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Biomedical subjects

M J Tikkanen

Publications and source records attributed to M J Tikkanen.

At least 19 recordsLinked to original sources
PubMed2006

Safety aspects and cholesterol-lowering efficacy of low fat dairy products containing plant sterols.

OBJECTIVE: The aim of this study was to investigate whether a plant sterol mixture would reduce serum cholesterol when added to low fat dairy products in subjects with hypercholesterolaemia, and to examine the effects of the mixture on the serum plant sterol and fat-soluble vitamin levels. DESIGN: A parallel, double-blind study. SETTING: The study was performed in three different locations in Finland. SUBJECTS: In total, 164 mildly or moderately hypercholesterolaemic subjects participated in the study. METHODS: The subjects were randomly divided into two groups: a plant sterol group and a control group. The subjects consumed the products for 6 weeks after a 3-week run-in period. The targeted plant sterol intake was 2 g/day in the sterol group. RESULTS: During the treatment period, there was a 6.5% reduction in serum total cholesterol in the sterol group while no change was observed in the control group (P<0.0005). Serum low-density lipoprotein (LDL) cholesterol was reduced by 10.4% in the sterol group and by 0.6% in the control group (P<0.00005). There was no change during the trial in serum high-density lipoprotein (HDL) cholesterol or triacylglycerol concentrations. The HDL/LDL cholesterol ratio increased by 16.1% in the sterol group and by 4.3% in the control group (P=0.0001). Serum plant sterol levels increased significantly (P=0.0001) in the sterol group. None of the fat-soluble vitamin levels decreased significantly when changes in serum total cholesterol were taken into account. The hypocholesterolaemic effect of sterol administration was not influenced by apolipoprotein E phenotype. CONCLUSIONS: Yoghurt, low-fat hard cheese and low-fat fresh cheese enriched with a plant sterol mixture reduced serum cholesterol in hypercholesterolaemic subjects and no adverse effects were noted in the dietary control of hypercholesterolaemia.

Anticholesteremic Agents↗
PubMed2005

Effects of oral and transdermal estradiol administration on levels of sex hormone-binding globulin in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy.

SHBG, the most important transport protein for sex steroids, is produced in the liver under the control of estrogen action. In a randomized, double-blind, prospective crossover study we compared basal levels of serum SHBG and their responses to increasing doses of oral and transdermal estradiol (E2), followed by E2 plus oral progestin (medroxyprogesterone acetate [MPA]), in 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), which could affect the synthesis of SHBG. Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 plus MPA combination were assayed for SHBG and E2. Basal levels of SHBG showed no difference between the study groups. Oral but not transdermal E2 increased SHBG concentrations by 67-171% in the control group, but the response was smaller (42-121%) in the ICP group. Addition of MPA decreased SHBG levels by 14-18% in both groups during both treatments. In conclusion, a history of ICP is associated with blunted responses of SHBG to oral estrogen.

Administration, Cutaneous↗
PubMed2005

Plant sterols and stanols.

The expanding market of 'functional foods' containing plant sterols and stanols has focused interest on their cholesterol-lowering effects as well on possible adverse effects. Trials of cholesterol lowering demonstrate that intake of 2 g/day of plant sterols and stanols reduces serum low-density lipoprotein (LDL) cholesterol concentrations by approximately 10%. Safety concerns regarding elevations in serum plant sterol levels, or effects on fat-soluble vitamin absorption or hypothetical effects on serum sex hormone balance have received attention and been addressed in studies. Plant sterol (but not stanol) supplementation increased serum plant sterol concentrations but these levels remained much lower than those observed in homozygous sitosterolemia making an adverse health effect unlikely. Prolonged statin therapy also causes elevations in all cholesterol-adjusted plant sterol levels as well as small but significant elevations in serum unadjusted campesterol levels from baseline. This is probably caused by a statin-induced reduction in biliary cholesterol efflux resulting in a diminished intestinal cholesterol pool. The diminished competition with cholesterol molecules allows more plant sterol molecules to become incorporated in mixed micelles facilitating their uptake in enterocytes. With the exception of beta-carotene, reductions in serum concentrations of fat-soluble (pro)vitamins are usually abolished by adjustment for cholesterol suggesting that they reflect reductions in carrier lipoproteins, mainly LDL. The small reductions in serum beta-carotene are not regarded as a major concern, nor have any adverse effects on sex hormone metabolism been demonstrated apart from parenteral administration of large doses in experimental animals. However, as increasing consumer populations become exposed to a large variety of food products enriched with plant sterols and stanols the likelihood of rare adverse effects increases and surveillance is necessary.

Animals↗
PubMed2005

Effects of vitamin E on the toxicity of oxidized LDL on endothelial cells in vitro in smokers vs nonsmokers on diets rich in fish.

OBJECTIVE: To clarify whether supplementation of vitamin E can alter the low density lipoprotein (LDL) oxidation properties and thereby affect endothelial cell function and prostacyclin production in smokers compared to nonsmokers on diets rich in fish in a pilot study. DESIGN: The LDL of six smokers and six nonsmokers on habitual high fish diet was isolated before and after an 8-week supplementation of vitamin E (800 IU/day). LDL was oxidized by incubation with CuSO4. Cytotoxicity of LDL oxidized to different degrees on endothelial cells was investigated in vitro in these two groups. SETTING: Helsinki University Central Hospital; Institute of Biomedicine, Pharmacology, University of Helsinki. RESULTS: At baseline, the rate of oxidation was higher in nonsmokers than in smokers. The lag phase increased significantly after the supplementation of vitamin E both in smokers and nonsmokers. Native LDL dose dependently tended to reduce the viability of endothelial cells in vitro more markedly when isolated from smokers than from nonsmokers. Vitamin E supplementation had no beneficial effect on the cytotoxicity of oxidized LDLs in endothelial cell culture. On the other hand, simultaneous administration of Trolox, the water-soluble analogue of vitamin E, attenuated the LDL cytotoxicity on endothelial cells. The vitamin E supplementation to LDL donors attenuated the increase in prostacyclin production both in smokers and nonsmokers. CONCLUSION: Supplementation of LDL donors (healthy male volunteers on habitual fish diet) with vitamin E increased the lag phase of LDL oxidation, but, on the other hand, did not influence in vitro cytotoxicity of LDL, or prostacyclin production.

Adult↗
PubMed2004

Levels of serum C-reactive protein during oral and transdermal estradiol in postmenopausal women with and without a history of intrahepatic cholestasis of pregnancy.

Liver dysfunction may affect the production and release of C-reactive protein (CRP). We designed a double-blind prospective crossover study involving 40 postmenopausal women with or without a history of intrahepatic cholestasis of pregnancy (ICP), where we compared the basal levels of CRP and their responses to increasing doses of oral and transdermal estradiol (E2), followed by addition of oral medroxyprogesterone acetate (MPA). Serum samples collected at baseline, on the last day of each E2 period, and on the last day of the E2 + MPA combination were assayed for CRP, estrogens, and liver enzymes. There was no difference in basal CRP between the study groups. Both regimens (oral and transdermal E2) were accompanied by significant rises in estrone and E2 concentrations; the former were 16 times higher during the oral than during the transdermal regimen. Oral E2 elevated CRP dose dependently, and this response was unaffected by a history of ICP or the use of MPA. The activities of liver transaminases varied but were in normal ranges during E2 use, in women with and without a history of ICP. In conclusion, the synthesis of CRP is not affected by a history of ICP. It is readily and dose dependently stimulated by oral but not by transdermal E2 in as soon as 2 wk.

Administration, Cutaneous↗
PubMed2002

Lipophilic oestrogen derivatives contained in lipoprotein particles.

Steroid fatty acid esters constitute a unique family of lipophilic hormones carried exclusively in circulating lipoproteins. Our studies have focused on the formation of 17beta fatty acid esters of labelled oestradiol in in vitro incubations with human ovarian follicular fluid and plasma and demonstrated the accumulation of these labelled derivatives in lipoprotein particles. The oestradiol esters are formed in a reaction catalysed by lecithin : cholesterol acyltransferase in association with high-density lipoprotein particles and they can be transferred to low-density lipoprotein particles in a process mediated by cholesteryl ester transfer protein. Using a novel quantitative method for the determination of oestradiol esters their endogenous concentrations in follicular fluid and in early and late pregnancy plasma have been determined. In addition, using labelled genistein and its chemically synthesized fatty acid esters, we also demonstrated that phytoestrogen derivatives could be incorporated in lipoprotein particles. Both oestradiol and genistein contain aromatic hydroxyl groups which cause them to exert powerful antioxidant activity in lipid-aqueous systems in vitro. The physiological role of the steroidal fatty acid esters remains to be elucidated. In theory, the hormonal esters might form a reservoir constituted by esterified hormones stored in lipoprotein particles and perhaps in fat tissue, or they might use lipoproteins as vehicles for endocrine transport, or they could act as antioxidant protection of the lipoprotein particles. Enzyme systems necessary for the formation of lipophilic oestrogen and phytoestrogen derivatives as well as for their incorporation in lipoprotein particles are present in human body fluids. Because of their water-insolubility, steroid fatty acid esters are carried exclusively by circulating lipoproteins. These esters can provide antioxidant protection for lipoprotein particles.

Chromatography↗
PubMed2001

Effect of a diet based on low-fat foods enriched with nonesterified plant sterols and mineral nutrients on serum cholesterol.

Plant sterols have been incorporated into nutritional fats to achieve cholesterol lowering, but studies using enrichment of low-fat foods with plant sterols have not been reported. Our study was aimed at determining the effect of dietary intake of low-fat foods containing natural nonesterified plant sterols together with recommended doses of calcium, magnesium, and potassium on serum cholesterol and low-density lipoprotein (LDL) cholesterol-lowering in persons with mild to moderate hypercholesterolemia. This was a randomized, double-blind, placebo-controlled feeding trial lasting 15 weeks and performed in 2 university hospital centers. Seventy-eight subjects aged 25 to 75 years with serum cholesterol concentrations varying between 6 mmol/L (232 mg/dl) and 8 mmol/L (310 mg/dl) were randomly allocated to active treatment consisting of intake of bread, meat products, and jam enriched with 1.25 to 5.0 g/day of plant sterols and the slightly elevated concentrations of mineral nutrients, or the corresponding placebo food items. Serum lipid, high-density lipoprotein cholesterol and calculated LDL cholesterol concentrations were determined. Seventy-one persons completed the trial. Reduction in serum total cholesterol was 8% in the active treatment group and 3% in the placebo group (p = 0.0071) and that of LDL cholesterol was 13% in the active treatment group and 5% in the placebo group (p = 0.0070). In conclusion, natural nonesterified plant sterols contained in low-fat food items and ingested in moderate doses reduced serum total and LDL cholesterol concentrations to the same extent as reported previously for esterified plant sterol derivatives added to nutritional fats. The presence of mineral nutrients in doses recommended for blood pressure-lowering did not interfere with the cholesterol-lowering efficacy of the sterols, providing a promising approach to dietary prevention of cardiovascular diseases.

Adult↗
PubMed2001

Accumulation of high-density lipoprotein-derived estradiol-17beta fatty acid esters in low-density lipoprotein particles.

Estrogens are known to be powerful antioxidants in lipid-aqueous systems, as demonstrated by their inhibition of low-density lipoprotein (LDL) oxidation in vitro. Studies reporting that endogenous human estrogens could be rendered fat-soluble by esterification with fatty acids in vivo, and the subsequent detection of such esters in blood and fat tissue suggested a possible mechanism explaining how estrogens might protect LDL. Because of their lipophilicity, esterified estrogens may become incorporated in the lipoprotein structure, providing antioxidant potential for the particles. We incubated labeled 17beta-estradiol with ovarian follicular fluid and with plasma in the absence and presence of the LCAT inhibitor DTNB. This was followed by ultracentrifugal isolation of LDL and high-density lipoprotein and analysis of the radioactive label in the "ester" and "free" fractions purified from these lipoproteins. The results indicated that LCAT-mediated synthesis of esterified 17beta-estradiol occurred in high-density lipoprotein particles, and suggested a novel cholesterol ester transfer protein-mediated mechanism for their transfer to LDL particles.

Carrier Proteins↗
PubMed2001

Quantitative determination of estradiol fatty acid esters in human pregnancy serum and ovarian follicular fluid.

BACKGROUND: Lipophilic estradiol derivatives carried by lipoprotein particles in blood may mediate antioxidant or endocrine effects. We developed a new quantitative method to determine the concentration of circulating lipophilic estradiol fatty acid esters in human early- and late-pregnancy serum and in ovarian follicular fluid. METHODS: After extraction from serum or follicular fluid, estradiol fatty acid esters were separated from nonesterified estradiol by Sephadex LH-20 column chromatography. The estradiol ester fraction was hydrolyzed by saponification and further purified by several chromatographic steps. The hydrolyzed estradiol esters were measured by time-resolved fluoroimmunoassay. RESULTS: The average estradiol fatty acid ester concentration in serum increased 10-fold during pregnancy, from 40.4 pmol/L (expressed as pmol/L estradiol; range, 25.0-64.2 pmol/L) in early pregnancy (n = 8) to 404 pmol/L (196-731 pmol/L) in late pregnancy (n = 10). The ratio of estradiol ester to nonesterified estradiol remained relatively constant during pregnancy, at 0.4-0.6%. In 10 follicular fluid samples, the mean estradiol ester concentration was 106 nmol/L (56.9-262 nmol/L). Compared with serum, a greater proportion of estradiol in follicular fluid (3.0-10%) was in the esterified form. CONCLUSION: The new method provides a means to measure circulating estradiol fatty acid ester concentrations in human pregnancy serum.

Esters↗
PubMed2000

Dietary soy-derived isoflavone phytoestrogens. Could they have a role in coronary heart disease prevention?

Soy protein-containing foods are a rich source of isoflavone phytoestrogens, such as genistein and daidzein. There is great interest in these substances, as lower rates of chronic diseases, including coronary heart disease, have been associated with high dietary intake of soy-containing foods. Soy phytoestrogens bind weakly to estrogen receptors, and some bind more strongly to estrogen receptor-beta compared with estrogen receptor-alpha. A meta-analysis has indicated that isoflavone phytoestrogens lowered plasma cholesterol concentrations in subjects with initially elevated levels, but had little effect in subjects with normal cholesterol concentrations. These substances reportedly may also have beneficial effects on arterial endothelial function. In addition to these potentially antiatherogenic effects, many laboratories are investigating other possible mechanisms, including antioxidative and antiproliferative properties of these substances. We have shown that dietary supplementation with soy-derived isoflavones reduced the in vitro oxidation susceptibility of low-density lipoprotein (LDL). To further explore this phenomenon, we incorporated genistein and daidzein into LDL molecules in vitro with the aid of an artificial transfer system. However, it was necessary to convert the isoflavone molecules to fat-soluble derivatives, fatty acid esters (analogous to esterified endogenous estrogens, which are known to occur in vivo), to achieve significant incorporation. The LDLs containing esterified isoflavones were shown to be less susceptible to oxidation in vitro than native LDL. We also employed U937 cell cultures for investigating the effects of isoflavone-containing LDLs on cell proliferation. Some of these LDLs exhibited antiproliferative effects in cultured U937 cells. In summary, lipophilic phytoestrogen derivatives could be incorporated into LDLs, increasing their oxidation resistance and antiproliferative efficacy ex vivo, both of which are, in theory, antiatherogenic effects. Further studies are needed to assess to what extent analogous effects could be produced in vivo and whether such substances have a role in hormone replacement and coronary heart disease prevention in postmenopausal women.

Antioxidants↗
PubMed2000

Oxidized LDL from subjects with different dietary habits modifies atherogenic processes in endothelial and smooth muscle cells.

Low-density lipoprotein (LDL) activates a number of processes involved in atherogenesis and vasoconstriction. Evidence suggests that oxidation increases the atherogenicity of LDL. We investigated the effects of oxidized LDL (ox-LDL) on cytotoxicity, prostacyclin (PGI2), and cyclic guanosine-3',5'-monophosphate (cGMP) production in rat vascular smooth muscle cell (VSMC) and rat heart endothelial cell (EC) culture, as well as EC- and VSMC-mediated LDL oxidation. Native LDL (n-LDL) was isolated from subjects on three long-term diets with differing fatty acid content (control diet rich in saturated fat and vegetarian and fish diets). The Cu2+-catalyzed oxidation of n-LDL was monitored using conjugated diene formation and stopped at various time points to achieve 20%, 45%, 70%, and 100% levels of ox-LDL. The lag phase of oxidation by Cu2+ was shortest and thiobarbituric acid-reactive substance (TBARS) formation by VSMC-mediated oxidation was highest with n-LDL obtained from the fish diet group. There were no differences between the ox-LDLs obtained from the different diet groups in their cytotoxicity in EC culture. The degree of oxidation did not influence LDL cytotoxicity. In VSMC culture PGI2 production was increased by ox-LDLs from all diet groups. In EC culture only the extensively oxidized LDLs obtained from the vegetarian diet group were able to induce PGI2 production. The LDLs did not affect basal cGMP production in either EC or VSMC culture.

Adult↗
PubMed2000

Expression of low and high density lipoprotein receptor genes in human adrenals.

Corticosteroids are synthesized from cholesterol which may arise from de novo synthesis or from the uptake of low or high density lipoproteins (LDL or HDL). In the present study, we compared the expression and regulation patterns of LDL receptor and CLA-1 (CD36 and LIMPII Analogous-1, an HDL receptor) genes in adult human adrenocortical tissues to shed more light on the relative contribution of LDL and HDL in human adrenal steroidogenesis. By screening 64 normal and pathological adrenal samples by Northern blotting, we found a positive correlation between LDL receptor and CLA-1 mRNA expression in the adrenal tissues (r=0.547; spearman rank correlation test P<0.01). Adrenal tissues adjacent to Cushing's adenomas contained consistently less LDL receptor and CLA-1 mRNA than normal adrenals (Mann-Whitney P<0.05). In primary cultures of normal adrenal cells, accumulation of both LDL receptor and CLA-1 mRNAs was upregulated by ACTH in a dose- and time-dependent manner, with an earlier induction of LDL receptor than CLA-1 mRNA expression. (Bu)(2)cAMP also increased the levels of these two mRNAs. Addition of LDL, but not HDL, into the culture medium increased cortisol production in untreated adrenocortical cells. Both LDL and HDL enhanced ACTH-induced cortisol production, with the effect of LDL much stronger than that of HDL. Our data show that LDL receptor and CLA-1's expression is ACTH-dependent and occurs in parallel in human adrenal tissues. LDL rather than HDL may be used as the preferential source of cholesterol for steroidogenesis in human adult adrenocortical cells.

Adrenal Glands↗
PubMed2000

Associations between change in C-reactive protein and serum lipids during statin treatment.

Hypolipidaemic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment reduces cardiovascular risk and is also associated with the reduction of C-reactive protein (CRP) concentrations. However, there is scant data concerning the relationship between CRP and lipid changes during statin treatment. We studied 60 hypercholesterolaemic coronary patients who participated in the Treat to Target (3T) study comparing atorvastatin and simvastatin. Serum lipids and CRP (with a sensitive method) were measured before treatment at baseline and after 12 months of statin treatment. Low-density lipoprotein (LDL) cholesterol was substantially decreased and high-density lipoprotein (HDL) cholesterol increased during statin treatment. CRP decreased significantly (sign test P = 0.03) during treatment, and the changes of CRP were significantly associated with changes in HDL cholesterol (r = -0.45; P < 0.001) and apolipoprotein A1 (r = -0.40; P < 0.001) but not with changes in LDL cholesterol or triglycerides. The change in HDL cholesterol explained 20% of the change in CRP during statin treatment. The results are in line with previous suggestions that HDL has anti-inflammatory properties.

Anticholesteremic Agents↗
PubMed2000

A long-term fish diet modifies the toxic properties of human partially oxidized LDL on vascular preparations in vitro.

Both LDL oxidation and LDL fatty acid composition affect vascular relaxation and contraction. The aim of this study was to investigate whether long-lasting dietary habits (vegetarian, fish and high saturated fat as a control group) can change those properties of partially oxidized LDL (ox-LDL) which are reflected in altered vascular responses measured with a bioassay. The effects of ox-LDL were investigated on rat mesenteric arteries. In endothelium intact arterial rings the contractile responses to noradrenaline (NA) tended to be diminished in the presence of ox-LDL derived from the fish diet group compared with the other groups. In the endothelium denuded arterial rings the contractile responses to NA and KCl were significantly enhanced by ox-LDL from the fish diet group compared with the control group. The ox-LDL from the fish diet group increased the diclofenac, L-NAME resistant relaxations to ACh compared to the control diet group suggesting the role of endothelium derived hyperpolarizing factor (EDHF). In conclusion, partially oxidized LDL from subjects living on a fish diet is biologically more vasoactive in bioassay systems than partially oxidized LDL from those living on vegetarian or saturated fatty acid containing diets. The impaired responses in vasoconstriction and improved vasodilation seem to be endothelium dependent.

Acetylcholine↗
PubMed2000

Dietary fatty acid composition influences the degree of human LDL oxidation, but has only minor effects on vascular tone in a bioassay system.

BACKGROUND AND AIM: Oxidized LDL has been detected in atherosclerotic vessels and presumed to be one of the major risk factors in atherosclerosis and cardiovascular diseases. The aims of the present study were to clarify whether the oxidation degree of LDL influences arterial tone and whether different long-lasting dietary habits have effects on biological variables. METHODS AND RESULTS: The lag phase of LDL oxidation was shorter (117 +/- 6 min) in the fish diet group than in the vegetarian (153 +/- 5 min) or the control diet group (152 +/- 10 min). The rat mesenteric arterial rings, which were preincubated with LDL oxidized to 1-30%, from the vegetarian and the fish diet groups showed (p < 0.05) decreased NA-induced maximal contraction forces when compared to the control diet. The LDL oxidation degrees of 31-60% and 61-90% had no effect on NA- and KCl-induced maximal contraction forces when compared to native LDL, nor were there differences between the diet groups. Endothelium-dependent and independent relaxation responses behaved similarly in all groups and were independent of the degree of oxidation. CONCLUSIONS: Dietary habits change the fatty acid composition of LDL, but have only minor effects on the vasoactive properties of oxidized LDL.

Adult↗
PubMed1999

Antioxidant protection of lipoproteins containing estrogens: in vitro evidence for low- and high-density lipoproteins as estrogen carriers.

Some recent studies have reported that low-density lipoprotein (LDL) isolated from estrogen-treated postmenopausal women exhibited increased oxidation resistance ex vivo. However, the underlying mechanisms responsible for this effect are not clear. We explored the possibility that lipophilic derivatives of 17beta-estradiol (E(2)) could be incorporated into LDL and high-density lipoprotein (HDL) particles inhibiting lipoprotein oxidation. Introduction of small amounts of esterified E(2) into lipoproteins by means of incubation of free E(2) and E(2) 17-stearate in plasma did not result in any antioxidant effect. Using an artificial transfer system (Celite dispersion), larger amounts of E(2) esters could be incorporated into lipoproteins. Concentrations ranging between 0.27 and 1.38 molecules/LDL particle for E(2) 17-stearate and between 0.36 and 1.93 molecules/LDL particle for E(2) 17-oleate resulted in increased Cu(2+)-induced oxidation resistance of LDL as indicated by statistically significant lag time prolongations. Significant prolongations of lag times were also observed for HDL following incorporation of E(2) esters using Celite as transfer system. Our results suggest that free E(2) can be esterified and incorporated into lipoproteins during incubation in plasma. However, incorporation of supraphysiologic concentrations of E(2) esters into lipoproteins by means of the artificial transfer system was required in order to reduce their oxidation susceptibility.

Adult↗