Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the 21st century, patients suffering from diabetes mellitus (DM), a lifestyle-related disease, will increase more than in the 20th century. DM is threatening because of the development of many severe secondary complications, including atherosclerosis, microangiopathy, renal dysfunction and failure, cardiac abnormalities, diabetic retinopathy, and ocular disorders. Generally, DM is classified as either insulin-dependent type 1 or noninsulin-dependent type 2 DM. Type 1 DM is treated only by daily insulin injections; type 2 DM is treated by several types of synthetic therapeutic substances together with a controlled diet and physical exercise. Even with these measures, the daily necessity for several insulin injections can be painful both physically and mentally, whereas the synthetic therapeutic substances used over the long term often have side effects. For those reasons, the creation and development of a new class of pharmaceuticals for treatment of DM in the 21st century would be extremely desirable. In the last half of the 20th century, investigations of the relationships among diseases and micronutrients, such as iron, copper, zinc, and selenium, have been numerous. Research into the development of metallopharmaceuticals involving the platinum-containing anticancer drug, cisplatin, and the gold-containing rheumatoid arthritis drug, auranofin, has also been widespread. Such important findings prompted us to develop therapeutic reagents based on a new concept to replace either insulin injections or the use of synthetic drugs. After many trials, we noticed that vanadium might be very useful in the treatment of DM. Before the discovery of insulin by Banting and Best in 1921 and its clinical trial for treating DM, the findings in 1899, in which orally administered sodium vanadate (NaVO(3)) was reported to improve human DM, gave us the idea to use vanadium to treat DM. However, it has taken a long time to obtain a scientific explanation as to why the metal ion exhibits insulin-mimetic or blood-glucose lowering effects in in vitro and in vivo experiments. After investigations from many perspectives involving biochemistry and bioinorganic chemistry, vanadyl sulfate (VOSO(4)) and its complexes with several types of ligands have been proposed as useful for treating DM in experimental diabetic animals. On the basis of a mechanistic study, this article reports on recent progress regarding the development of antidiabetic vanadyl complexes, emphasizing that the vanadyl ion and its complexes are effective not only in treating or relieving both types of DM but also in preventing the onset of DM.
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PMID:A new concept: the use of vanadium complexes in the treatment of diabetes mellitus. 1220 6

Radiation hazards in outer space present an enormous challenge for the biological safety of astronauts. A deleterious effect of radiation is the production of reactive oxygen species, which result in damage to biomolecules (e.g., lipid, protein, amino acids, and DNA). Understanding free radical biology is necessary for designing an optimal nutritional countermeasure against space radiation-induced cytotoxicity. Free radicals (e.g., superoxide, nitric oxide, and hydroxyl radicals) and other reactive species (e.g., hydrogen peroxide, peroxynitrite, and hypochlorous acid) are produced in the body, primarily as a result of aerobic metabolism. Antioxidants (e.g., glutathione, arginine, citrulline, taurine, creatine, selenium, zinc, vitamin E, vitamin C, vitamin A, and tea polyphenols) and antioxidant enzymes (e.g., superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidases) exert synergistic actions in scavenging free radicals. There has been growing evidence over the past three decades showing that malnutrition (e.g., dietary deficiencies of protein, selenium, and zinc) or excess of certain nutrients (e.g., iron and vitamin C) gives rise to the oxidation of biomolecules and cell injury. A large body of the literature supports the notion that dietary antioxidants are useful radioprotectors and play an important role in preventing many human diseases (e.g., cancer, atherosclerosis, stroke, rheumatoid arthritis, neurodegeneration, and diabetes). The knowledge of enzymatic and non-enzymatic oxidative defense mechanisms will serve as a guiding principle for establishing the most effective nutrition support to ensure the biological safety of manned space missions.
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PMID:Free radicals, antioxidants, and nutrition. 1236 82

Universally, the general population is exposed to a variety of "toxic" substances. Some of these are from manufactured goods and some from air and water pollution. Toxins are also normally found in many foods; however, unless the exposure is overwhelming, we are many times (even unknowingly) protected by the foods we eat. A judicious choice of food will counteract noxious agents. Therefore, the diet can be a major factor in determining who does and who does not show toxic symptoms following exposure. This review will cover three aspects. The first will be on protectors against metal toxicity. For example, whereas humans can consume fish that have absorbed mercury from contaminated bay water, selenium can act as a natural antagonist for mercury poisoning. (Naturally, too much selenium itself can be detrimental!) Some vegetables can accumulate cadmium from contaminated soil, and zinc from a variety of nuts is an antagonist of cadmium toxicity. Nitrites in preserved meats can be converted into nitroamines by saliva or mild stomach acid. Vitamin C found in oranges and bell peppers can inhibit that conversion. In addition, calcium antagonizes both lead and aluminum toxicity. The second aspect is on oxidants and antioxidants. Oxidative stress can lead to some cancers, atherosclerosis, and adverse effects of aging. Antioxidants are the best protectors of the damage caused by reactive oxygen species (ROS). The most effective antioxidants are found in highly colored fruits and vegetables such as carrots, tomatoes, and berries, called carotenoids. Flavonoids (polyphenols), another class of effective antioxidants that negate ROS, may or may not be colored. The third aspect is on gaps in current knowledge. Many foods naturally contain chemicals that are, in larger concentrations, quite toxic or carcinogenic. Biotransformations (detoxification mechanisms) involving type I and type II enzymes are known. Some foods do modify these enzymes either positively or negatively. Grapefruit contains a substance that inhibits an isoform of P450, making some cardiac drugs, as substrates, more toxic. There is inadequate information on what specific components are in a variety of foods that are associated with cancer prevention. The experimental carcinogenic compound (and suspected as a human carcinogen) found in overcooked, burnt, and fried meats and fish, namely IQ (2-amino-3-methyl-3H-imidazo[4,5f]quinoline, will be used as a prototype for what needs to be known about foods that will affect toxins.
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PMID:Can nutrition affect chemical toxicity? 1239 88

Selenium is an essential trace element that is an integral part of many proteins, with catalytic and structural functions. The antioxidant properties of some selenoproteins, such as glutathione peroxidase, may be particularly important in carcinogenesis and heart disease. The content of selenium in food depends on the selenium content of the soil where the plants are grown or the animals are raised. Moreover, the metabolism of selenium is determined by its dietary form: some forms are better utilized than others. Therefore, wide variations have been found in selenium status in different parts of the world. In animal studies, selenium deficiency is associated with cardiomyopathy and sudden death, as well as reduced T-cell counts and impaired lymphocyte proliferation and responsiveness. Abnormalities in liver function, brain, heart, striated muscle, pancreas and genital tract have also been reported. In humans, selenium deficiency has been implicated in the etiology of cardiovascular disease and other conditions in which oxidative stress and inflammation are prominent features, but there is still only limited evidence from epidemiological and ecological studies for this, and the therapeutic benefit of selenium administration in the prevention and treatment of cardiovascular diseases remains insufficiently documented. Interventions studies are currently in progress to assess the benefits of selenium supplements in primary and secondary prevention of atherosclerosis. The results to date are inconclusive and further controlled trials are needed.
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PMID:The controversy surrounding selenium and cardiovascular disease: a review of the evidence. 1255 53

Antioxidant effect of a complex preparation including antioxidant vitamins C, E, provitamin A and selenium was studied on the model of Cu(2+)-initiated free-radical oxidation of LDL isolated from human blood plasma. The antioxidant effect of combined administration of alpha-tocopherol+ascorbic acid and alpha-tocopherol+beta-carotene is far more pronounced that the antioxidant effect of individual components of these cocktails. Moreover, in the model system the combined action of all antioxidant components completely inhibited free-radical oxidation of LDL. A 30-day course of peroral administration of antioxidant vitamin cocktail and selenium to rats pronouncedly enhanced the antioxidant potential of liver and completely suppressed free-radical processes in the myocardium. It is suggested that preparations containing antioxidant vitamins and selenium can be perspective for prevention and complex therapy of atherosclerosis.
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PMID:A complex of antioxidant vitamins effectively inhibits free-radical oxidation of LDL phospholipids in blood plasma and membrane structures of the liver and myocardium. 1280 19

Numerous recent investigations on the development and morphology of atherosclerotic lesions have shown programmed cell death or apoptosis to be an important factor in atherogenesis. Enzymes known as caspases are essential for completion of the apoptotic program. With regard to the origin of signals inducing apoptosis, there are two ways of initiating caspase activation: (a) cellular death receptor-mediated activation; and (b) activation mediated by mitochondrial permeability and expression of the p53 oncogene. Both of these pathways are involved in atherogenesis. Oxidative stress, angiotensin II and cholesterol overload are the primary factors that induce apoptosis in vascular cells. Considering apoptosis in endothelial cells, exposed phosphatidylserine on the cell membrane activates thrombin increasing the probability of arterial thromboses. Further progression of atherosclerosis is promoted by the formation of apoptotic bodies with oxidized phospholipids exposed on the membrane; these also activate adhesion of monocytes. Apoptosis of smooth muscle cells is usually observed in the fibrous portion of an atherosclerotic plaque in which the cells produce collagen important for plaque stability. As apoptosis occurs in smooth muscle cells, the fibrous cap grows thinner. This can result in both plaque rupture, formation of thrombi as well as calcification of the plaque from apoptotic smooth muscle cells remnants. Smooth muscle cells apoptosis is beneficial in that it offers protection to the walls of arteries against proliferative restenosis induced by invasive procedures. Apoptosis of macrophages contributes to the formation and progression of the lipidic core and promotes thrombosis of atherosclerosis in damaged arteries. By contrast, apoptosis of macrophages diminishes the production of matrix methaloproteinases that decompose collagen fibers. New facts concerning the effects of antioxidants (selenium, vitamin C and vitamin E), inhibitors of angiotensin converting enzyme, beta-blockers, calcium chanel blockers, and statins are also considered in this review.
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PMID:[Programmed cellular death and atherogenesis: from molecular mechanisms to clinical aspects]. 1282 74

Phospholipid hydroperoxide glutathione peroxidase (GPx4) is the only antioxidant enzyme known to directly reduce phospholipid hydroperoxides within membranes and lipoproteins, acting in conjunction with alpha-tocopherol to inhibit lipid peroxidation. Peroxidation of lipids has been implicated in a number of pathophysiological processes, including inflammation and atherogenesis. We investigated the relative positive and negative effects of specific polyunsaturated fatty acids (PUFAs) and inflammatory cytokines on the activity and gene expression of the selenium-dependant redox enzyme GPx4. In human umbilical vein endothelial cells (HUVEC), GPx4 mRNA levels and activity were increased optimally by 114 nM selenium (as sodium selenite). Docosahexaenoic acid (DHA) and conjugated linoleic acid (CLA) further increased mRNA levels whereas arachidonic acid (ARA) had no effect; enzyme activity was decreased by DHA, was unaffected by CLA or was increased by ARA. GPx4 protein levels increased with selenium, ARA and DHA addition but not with CLA. Interleukin-1beta (IL-1beta) increased GPx4 mRNA, protein and activity whereas TNFalpha at 1 ng/ml increased activity while at 3 ng/ml it reduced activity and mRNA. Conversely, alpha-tocopherol reduced mRNA levels without affecting activity. These results indicate that lipids, cytokines and antioxidants modulate GPx4 in a complex manner that in the presence of adequate selenium, may favour protection against potentially proatherogenic processes.
Atherosclerosis 2003 Nov
PMID:Regulation of selenoprotein GPx4 expression and activity in human endothelial cells by fatty acids, cytokines and antioxidants. 1464 6

The literature data were surveyed to clarify the role of magnesium and potassium in the development of atherosclerosis (AS) in cows and the findings were compared with human data. Special attention was paid to the eastern Finland where AS is very common in humans and absent in the cattle. A hypothesis is proposed that high magnesium and potassium intakes at plant feeding protect from severe AS processes at least in cows in the absence of chronic infections. In about 1500 necropsies in calves and cows on plant feeding, neither antemortem clinical AS symptoms nor postmortal macroscopical AS were detected in the endocardium or in aorta. Also, abattoiries in endemic selenium- and vitamin E-deficient areas report that no macroscopic AS have been found in the inspected more than 400000 slaughtered cattle. In vitamin D(3) poisoned cows AS is readily detected. The milk-fed calves in magnesium deficiency experiments regularly show AS after 3 months of age. Adult ruminating cattle get daily 150-300 g potassium while the need is 35 g. During the indoor feeding period the cows suffered in eastern Finland often from carotene, vitamin E and selenium deficiencies as well as also of energy, protein, phosphorus and zinc deficiencies before grass ensiling feeding started. Endemic goiter prevalence was about 30%. Still such cows did not have AS under such unfavorable conditions. The findings support the hypothesis that the high magnesium and potassium intakes protect cows from AS.
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PMID:Does high plant feed magnesium and potassium protect healthy ruminants from atherosclerosis? A review. 1464

We report here a proteomic analysis of differentially expressed liver proteins of both C57BL/6J (B6, atherosclerosis-susceptible strain) and C3H/HeJ mice (C3H, atherosclerosis-resistant strain), which were fed either control or a high-fat enriched atherogenic diet for eight weeks. We observed differential patterns of plasma lipids between the two strains when both were fed atherogenic diets. That is, although low density lipoprotein cholesterol level was highly elevated in both, the levels of total cholesterol and triglyceride in B6 mice were much lower than those in C3H mice when they were fed atherogenic diets. However, the high density lipoprotein cholesterol level was increased in the latter but decreased in the former. Histopathological observation revealed that more prominent lipid droplets were present in B6 mice than in C3H mice, when they were maintained on the atherogenic diets. Proteomic analysis of liver tissues of these two strains showed that a total of 30 proteins were significantly changed in the livers obtained from both strains after being fed the atherogenic diet. Of these, 14 protein spots including carbonic anhydrase III, senescence marker protein 30 and selenium binding protein 2 were differentially changed only in B6 mice, which was also confirmed in part by Western blotting. An additional 16 protein spots including glutathione S-transferase subclass, apolipoprotein E and chaperonin proteins were changed in both strains. We also identified 28 proteins that were differentially expressed in the livers of both B6 and C3H mice, regardless of diet feeding condition. Of these, 4 protein spots in B6 mice and 11 protein spots in C3H mice were up-regulated. Thirteen strain specific protein spots including antioxidant protein 2, apolipoprotein E and apolipoprotein A-I were also detected in different positions in two-dimensional electrophoresis. These results suggest a clear distinction in differential expression of oxidative stress proteins and lipid metabolism related proteins between the two strains in response to atherogenic diet feeding, which might account for their difference in susceptibility to atherogenesis.
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PMID:Proteomic analysis of diet-induced hypercholesterolemic mice. 1476 Jul 24

Atherosclerosis is a complex process with multiple mechanisms and factors contributing to its initiation and progression. Detection and quantification of coronary artery calcium (CAC) scores with electron beam tomography has been shown to correlate with obstructive and nonobstructive coronary artery disease (CAD). Pathogen-triggered calcification could play a role in CAD. Recent reports suggest that infectious blood nanobacteria (NB) emerge to be such a trigger. So far, minimal or no reversal of atherosclerosis has been claimed by therapies with iv ethylenediaminetetraacetic acid disodium salt (EDTA), antibiotics, or other regimens, and therapies for atherosclerosis remain non-curative. We have now combined EDTA with antibiotic tetracycline (comET), an in vitro proven nanobacteriocidal treatment, and tested comET therapy in patients with documented CAD. Three hypotheses were probed: (1) Are NB present in patients with CAD?; (2) Does treatment with comET affect blood NB antigen and serology?; (3) Does a comET decrease CAC scores? One hundred patients with stable CAD and positive CAC scores were enrolled into a 4 month study of comET therapy. ComET therapy is composed of (1) Nutraceutical Powder (Vitamin C, Vitamin B6, Niacin, Folic Acid, Selenium, EDTA, l-Arginine, l-Lysine, l-Ornithine, Bromelain, Trypsin, CoQ10, Grapeseed Extract, Hawthorn Berry, Papain) 5cm(3) taken orally every evening; (2) Tetracycline HCl 500mg taken orally every evening; (3) EDTA 1500mg taken in a rectal suppository base every evening. CAC scoring was repeated at 4 months and serum samples were analyzed for NB antigen and serology at baseline, 2 and 4 months. Complete blood count, metabolic panel, liver function, C-reactive protein (hs-CRP) and lipids were analyzed at baseline and 4 months. Seventy-seven patients completed the study and all patients were positive for NB serology, antigen or both. Responders (n = 44; 57%) had significant decreases in total CAC scores (P = 0.001), the average decrease being 14%. Non-responders (n = 33; 44%) had no change or had increases in CAC scores. Angina was decreased or ablated in 16 of 19 patients (84%). Lipid profiles improved to non-atherogenic direction significantly (P = 0.001), a remarkable finding in a patient group where 86% were on continuous statin medication already before the trial. No adverse physiologic effects were seen in renal, hepatic, or hematopoetic systems. In conclusion, CAC scores decreased during ComET therapy trial in most CAD patients inferring regression of calcified coronary artery plaque volume. The patients tolerated the therapy well and their angina and lipid profiles improved. Further treatment trials for long term therapy with matched controls are warranted.
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PMID:Calcification in coronary artery disease can be reversed by EDTA-tetracycline long-term chemotherapy. 1536 20


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