Biomedical subjects

Tom Saldeen

Publications and source records attributed to Tom Saldeen.

10 recordsLinked to original sources

PubMed2006

A new predictor of risk for sudden cardiac death.

BACKGROUND: Long-chain fatty acids, particularly omega-3 fatty acids found primarily in fish oil, are beneficial in different physiological conditions in the human body. High intake of omega-3 fatty acids has been found to have a strong inverse relationship to sudden cardiac death. An index showing the relationship between different fatty acids in the blood could be an important risk indicator for sudden cardiac death. METHODS: Whole-blood samples from the fingertip were collected and fatty acids were measured by a new simple method using direct transmethylation. Two groups were compared: subjects who had been taking fish oil daily during the last 6 years, and subjects who had not been taking fish oil. RESULTS: Six different fatty acid indices were calculated. Five of them take both DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) into consideration, and the sixth includes only EPA and not DHA in the calculation. This latter index, the ratio between EPA and arachidonic acid, gave the best result, with the largest difference between the two groups. This index varied between 5 and 118 among the different individuals; 70% of the fish oil consumers having an index > or =50. Based on the present knowledge about the relationship between blood levels of omega-3 fatty acids and sudden cardiac death obtained from studies of 14,000 individuals, a subject with an index below 50 should be advised to increase his/her intake of omega-3 fatty acids. CONCLUSION: The EPA/arachidonic acid index may be an important new predictor of risk for sudden cardiac death, and reflects the individual requirement for consumption of omega-3 fatty acids.

Aged↗

PubMed2004

Women and omega-3 Fatty acids.

Omega-3 fatty acids (omega-3 FA) are constituents of the membranes of all cells in the body and are precursors of locally produced hormones, eicosanoids, which are important in the prevention and treatment of various diseases, especially in women. Omega-3 FA are of interest in some of the most common conditions affecting women. One mechanism underlying dysmenorrhea is a disturbed balance between antiinflammatory, vasodilator eicosanoids derived from omega-3 FA and proinflammatory, vasoconstrictor eicosanoids derived from omega-6 FA. Increased intake of omega-3 FA can reverse the symptoms in this condition by decreasing the amount of omega-6 FA in cell membranes. An increased prostacyclin/thromboxane ratio induced by omega-3 FA can facilitate pregnancy in women with infertility problems by increasing uterine blood flow. Supplementation with omega-3 FA during pregnancy lowers the risk of premature birth and can increase the length of pregnancy and birth weight by altering the balance of eicosanoids involved in labor and promote fetal growth by improving placental blood flow. Intake of omega-3 FA during pregnancy and breast feeding may facilitate the child's brain development. There is also some evidence that supplementation with omega-3 FA might help to prevent preeclampsia, postpartum depression, menopausal problems, postmenopausal osteoporosis, and breast cancer. Furthermore, because elevated triglyceride levels are associated with cardiovascular disease, especially in women; and because omega-3 FA have powerful effects on triglycerides, women in particular gain from an increased intake of these fatty acids. This is especially important in women receiving hormone therapy, which can increase triglyceride levels. The quality of the omega-3 FA preparation is important. It should have an appropriate antioxidant content not to induce lipid peroxidation, and its content of dioxin and polychlorinated biphenyls (PCBs) should be well below the established safe limit.

Brain↗

PubMed2003

Eicosapentanoic acid inhibits hypoxia-reoxygenation-induced injury by attenuating upregulation of MMP-1 in adult rat myocytes.

BACKGROUND: Myocardial hypoxia-reoxygenation (H-R) is associated with upregulation of metalloproteinases (MMPs). Upregulation of MMPs is associated with cell injury. Previous studies have shown that fish oil can protect myocardium from injury induced by H-R. This study was designed to examine the effect of eicosapentanoic acid (EPA), one of the major components in fish oil, on the modulation of MMP-1 expression in response to H-R in cultured adult rat myocytes. METHODS AND RESULTS: Myocytes isolated from adult Sprague-Dawley rat hearts were cultured with or without EPA or arachidonic acid (AA) (10 and 50 microM) and exposed to 24 h of hypoxia followed by 3 h of reoxygenation (H-R). H-R resulted in myocyte injury (measured on LDH release), increase in p38MAPK phosphorylation (Western analysis), augmentation of lipid peroxidation, and upregulation of MMP-1 activity (zymography) and expression (RT-PCR and Western analysis) (all P<0.01 vs. control, n=5). Pretreatment of myocytes with EPA, but not AA, resulted in a reduction in LDH release, and attenuation of p38MAPK phosphorylation and MMP-1 activity and expression in response to H-R (all P<0.05 vs. H-R alone). Pretreatment of myocytes with EPA also reduced lipid peroxidation in myocytes exposed to H-R (P<0.05 vs. H-R alone). A high concentration of EPA (50 microM) was more potent than the lower concentration of EPA (10 microM). CONCLUSIONS: These observations suggest that EPA attenuates an increase in MMP-1 following H-R, which may be a basis of protection of myocytes from the adverse effects of H-R. p38MAPK phosphorylation may be an important signaling event in this process.

Animals↗

PubMed2003

EPA and DHA attenuate ox-LDL-induced expression of adhesion molecules in human coronary artery endothelial cells via protein kinase B pathway.

Uptake of oxidized low-density lipoprotein (ox-LDL) by endothelial cells is a critical step for the initiation and development of atherosclerosis. Adhesion molecules are inflammatory makers, which are upregulated by ox-LDL and play a pivotal role in atherogenesis. A number of studies suggest that fish and its constituents can reduce inflammation and decrease atherosclerosis. We hypothesized that fish oil constituents namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) may reduce expression of adhesion molecules induced by ox-LDL. Cultured human coronary artery endothelial cells (HCAECs) were incubated with ox-LDL for 24 h. Parallel groups of cells were pretreated with DHA or EPA (10 or 50 microM) overnight before incubation with ox-LDL. Ox-LDL markedly increased the expression of P-selectin and intracellular adhesion molecule-1 (ICAM-1) (both protein and mRNA) in HCAECs, and enhanced the adhesion of monocytes to the cultured HCAECs. Both EPA and DHA decreased ox-LDL-induced upregulation of expression of P-selectin and ICAM-1, and the enhanced adhesion of monocytes to HCAECs. To determine the role of protein kinase B (PKB) as an intracellular-signaling pathway, HCAECs were treated with the PKB upstream inhibitor wortmannin (100 nM) or transfected with plasmids encoding dominant-negative mutants of PKB (PKB-DN) before treatment with DHA. Ox-LDL alone downregulated the activity of PKB; DHA attenuated this effect of ox-LDL, and both wortmannin and PKB-DN blocked the effect of DHA. The present study in human coronary endothelial cells suggests that both EPA and DHA attenuate ox-LDL-induced expression of adhesion molecules, and the adhesion of monocytes to HCAECs by modulation of PKB activation. These effects may be important mechanisms of anti-atherosclerotic effects of fish and fish oils.

Arteries↗

PubMed2003

Mixed tocopherols inhibit platelet aggregation in humans: potential mechanisms.

BACKGROUND: Epidemiologic studies have shown an inverse correlation between acute coronary events and high intake of dietary vitamin E. Recent clinical studies, however, failed to show any beneficial effects of alpha-tocopherol on cardiovascular events. Absence of tocopherols other than alpha-tocopherol in the clinical studies may account for the conflicting results. OBJECTIVE: This study compared the effect of a mixed tocopherol preparation rich in gamma-tocopherol with that of alpha-tocopherol on platelet aggregation in humans and addressed the potential mechanisms of the effect. DESIGN: Forty-six subjects were randomly divided into 3 groups: alpha-tocopherol, mixed tocopherols, and control. ADP and phorbol 12-myristate 13-acetate-induced platelet aggregation, nitric oxide (NO) release, activation of endothelial constitutive nitric-oxide synthase (ecNOS; EC 1.14.13.39) and of protein kinase C (PKC), and ecNOS, superoxide dismutase (SOD; EC 1.15.1.1), and PKC protein content in platelets were measured before and after 8 wk of administration of tocopherols. RESULTS: ADP-induced platelet aggregation decreased significantly in the mixed tocopherol group but not in the alpha-tocopherol and control groups. NO release, ecNOS activation, and SOD protein content in platelets increased in the tocopherol-treated groups. PKC activation in platelets was markedly decreased in the tocopherol-treated groups. Mixed tocopherols were more potent than alpha-tocopherol alone in modulating NO release and ecNOS activation but not SOD protein content or PKC activation. CONCLUSIONS: Mixed tocopherols were more potent in preventing platelet aggregation than was alpha-tocopherol alone. Effects of mixed tocopherols were associated with increased NO release, ecNOS activation, and SOD protein content in platelets, which may contribute to the effect on platelet aggregation.

Adult↗

PubMed2003

TGF-beta 1 attenuates myocardial ischemia-reperfusion injury via inhibition of upregulation of MMP-1.

Ischemia-reperfusion (I/R) is thought to upregulate the expression and activity of matrix metalloproteinases (MMPs), which regulate myocardial and vascular remodeling. Previous studies have shown that transforming growth factor-beta(1) (TGF-beta(1)) can attenuate myocardial injury induced by I/R. TGF-beta(1) is also reported to suppress the release of MMPs. To study the modulation of MMP-1 by TGF-beta(1) in I/R myocardium, Sprague-Dawley rats were given saline and subjected to 1 h of myocardial ischemia [total left coronary artery (LCA) ligation] followed by 1 h of reperfusion (n = 9). Parallel groups of rats were pretreated with recombinant TGF-beta(1) (rTGF-beta(1), 1 mg/rat, n = 9) before reperfusion or exposure to sham I/R (control group). I/R caused myocardial necrosis and dysfunction, indicated by decreased first derivative of left ventricular pressure, mean arterial blood pressure, and heart rate (all P < 0.01 vs. sham-operated control group). Simultaneously, I/R upregulated MMP-1 (P < 0.01). Treatment of rats with rTGF-beta(1) reduced the extent of myocardial necrosis and dysfunction despite I/R (all P < 0.01). rTGF-beta(1) treatment also inhibited the upregulation of MMP-1 in the I/R myocardium (P < 0.05). To determine the direct effect of MMP-1 on the myocardium, isolated adult rat myocytes were treated with active MMP-1, which caused injury and death of cultured myocytes, measured as lactate dehydrogenase release and trypan blue staining, in a dose- and time-dependent manner (P < 0.05). Pretreatment with PD-166793, a specific MMP inhibitor, attenuated myocardial injury and death induced by active MMP-1. The present study for the first time shows that MMP-1 can directly cause myocyte injury or death and that attenuation of myocardial I/R injury by TGF-beta(1) may, at least partly, be mediated by the inhibition of upregulation of MMP-1.

Animals↗

PubMed2002

Citalopram in fatal poisoning cases.

Citalopram, a selective serotonin reuptake inhibitor, is the most frequently prescribed antidepressant in Sweden. To investigate the extent to which citalopram in overdose is found in fatal poisoning cases compared with other drugs, all fatal poisonings in one forensic medicine district in Sweden during the years 1994-1999 were examined. Drugs found in overdose in more than 10 cases were included. The ratio between number of cases with each included drug and prescription of defined daily dose/1,000 inhabitants/day (DDD) was determined. Citalopram was the fourth most frequently found drug in overdose, occurring in 22 (6%) of the 358 fatal poisoning cases, after dextropropoxyphene (DXP), flunitrazepam and nitrazepam, which were present in 111 (31%), 56 (16%) and 31 (9%) cases, respectively. When related to the prescription rate, citalopram was significantly less represented than five of the other seven included drugs, namely DXP, flunitrazepam, nitrazepam, amitriptyline and clomipramine. Propiomazine and zopiclone occurred to the same extent as citalopram. According to the assessments of the forensic physicians, citalopram was the cause of death in five cases (1.4%) and contributed to death in another nine cases (2.5%). It is concluded that citalopram, in spite of its high prescription rate, has not become a drug of importance in fatal poisoning cases. Since, this result may not be generalisable to non-fatal poisoning cases, it is recommended that the prevalence of citalopram in these cases be examined separately.

Adult↗

PubMed2002

Mixed tocopherol preparation is superior to alpha-tocopherol alone against hypoxia-reoxygenation injury.

Hypoxia-reoxygenation (H-R) is associated with alterations in oxidant-antioxidant balance and L-arginine-nitric oxide system. Tocopherols decrease the activity of reactive oxygen species (ROS) and yet are not beneficial in clinical trials. It has been proposed that mixed tocopherols as found in nature may be more tissue protective than alpha-tocopherol alone found in commercial preparations. We compared the effect of a mixed tocopherol preparation with that of alpha-tocopherol alone on superoxide dismutase (SOD) activity and iNOS expression in cultured myocytes exposed to H-R. Myocytes from Sprague-Dawley rat hearts were subjected to hypoxia for 24 h followed by reoxygenation for 3 h H-R. Parallel groups of myocytes were pretreated with alpha-tocopherol alone or a mixed-tocopherol preparation (containing alpha-, gamma-, and delta-tocopherols) (50 microM) for 30 min. H-R resulted in myocyte injury (determined by LDH release), a decrease in SOD activity and an upregulation of iNOS expression/activity. Both tocopherol preparations attenuated cell injury and markedly decreased the effects of H-R on SOD activity and iNOS expression/activity (all P < 0.05 vs H-R group, n = 5). However, mixed-tocopherol preparation was much superior to alpha-tocopherol in terms of myocyte protection from the adverse effect of H-R (P < 0.05). Lack of efficacy of commercial tocopherol preparations in clinical trials may reflect absence of gamma- and delta-tocopherols.

Animals↗

PubMed2002

Mixed tocopherols have a stronger inhibitory effect on lipid peroxidation than alpha-tocopherol alone.

Intake of vitamin E with food (mixed tocopherols) has been found to counteract the development of atherosclerotic cardiovascular disease, whereas intake of large amounts of pure alpha-tocopherol has shown only a slight or no effect in clinical studies. This study was designed to investigate the effects of alpha-tocopherol alone and a mixed tocopherol preparation (gamma-, delta-, and alpha-tocopherol) on hydrogen peroxide-induced lipid peroxidation in human erythrocytes. Erythrocytes were incubated with different concentrations of alpha-tocopherol or mixed tocopherols and then exposed to hydrogen peroxide. Tocopherol levels and malondialdehyde-thiobarbituric acid-reactive substances were determined by high-performance liquid chromatography and fatty acids by gas chromatography. Incubation of erythrocytes with tocopherols (30-120 microM) increased the tocopherol level in a concentration-dependent manner. The uptake of gamma- and delta-tocopherols was much higher than that of alpha-tocopherol. Hydrogen peroxide strongly increased lipid peroxidation and decreased polyunsaturated fatty acids in erythrocytes. Both alpha-tocopherol and the tocopherol mixture protected the cells from lipid peroxidation, the mixture being much more potent than alpha-tocopherol alone. This study indicates that a mixture of tocopherols has a stronger inhibitory effect on lipid peroxidation induced in human erythrocytes than alpha-tocopherol alone, due to higher uptake of gamma- and delta-tocopherol in the cells.

Adult↗

PubMed2002

Statins modulate oxidized low-density lipoprotein-mediated adhesion molecule expression in human coronary artery endothelial cells: role of LOX-1.

LOX-1, a receptor for oxidized low-density lipoprotein (ox-LDL), plays a critical role in endothelial dysfunction and atherosclerosis. LOX-1 activation also plays an important role in monocyte adhesion to endothelial cells. A number of studies show that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduce total LDL cholesterol and exert a cardioprotective effect. We examined the modulation of LOX-1 expression and its function by two different statins, simvastatin and atorvastatin, in human coronary artery endothelial cells (HCAECs). We observed that ox-LDL (40 microg/ml) treatment up-regulated the expression of E- and P-selectins, VCAM-1 and ICAM-1 in HCAECs. Ox-LDL mediated these effects via LOX-1, since antisense to LOX-1 mRNA decreased LOX-1 expression and subsequent adhesion molecule expression. Pretreatment of HCAECs with simvastatin or atorvastatin (1 and 10 microM) reduced ox-LDL-induced expression of LOX-1 as well as adhesion molecules (all P < 0.05). A high concentration of statins (10 microM) was more potent than the low concentration (1 microM) (P < 0.05). Both statins reduced ox-LDL-mediated activation of the redox-sensitive nuclear factor-kappaB (NF-kappaB) but not AP-1. These observations indicate that LOX-1 activation plays an important role in ox-LDL-induced expression of adhesion molecules. Inhibition of expression of LOX-1 and adhesion molecules and activation of NF-kappaB may be another mechanism of beneficial effects of statins in vascular diseases.

Atorvastatin↗