mediated protection from apoptosis. TNF-alpha-mediated IL-6 induction was inhibited by a kinase-inactive form of the MAPKKK, TGF-beta activated protein kinase (Tak1), which is known to activate p38 and NF-kappaB in other cell types. Thus, by stimulating both p38 and NF-kappaB, Tak1-activating cytokines, like TNF-alpha, can induce IL-6 expression and release. Moreover, the myocyte-derived IL-6 may then function in an autocrine and/or paracrine fashion to augment myocardial cell survival during stresses that activate p38. (+info)
alpha B-crystallin gene induction and phosphorylation by MKK6-activated p38. A potential role for alpha B-crystallin as a target of the p38 branch of the cardiac stress response.
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The MAPK kinase MKK6 selectively stimulates p38 MAPK and confers protection against stress-induced apoptosis in cardiac myocytes. However, the events lying downstream of p38 that mediate this protection are unknown. The small heat shock protein, alphaB-crystallin, which is expressed in only a few cell types, including cardiac myocytes, may participate in MKK6-mediated cytoprotection. In the present study, we showed that, in cultured cardiac myocytes, expression of MKK6(Glu), an active form of MKK6, led to p38-dependent increases in alphaB-crystallin mRNA, protein, and transcription. MKK6(Glu) also induced p38-dependent activation of the downstream MAPK-activated protein kinase, MAPKAP-K2, and the phosphorylation of alphaB-crystallin on serine-59. Initially, exposure of cells to the hyperosmotic stressor, sorbitol, stimulated MKK6, p38, and MAPKAP-K2 and increased phosphorylation of alphaB-crystallin on serine 59. However, after longer times of exposure to sorbitol, the cells began to undergo apoptosis. This sorbitol-induced apoptosis was increased when p38 was inhibited in a manner that would block alphaB-crystallin induction and phosphorylation. Thus, under these conditions, the activation of MKK6, p38, and MAPKAP-K2 by sorbitol can provide a degree of protection against stress-induced apoptosis. Supporting this view was the finding that sorbitol-induced apoptosis was nearly completely blocked in cells expressing MKK6(Glu). Therefore, the cytoprotective effects of MKK6 in cardiac myocytes are due, in part, to phosphorylation of alphaB-crystallin on serine 59 and to the induction of alphaB-crystallin gene expression. (+info)
Pharmacokinetics and biological fate of 3-(2,2, 2-trimethylhydrazinium)propionate dihydrate (MET-88), a novel cardioprotective agent, in rats.
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In this study, we examined the disposition, metabolism, and excretion of a novel cardioprotective agent, 3-(2,2, 2-trimethylhydrazinium)propionate dihydrate (MET-88), in rats. The disposition of MET-88 after oral and i.v. administration of 2, 20, and 60 mg/kg indicated that the pharmacokinetics of MET-88 were nonlinear. The profiles of radioactive MET-88 and total radioactivity in plasma were consistent at doses of 20 and 60 mg/kg. However, at 2 mg/kg, the plasma MET-88 levels were obviously lower than the total. The excretion of radioactivity after oral administration of MET-88 indicated that increasing doses led to a shift from exhaled CO(2) to urinary excretion as the major excretion route. Major metabolites in plasma after oral administration of MET-88 were glucose, succinic acid, and 3-hydroxypropionic acid, and in vitro studies revealed that MET-88 was converted to 3-hydroxypropionic acid by gamma-butyrobetaine hydroxylase (EC 1.14. 11.1). An isolated liver perfusion system modified to trap CO(2) gas was used to examine the excretion pathway of MET-88. [(14)C]CO(2) gas was decreased by the addition of iodoacetic acid, DL-fluorocitric acid, or gamma-butyrobetaine to this system, and subsequent thin-layer chromatography analyses of perfusates revealed that MET-88 was first converted to 3-hydroxypropionic acid by gamma-butyrobetaine hydroxylase and then was biosynthesized to glucose and metabolized to CO(2) gas via the glycolytic pathway and tricarboxylic acid cycle. (+info)