Effect of anti-hyperlipidemia drugs on the alpha-tocopherol concentration and their potential for murine malaria infection.

The current preventions of malaria are protection against mosquito bites and taking chemoprophylactic anti-malarial drugs. However, drug therapies are usually associated with adverse events and emergency of drug-resistant malaria parasites. Previous study showed that host plasma alpha-tocopherol deficiency enhanced resistance against malaria infection in mice. Here, we report a new prevention strategy against malaria by using anti-hyperlipidemia drugs, ezetimibe, berberine, cholestyramine, and probucol to modify the host plasma alpha-tocopherol concentration. The drugs were mixed with diet and fed to C57BL/6J mice for 2 weeks. Although all drugs reduced plasma alpha-tocopherol concentration after 2 weeks of feeding, probucol-treated mice showed 90 % reduction and it was the lowest alpha-tocopherol concentration among the four drugs. Ezetimibe, berberine, and combination of ezetimibe and berberine pretreatment for 2 weeks were not effective against infection of Plasmodium yoelii XL17, a lethal strain, for survival and parasitemia in mice. Two-week pretreatment and 1-week treatment after infection of cholestyramine had also no effect on malaria infection. Survival rates of cholestyramine, ezetimibe, and/or berberine treated mice were 0-22 %. However, probucol caused significant decrease in parasitemia and increased in mice survival following 2-week pretreatment and 1-week treatment after infection. All control mice died while all probucol treated mice survived during the course of infection. Thus, probucol which reduced plasma alpha-tocopherol concentration was effective in enhancing the host to resist malaria infection in mice. Our finding indicates that plasma alpha-tocopherol reducing drugs like probucol might be a candidate for beneficial prevention strategy for travelers from malaria-free area.

Excess α-tocopherol decreases extrahepatic phylloquinone in phylloquinone-fed rats but not menaquinone-4 in menaquinone-4-fed rats.

SCOPE: The effects of vitamin E on vitamin K metabolism were elucidated by comparing the effect of tocopherol intake on vitamin K concentrations in rats fed phylloquinone (PK) or menaquinone (MK)-4. METHODS AND RESULTS: Initially, the dietary effect of RRR-α-tocopherol, but not RRR-γ-tocopherol, in decreasing extrahepatic PK concentrations was confirmed. Subsequently, rats were fed a PK or MK-4-containing diet (0.75 mg/kg) with RRR-α-tocopherol (0, 10, 50, or 500 mg/kg) for 6 weeks. In rats fed PK, α-tocopherol consumption decreased PK in kidney, lung, heart, muscle, testis, and brain but not in serum and liver. However, in rats fed MK-4, α-tocopherol consumption did not decrease MK-4 in serum and tissues. Finally, vitamin K- and E-depleted rats were administered PK or MK-4 (0.2 mg) with RRR-α-tocopherol (0, 1, or 10 mg) by gavage. After PK administration, α-tocopherol was observed to decrease PK in kidney, adrenal gland, lung, testis, and brain but not in serum and liver, whereas, after MK-4 administration, α-tocopherol did not affect MK-4 in serum and tissues. CONCLUSION: Excess α-tocopherol decreased extrahepatic PK in rats fed PK but not MK-4 in rats fed MK-4.

Nitrogen-bisphosphonate therapy is linked to compromised coenzyme Q10 and vitamin E status in postmenopausal women.

BACKGROUND: Nitrogen-bisphosphonates (N-BPs) are the most widely used drugs for bone fragility disorders. Long-term or high-dose N-BP use is associated with unusual serious side effects such as osteonecrosis of the jaw, musculoskeletal pain, and atypical fractures of long bones. It has escaped notice that the pathway N-BPs block is central for the endogenous synthesis of coenzyme Q10, an integral enzyme of the mitochondrial respiratory chain and an important lipid-soluble antioxidant. Our objective was to assess the coenzyme Q10 and antioxidant status in relation to N-BP exposure in women with postmenopausal osteoporosis. METHODS: Seventy-one postmenopausal women (age, 73.5 ± 5.5 y) with osteoporosis and no other malignancy were included in this cross-sectional study. Seventeen were treatment naive, 27 were on oral N-BP, and 27 were on i.v. N-BP. RESULTS: Vitamin E γ-tocopherol levels (µmol/mL) were significantly reduced in N-BP users [oral, H(2) = 18.5, P = .02; i.v., H(2) = 25.2, P < .001; mean rank comparisons after Kruskal-Wallis test). Length of time (days) of N-BP exposure, but not age, was inversely associated with the coenzyme Q10/cholesterol ratio (µmol/mol) (ß = -0.27; P = .025), which was particularly low for those on i.v. N-BP (mean difference = -35.0 ± 16.9; 95% confidence interval, -65.2 to -4.9; P = .02). CONCLUSION: The degree of N-BP exposure appears related to compromised coenzyme Q10 status and vitamin E γ-tocopherol levels in postmenopausal women with osteoporosis. This phenomenon may link to certain adverse N-BP-associated effects. Confirmation of this would suggest that therapeutic supplementation could prevent or reverse certain complications of long-term N-BP therapy for at-risk individuals.

Dietary oxidised frying oil causes oxidative damage of pancreatic islets and impairment of insulin secretion, effects associated with vitamin E deficiency.

We previously reported that, in rodents, a diet with a high oxidised frying oil (OFO) content leads to glucose intolerance associated with a reduction in insulin secretion. The present study aimed at investigating the impairment of pancreatic islets caused by dietary OFO. C57BL/6J mice were divided into three groups to receive a low-fat basal diet containing 5 g/100 g of fresh soyabean oil (LF group) or a high-fat diet containing 20 g/100 g of either fresh soyabean oil (HF group) or OFO (HO group). After 8 weeks, mice in the HO group showed glucose intolerance and hypoinsulinaemia, and their islets showed impaired glucose-stimulated insulin secretion (P < 0·05; HO group v. LF and HF groups). Significantly higher oxidative stress and a lower mitochondrial membrane potential were observed in the islets in the HO group compared with the LF and HF groups. Immunoblots showed that the reduction in insulin levels in HO islets was associated with activation of the c-Jun NH2-terminal kinase and a reduction in levels of pancreatic and duodenal homeobox factor-1. In a second study, when dietary OFO-induced tissue vitamin E depletion was prevented by large-dose vitamin E supplementation (500 IU(1·06 mmol all-rac-α-tocopherol acetate)/kg diet; HO+E group), the OFO-mediated reduction in islet size and impairment of glucose tolerance and insulin secretion were significantly attenuated (P < 0·05; HO group v. HO+E group). We conclude that a high level of dietary OFO ingestion impairs glucose metabolism by causing oxidative damage and compromising insulin secretion in pancreatic islets, and that these effects can be prevented by vitamin E supplementation.

[Induction and prevention of kidney injury induced by GSH depletion and vitamin E deficiency in rats].

Four-week-old Wistar male rats were fed a vitamin E (VE)-deficient diet for 8 weeks, followed by intraperitoneal injection of DL-buthionine- [S, R] -sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase, at the dose of 1 mmol/kg body weight. As we reported previously, GSH depletion by administration of BSO induced acute tubular necrosis in the kidney of VE-deficient rats and was accompanied by decrease of renal TBA value and marked increase of renal lipofuscin content. In this study, we examined the effect of administration of AsA or Trolox C on these kidney injuries. AsA or Trolox C treatment increased renal GSH content and inhibited the increase of renal lipofuscin production. The increase of BUN and creatinine levels and LDH activity in the sera of rats administered BSO were inhibited by AsA or Trolox C treatment. AsA treatment completely protected the necrosis of epithelia of proximal renal tubules. These results suggest that GSH has an important role in preventing lipofuscin production through the reaction of lipid peroxides with amino acids. AsA spares GSH indicating that these compounds have similar antioxidant actions and that AsA can serve as an essential antioxidant in the presence of severe GSH deficiency.

Vitamin E is protective against iron toxicity and iron-induced hepatic vitamin E depletion in mice.

This study examined the effect of excess dietary iron on liver function, iron and vitamin E status and the protective activity of vitamin E. Consumption of excess dietary iron (3000, 5000, 8000 mg iron/kg/diet) compared with consumption of the control diet (120 mg iron/kg diet) by weanling male CD-1 mice for 7 wk resulted in accumulation of iron in liver, increased relative liver weights and a reduction in hepatic vitamin E stores. The concentration of vitamin E in the liver was negatively correlated with dietary iron concentration (r = 0.998). Weekly administration of vitamin E (20 mg/kg, subcutaneously) prevented iron-induced liver damage without altering hepatic iron stores. Pretreatment of adult male CD-1 mice with a single subcutaneous dose of vitamin E (20 mg/kg body wt) 24 h prior to a lethal dose of iron (60 mg/kg, intraperitoneally) resulted in 100% protection. A similar dose of vitamin E given 5, 30 or 60 min (intravenously) after iron intoxication enhanced survival to 90, 70 and 80%, respectively, compared with the untreated control group. Vitamin E treatment 30 min after iron intoxication reduced mortality by 75% compared with intravenous treatment with 10 mg/kg of deferoxamine (Desferal). Data in this study indicate that vitamin E may be a useful antidote for iron toxicoses and that iron-induced depletion of vitamin E may play a role in the pathogenesis of iron toxicity.

Amounts of twelve elements required to induce selenium-vitamin E deficiency in ducklings.

Mortality and myopathy of selenium-vitamin E (Se-E) deficiency was produced, in a concentration-dependent pattern, during a 4-week study of 750 ducklings fed a commercial duck starter mash that contained adequate amounts of Se and E, and supplemented with multiple amounts of Ag (50 to 3,000 mg/kg of feed, as acetate), Zn (3,000 to 6,000 mg/kg, as sulfate), Cd (10 to 500 mg/kg, as sulfate), Te (25-500 mg/kg, as tetrachloride), Co (100 to 1,000 mg/kg, as chloride), Cu (500 to 1,500 mg/kg, as sulfate), Hg (200 to 400 mg/kg, as chloride), and Sn (1,000 mg/kg, as chloride). Also, feeding supplements of Pb (500 mg/kg, as acetate), As (600 mg/kg, as sodium arsenilate), Fe (5,000 mg/kg, as sulfate), and S (5,000 mg/kg, as sodium sulfite) produced a low-to-medium frequency of lesions of Se-E deficiency. In ducklings with muscle lesions, the gizzard was most often affected (84.2%), followed in decreasing order by skeletal muscles (69.7%), intestine (34.9%), and heart (23.0%). The frequency of skeletal muscle lesions was high in birds fed Ag, and myocardial necrosis was frequent in ducklings fed Te and Hg. Ducklings affected with myopathy were reluctant to stand. Subcutaneous edema, with or without hemorrhages, and pale areas of myonecrosis in gizzard, skeletal muscles, intestine, and heart were seen at necropsy. Birds fed Te and Hg often had hydropericardium and hemorrhagic myocardial necrosis. Seemingly, addition of many elements to a Se-E adequate commercial diet will increase the requirement for Se-E. In our duckling model, minimal amounts shown to induce Se-E deficiency were 50 mg of Ag/kg, 3,000 mg of Zn/kg, 10 mg of Cd/kg, 25 mg of Te/kg, 1200 mg of Co/kg, 500 mg of Cu/kg, 200 mg of Hg/kg, 1,000 mg of Sn/kg, 500 mg of Pb/kg, 600 mg of As/kg, 5,000 mg of Fe/kg, and 5,000 mg of S/kg.

Induction of lesions of selenium-vitamin E deficiency in ducklings fed silver, copper, cobalt, tellurium, cadmium, or zinc: protection by selenium or vitamin E supplements.

In 3 experiments, 684 newly hatched White Pekin ducklings were fed (for 15 to 28 days) a commercial starter mash that was adequate in selenium and vitamin E (Se-E) content, either alone or with supplements of Ag (3,000 mg/kg of feed, as acetate), Cu (1,500 mg/kg, as sulfate), Co (200 or 500 mg/kg, as chloride), Te (500 mg/kg, as tetrachloride), Cd (100 or 500 mg/kg, as sulfate), Zn (3,000 or 6,000 mg/kg, as sulfate), or V (100 mg/kg, as vanadate). The ducklings fed Ag, Cu, Co, Te, Cd, and Zn frequently developed lesions characteristic of Se-E deficiency, such as necrosis of skeletal and cardiac muscle and of smooth muscle of the gizzard and intestine. Complete protection from the muscle lesions produced by Cu, Co, Te, Cd, and Zn supplements was provided by vitamin E (200 IU of alpha-tocopherol acetate/kg) and Se (2 mg/kg, as selenite). Ducklings fed Ag were protected by supplements of vitamin E and partial protection was achieved by Se addition. The birds fed excessive Zn developed pancreatic necrosis and fibrosis that was not prevented by supplements of Se or vitamin E. Terminally, blood glutathione peroxidase activity was low and hepatic Se concentration was increased in the ducklings fed Ag. However, neither blood glutathione peroxidase activity nor hepatic Se concentrations was consistently abnormal in ducklings fed other trace elements, although lesions of Se-E deficiency were often present in these animals.

Comparison in inducing effect on vitamin E deficiency symptoms in chicks between dilauryl succinate and unsaturated fatty acids.

Dilauryl succinate (DLS) and unsaturated fatty acids (UFA) were compared for the effects of inducing vitamin E deficiency symptoms in chicks. Experimental diets containing DLS, UFA and DLS + UFA, respectively, were given to 1-day-old chicks for 28 days. The diet containing DLS but not UFA showed far less increase in peroxide value than those containing UFA or DLS + UFA when left in a battery brooder of 30 degrees. Vitamin E deficiency symptoms in chicks given DLS + UFA were more severe than those in chicks fed either DLS or UFA. No significant difference in vitamin E deficiency symptoms except incidence of encephalomalacia was observed between the chicks given DLS and UFA. Extracting UFA from the diet containing DLS + UFA resulted in the reduction of vitamin E deficiency induction to the same degree as the diet containing DLS. Synthetic antioxidants were effective in alleviating the vitamin E deficiency symptoms in the chicks fed UFA and DLS + UFA, while only slightly effective in those given DLS. It was found that the effects of DLS and UFA can be separated and combined technically and it was suggested that they have different mechanism in inducing vitamin E deficiency.

Serum vitamin E concentration in patients with severe multiple handicaps treated with anticonvulsants.

Serum vitamin E concentrations were measured in 47 severely handicapped patients, aged from 4 to 23 years, and in 22 controls. Thirty-three of the handicapped patients with seizures were treated with phenytoin and phenobarbital; the remaining 14 patients were not treated. The serum vitamin E levels were lower in the handicapped than in controls. Among the handicapped, those treated with anticonvulsants showed much lower levels of serum vitamin E than those untreated. Ten patients under anticonvulsant therapy were selected to receive d-1-alpha tocopherol acetate, 100 mg/day, based on their low serum vitamin E levels (range of 0.27 to 0.61 mg/100 ml). After one month of tocopherol treatment, both their serum vitamin E levels and hemolysis tests returned to normal. During a three-month tocopherol treatment period, both the frequencies of seizure attacks and the electroencephalogram (EEG) patterns remained unchanged. Supplementation with vitamin E is recommended in some patients under anticonvulsant therapy.

The influence of dietary mackerel oil on the condition of organs and on blood lipid composition in the young growing pig.

A feeding experiment was carried out in which piglets were fed to a diet enriched with either mackerel oil or olive oil. The oil consumption amounted to about 100 g per animal per day. The aim of this experiment was to study the effect of feeding high amounts of fish oil rich in polyunsaturated and long-chain monoenoic acids in order to determine if any morbid changes occurred in the animals as a result of this addition. The piglets fed olive oil served as controls. After 4 weeks, blood hemoglobin, plasma glucose, and serum triglycerides were significantly lower in the mackerel oil group as compared with the control group. There was no difference in serum cholesterol and serum lipid composition. Very low density lipoproteins were lower in the mackerel oil group. The fatty acid composition of blood serum, heart muscle, and liver showed considerable differences, omega3 acids being higher and both omega6 and omega9 acids being lower in the mackerel oil group than in the control group. Some increase in the amount of triglycerides in the heart muscle was observed in the mackerel oil group. Some characteristics of "yellow fat disease" developed in the mackerel oil group. This type of vitamin E deficiency seems to be the result of the considerable amount of omega3 fatty acids present in the mackerel oil. No clinical symptoms due to ingestion of long-chain monoenoic acids were observed.

Red cell metabolic and membrane features in haemolytic anaemia of alcoholic liver disease (Zieve's syndrome).

Zieve's syndrome (ZS), which consists of transient haemolytic anaemia, jaundice, hyperlipoproteinaemia, and alcohol-induced liver disease, was studied in male patients during the acute (n = 20) and the remittent (n = 10) phase. Chronic alcoholics (n = 10) without haemolysis and healthy male persons (n = 10) served as controls. Erythrocytes were separated into old and young cells by means of density-layer centrifugation. Those fractions which contained older red cells disclosed a pyruvate-kinase instability which resulted in impaired metabolism. Changes in membrane lipid composition as indicated by increased cholesterol and polyunsaturated fatty acids (PUFA) were also detected in patients during the acute phase of ZS. Alcohol-induced red-cell vitamin-E deficiency with a decrease in PUFA levels may provoke an oxidation of reduced red-cell glutathione which in turn results in the enzyme instability. This study lends further support to the hypothesis that the putative role of the red-cell metabolic injury in the origin of haemolysis in ZS cannot be envisaged without introducing membrane-linked and extracellular cofactors.

Preventive effect of selenium, methionine and antioxidants against encephalomalacia of chicks induced by dilauryl succinate.

The protective effect of supplemental selenium, methionine, ascorbic acid, menaquinone and five antioxidants against encephalomalacia of chicks fed a diet containing dilauryl succinate was examined. Diauryl succinate induces vitamin E deficiency signs such as fragility of the erythrocytes and encephalomalacia. Supplementation of selenium and methionine with or without simultaneous supplementation of a low level of dl-alpha-tocopheryl acetate had little effect on preventing encephalomalacia. The preventive effect of ascorbic acid, methylene blue, ethoyquine, 2,6-ditertiary-butyl-p-cresol and butylated hydroxyanisole was roughly in proportion to their dietary level, and a high level of any of them could almost completely protect the chicks from encephalomalacia, while diphenyl-p-phenylenediamine was not as effective and the effect was not proportional to the dose. Menaquinone had little effect. No difference was observed in the plasma tocopherol levels and peroxide levels in the adipose tissueof the chick fed eith er dilauryl succinate or cornstarch. The effect of dilauryl succinate appears to be independent of peroxides generated in the chick.

Induction of lesions of selenium-vitamin E deficiency in pigs fed silver.

Four weanling swine fed for 4 weeks a commercial ration adequate in selenium and vitamin E, but supplemented with 0.5% silver acetate, developed lesions typical of selenium-vitamin E deficiency. Clinically, the pigs fed this high level of silver had anorexia, diarrhea, and growth depression; 3 of 4 pigs died. At necropsy, hepatic lesions of hepatosis dietetica were present in 4 of 4 silver-fed pigs, and 1 of 4 pigs had cardiac and skeletal muscle lesions characteristic of selenium-vitamin E deficiency. Development of lesions and mortality was prevented in 2 pigs fed the silver diet supplemented with alpha-tocopherol (100 IU/kg of diet), but not in 2 pigs fed the ration supplemented with selenium as selenite (1 ppm). Four pigs fed a lower dose level of silver (0.2% silver acetate) for 6 weeks failed to develop clinical or pathologic features of selenium-vitamin E deficiency. However, hepatic selenium content was significantly increased in pigs fed the silver-supplemented ration.

Induced exudative diathesis in chicks by dietary silver.

Two experiments were conducted with chicks to compare the effectiveness of vitamin E,selenium and cystine in preventing the deleterious effects of dietary silver. Adding 900 p.p.m. silver to a diet marginal in vitamin E and selenium significantly depressed growth and caused a high mortality during the four-week experiment. Most of the mortality was due to exduative diathesis. Including either 1 p.p.m. selenium or 100 I.U. vitamin E per kg. in the diets with silver prevented the growth depression and mortality. Adding 0.15% cystine stimulated growth, but failed to rpevent mortality. In a second experiment, chicks were grown on the diet containing silver with and without cystine to 15 days of age, at which time approximately 50% of the chicks exhibited signs of exudative diathesis. At that time they were either continued on the same diet of fed diets supplemented with selenium or vitamin E. Both vitamin E and selenium reduced mortality during the following two-week period, but vitamin E. was more effective than selenium.

Precipitation of a selenium deficiency by high dietary levels of copper and zinc.

High mortality and a high incidence of exudative diathesis and muscular dystrophy were observed in chicks fed a diet supplemented with either 800 or 1600 ppm copper. Adding 0.5 ppm selenium to a basal diet containing 0.2 ppm prevented mortality and selenium deficiency signs. Dietary zinc levels of 2100 to 4100 ppm also resulted in high mortality, exudative diathesis, and muscular dystrophy. A selenium supplement of 0.5 ppm completely prevented the deficiency signs and markedly reduced mortality. The results demonstrate that both copper and zinc can induce a selenium deficiency in chicks when a diet relatively low in this element is fed.