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)

Parathyroid hormone-related peptide (PTHrP) was originally characterized as a tumor product responsible for hypercalcemia of malignancy and was subsequently found to be produced in many normal tissues. PTHrP is now suggested to play a critical role in the local modulation of vascular smooth muscle function. To elucidate the involvement of PTHrP in coronary atherosclerosis, we immunohistochemically examined coronary arteries obtained from 76 patients with various grades of atherosclerosis and compared the correlation between PTHrP staining and the percent stenosis. Smooth muscle cells at sites of coronary atherosclerosis overexpressed PTHrP, while cells from normal coronary arteries did not. The in situ hybridization using PTHrP riboprobe has also proven the overexpression of PTHrPmRNA in the affected lesions following atherectomy. The intensity of PTHrP expression by smooth muscle cells was significantly correlated with the degree of coronary artery stenosis. Coronary arterial PTHrP overexpression is closely related to the severity and/or progression of coronary atherosclerosis.
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PMID:Coronary atherosclerotic smooth muscle cells overexpress human parathyroid hormone-related peptides. 817 78

Epidemiological studies have consistently correlated plasma fibrinogen level to the risk of coronary heart disease (CHD) and acute ischemic stroke. Several mechanisms have been proposed such as the role of fibrinogen in the viscosity of blood, the participation of fibrinogen in both fibrin clot formation and platelet aggregation. However, there is no evidence that the increase in fibrinogen is directly responsible for the vascular disease since the cytokines which participate to the synthesis of fibrinogen by the hepatocytes, such as interleukin 6, could also induce an endothelial cell damage by increasing tumor necrotic factor (TNF) production. In these conditions fibrinogen increase could therefore only represent a marker of cytokine production which in turn is responsible for vascular injury. In addition, for the pathogenesis of atherosclerosis, the influence of fibrinogen is not only mediated by way of increased fibrinogen concentration but could be due to a structurally variant fibrinogen. The recent epidemiological studies have shown that the variation at the beta locus of fibrinogen is associated with an increase risk of peripheral atherosclerosis. The finding concerning dysfibrinogenemia and thrombosis (Dusart and Tampere) create further opportunities to enrich knowledge of the link between the association of abnormal gel structure and thrombotic diseases such as myocardial infarction or stroke at young age. This abnormal clot structure could contribute to thrombogenicity by decreasing the capacity of these clots to be degraded by fibrinolytic enzymes or by decreasing thrombin binding since fibrin is considered as a "thrombin trap".(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Fibrinogen, a vascular risk factor]. 819 48

Endothelium damage is associated with thrombotic risk in a variety of diseases including atherosclerosis, gram negative sepsis, viral infections and neoplastic disease. Therefore, it appears necessary to find a mean for the clinical investigation for such a damage. Among the markers of these cells, thrombomodulin which is a membrane glycoprotein, seems to be of great interest for this purpose. Actually, thrombomodulin is also found in plasma, following an endothelial lesion. Plasma levels of thrombomodulin are increased in a certain number of pathologies associated with endothelium lesion: atheromatous arterial disease, disseminated intravascular coagulation syndrome and also in systemic lupus erythematosus where the levels of plasma thrombomodulin are related to the severity of the pathology. Moreover, previous in vitro studies confirm the fact that the release of thrombomodulin from the endothelial cell membrane occurs during the course of injury by activated leukocytes or hydrogen peroxide. So, one can suppose a prospective interest in the measurement of plasma thrombomodulin as a diagnostic tool for the approach of endothelium damage.
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PMID:Plasma thrombomodulin: new approach of endothelium damage. 820 13

Altered homocysteine metabolism is implicated as a pathogenic factor in atherogenesis, neoplasia, and aging. Hereditary enzymatic deficiencies and nutritional deficiencies of folate, pyridoxine, or cobalamin are associated with elevated blood homocysteine, accelerated atherosclerosis, and manifestations of aging. The failure of malignant cells to metabolize homocysteine thiolactone to sulfate is attributed to deficiency of thioretinaco, a complex containing cobalamin, homocysteine thiolactone, and retinoic acid. The sulfhydryl group of homocysteine is believed to act catalytically with ferric or cupric ions in a mixed function oxidation system to generate hydrogen peroxide, oxygen radicals, and homocysteinyl radicals. These reactive species may interact with the active site of enzyme protein to cause inactivation of catalytic activity. Homocysteine thiolactone is oxidized to sulfate by a process involving ascorbate, thioretinamide, and superoxide, under the control of thyroxine and growth hormone. Thioretinaco is believed to be the active site of adenosine triphosphate (ATP) binding in oxidative phosphorylation with the participation of oxygen, ascorbate, proton gradient, and electron transport. Depletion of thioretinaco from mitochondrial and microsomal membranes may be associated with increased formation and release of radical oxygen species within neoplastic and senescent cells. Specific proposals are made for investigating the importance of homocysteine metabolism in the oxidative modification of proteins and lipids.
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PMID:Homocysteine metabolism and the oxidative modification of proteins and lipids. 832 40

Each cell is functionally restricted by differentiation, which determines its complement of active and inactive genes. Various diseases then become manifest in each cell, depending on these specific gene combinations. Neoplasia, for example, is due to a multistep series of genetic mutations. It is common in continuous replicators such as bronchial epithelium, colon, and marrow but rare in intermittent replicators such as endothelial and smooth muscle cells. In contrast, these latter cell types are centrally involved in degenerative phenomena such as atherosclerosis. However, in both continuous and intermittent replicators, reduction of gratuitous cell turnover will be of great benefit. The nonreplicating adult neuron almost never undergoes tumorigenesis compared with glial cells but gives rise to a variety of age-related degenerative diseases such as Alzheimer's or Parkinson's disease. In the nonreplicating neuron, therefore, it is imperative that we promote strategies to preserve cell viability by minimizing oxidative damage. Natural antioxidants such as vitamin C and E and beta carotene, as well as an optimal caloric and protein intake, should be cornerstones of treatment and prevention for the aging patient. A place for pharmacologic intervention is also likely soon. Current research should soon identify the precise mechanisms responsible for programmed cellular senescence and oxidative cellular damage so as to illuminate additional means of rational treatment, and perhaps more importantly, prevention.
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PMID:The biology of aging: looking to defuse the genetic time bomb. 836 65

Pentoxifylline lowers blood viscosity and increases erythrocyte flexibility in patients with atherosclerosis, thus increasing tissue oxygen delivery. Since tumor neo-vessels are associated with tissue hypoxia, which contributes to failure of radiation therapy, pentoxifylline might also be useful as a radiation sensitizer. Such drugs are often evaluated in the murine model, but serum levels of pentoxifylline and its metabolites have not been determined in the mouse after chronic oral dosing. We investigated this by administering pentoxifylline via liquid diet or solid diet to young adult male CF1 mice for one to six weeks and assaying plasma for the parent drug and its metabolites. At one, three, and six weeks, plasma levels of pentoxifylline and major derivatives were consistently detectable. Mice remained healthy during this period, indicating that ingestion of large amounts of this drug is well tolerated.
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PMID:Serum levels of pentoxifylline and its metabolites in non-tumor-bearing mice after chronic oral pentoxifylline administration. 840 77

A review of the perioperative morbidity and mortality and long-term survival in elderly and high-risk patients with colorectal neoplasia was undertaken. Elderly high-risk patients with localized disease were compared with those with advanced disease. Over a five-year period, 82 high-risk (at least one major organ system disease), or elderly (age > or = 70 years) patients underwent an operation for colorectal neoplasia. Overall, 43 of 82 (52 percent) had advanced disease (obstruction, perforation, hemorrhage, or metastatic disease), while 39 of 82 (48 percent) had localized disease. The mean age of all patients was 78.2 years. Preoperative comorbid diseases included: coronary atherosclerosis, 59 (72 percent); previous myocardial infarction, 17 (21 percent); previous arrhythmia, 10 (12 percent); emphysema, 32 (39 percent); renal failure, 6 (7 percent); and cirrhosis, 3 (4 percent). At the time of surgery, 26 patients (32 percent) had metastatic disease. Six patients (7 percent) died in the perioperative period. The presence of advanced neoplasia did not significantly affect 30-day mortality. There was no difference in major morbidity between patients operated on for localized and for advanced disease. The mean actuarial 18-month survival was less for patients with advanced disease (P < 0.05). Sixty-eight patients (83 percent) are alive at a follow-up of 17.7 +/- 29 months postoperatively. The morbidity and mortality associated with resection of colorectal neoplasia in high-risk elderly patients are acceptable even in the presence of advanced disease. In select patients, resection offers the best palliation and may improve the quality of remaining life.
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PMID:Advanced colorectal neoplasia in the high-risk elderly patient: is surgical resection justified? 842 20

The autoxidation of unsaturated lipids contained in oils, fats, and food and the endogenous oxidative degradation of membrane lipids by lipid peroxidation result in the formation of a very complex mixture of lipid hydroperoxides, chain-cleavage products, and polymeric material. Experimental animal studies and biochemical investigations lend support to the hypothesis that lipid-oxidation products, ingested with food or produced endogenously, represent a health risk. The oral toxicity of oxidized lipids is unexpectedly low. Chronic uptake of large amounts of such materials increases tumor frequency and incidence of atherosclerosis in animals. 4-Hydroxynonenal, a chain-cleavage product resulting from omega 6 fatty acids, disturbs gap-junction communications in cultured endothelial cells and induces several genotoxic effects in hepatocytes and lymphocytes. Although the concentrations of the aldehyde needed to produce these effects are in the range expected to occur in vivo, their pathological significance is far from clear. Recent findings strongly suggest that in vivo modification of low-density lipoprotein by certain lipid-peroxidation products (eg, 4-hydroxynonenal and malonaldehyde) renders this lipoprotein more atherogenic and causes foam-cell formation. Proteins modified by 4-hydroxynonenal and malonaldehyde were detected by immunological techniques in atherosclerotic lesions.
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PMID:Cytotoxicity and genotoxicity of lipid-oxidation products. 847 96

Molecular technologies for the permanent germ-line transformation of animals are now well established and routine. These new strains of animals, called transgenic, offer an unprecedented opportunity to gain a basic understanding of human genetic disorders. In this brief review we discuss the role of transgenic animals in the creation of new models of human disease and their experimental use in biomedical research. Models are now available for the study of the genetic processes involved in the pathogenesis of neoplasia, diabetes, atherosclerosis, and developmental abnormalities. Many others are available and new ones are being produced at a great rate. Principles of gene replacement therapy are amenable to analysis with transgenic animals and the information gained will be important for the development of rational therapy.
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PMID:Exploring pathogenetic mechanisms using transgenic animals. 848 48

Prostatic Intraepithelial Neoplasia (PIN) and prostatic cancer (PCA) are not caused by infection, allergic reaction, inadequate immunological response, ischemia, ageing, systemic hormones, carcinogens, nor prostatic ductal contents. PIN and PCA are apparently caused by increased inner acinar pressure due to partially blocked draining ducts. Only this explanation can account for all the observations about PIN and PCA. All other possible causes are disproved by specific observations. In order to further clarify the cause of PIN and PCA, it is important to discover if peripheral zone lesions cluster around ducts or blood vessels. PIN patterns are the morphological precursors of both PCA and prostatic cysts. Different PIN patterns represent different adaptive stages to increasing inner acinar pressure. The immediate tissue cause of PCA is PIN disruption seeding the stroma with high-grade PIN (HGPIN) cells. These cells, programmed for adaptive proliferation and mobility in PIN, are sufficient in the stroma to cause all stages and patterns of invasive PCA. No mutated cells are necessary. For reasons given, the primary cause of the initial ductal blockage that results in PIN and PCA cannot be inflammation, stones, proteineous plugs, infarction, venus thrombosis, ductal hyperplasia, nor a constricted penis at ejaculation. Only benign prostatic hyperplasia (BPH) can explain all the facts and is thus the primary cause of the ductal blockage resulting in cysts, PIN and PCA. The main causes of BPH are apparently disuse atrophy of sexual and abdominal muscles, and atherosclerosis of the capsular branch of the prostatic artery, causes atypical adenomatous hyperplasia (AAH) in the transition zone. The resulting muscular and glandular atrophy decreases local and general growth inhibitors. New growth in the adult prostate is abnormal because epithelial cells grow into ducts rather into the stroma. In such ducts, the growths cannot receive stromal growth inhibitory signals, and thus continue to grow indefinitely and result in BPH, AAH-adenosis, blockage of ducts, cysts, PIN and PCA.
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PMID:A unifying hypothesis that links benign prostatic hyperplasia and prostatic intraepithelial neoplasia with prostate cancer. Invited comments. 860 75


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