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)

Experimental evidence confirms that the matrix metalloproteinases (MMPs) play a fundamental role in a wide variety of pathologic conditions that involve connective tissue destruction including osteoarthritis and rheumatoid arthritis, tumor metastasis and angiogenesis, corneal ulceration, multiple sclerosis, periodontal disease, and atherosclerosis. Modulation of MMP regulation is possible at several biochemical sites, but direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention. Hypotheses concerning inhibition of specific MMP(s) with respect to disease target and/or side-effect profile have emerged. Examples are presented of recent advances in medicinal chemistry approaches to the design of matrix metalloproteinase inhibitors (MMPIs), approaches that address structural requirements and that influence potency, selectivity, and bioavailability. Two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: (1) the invention of alternatives to hydroxamic acid zinc chelators and (2) the construction of nonpeptide scaffolds. One current example in each of these two approaches from our own work is described.
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PMID:Design and synthetic considerations of matrix metalloproteinase inhibitors. 1041 20

Quality and number of subjects in blinded controlled clinical trials about the nutrition and dietary supplements discussed here is variable. Glucosamine sulfate and chondroitin sulfate have sufficient controlled trials to warrant their use in osteoarthritis, having less side effects than currently used nonsteroidal anti-inflammatory drugs, and are the only treatment shown to prevent progression of the disease. Dietary supplements of ephedrine plus caffeine for weight loss (weight loss being the current first line recommendation of physicians for osteoporosis) show some promise, but are not sufficient in number of study subjects. Phenylpropanolamine is proven successful in weight loss. Both ephedrine and phenylpropanolamine have resulted in deaths and hence are worrisome [table: see text] as an over-the-counter dietary supplement. Other commonly used weight loss supplements like Cola acuminata, dwarf elder, Yohimbine, and Garcinia camborgia are either lacking controlled clinical trials, or in the case of the last two supplements, have clinical trials showing lack of effectiveness (although Garcinia has been successful in trials as part of a mixture with other substances, it is unclear if it was a necessary part of the mixture). Safety of these weight loss supplements is unknown. Chromium as a body building supplement for athletes appears to have no efficacy. Creatine may help more in weight lifting than sprinting, but insufficient study subjects and safety information make more studies necessary. Carbohydrate loading is used commonly before endurance competitions, but may be underused as it may be beneficial for other sport performances. Supplements for muscle injury or cramps have had too few studies to determine efficacy. Although proper rehydration with fluids and electrolytes is necessary, a paucity of actual studies to maximize prophylactic treatment for exercise induced cramping still exists. Nutritional supplements for cardiovascular disorders are generally geared to prevention. The United States Department of Agriculture has good recommendations to prevent atherosclerosis; a stricter version by Ornish was shown to reverse coronary heart disease, and the low meat, high fruit, and vegetable DASH diet has been found to decrease hypertension. The epidemiologic studies of hyperhomocysteinemia are impressive enough to give folic acid (or vitamin B6 or B12) supplements to those with elevated homocysteine levels and test patients who have a history of atherosclerotic disease, but no controlled clinical trials have been completed. Soluble fiber has several positive studies in reduction of cholesterol levels and generally is accepted. The data on vitamin E are the most confusing. This vitamin was not helpful in cerebrovascular prevention in China and not helpful at relatively small doses (50 mg) in the United States or Finland against major coronary events. Levels of 400 mg appeared to decrease cardiovascular disease in the United States in studies based on reports by patients and in one large clinical trial. Vitamin E also was successful in prevention of restenosis after PTCA in one clinical trial. Both of these clinical trials need to be repeated in other developed country populations. Some nutritional and dietary supplements are justifiably useful at this point in time. Several meet the criteria of a late Phase 3 FDA clinical trial (where it would be released for public use), but many dietary supplements have insufficient numbers of studies. Some deaths also have occurred with some supplements. If these supplements were required to undergo clinical trials necessary for a new drug by the FDA, they would not be released yet to the public. Several nontoxic supplements appear promising, though need further study. Because they have essentially no toxicity (such as folic acid with B12, soluble fiber, and vitamin E) and may have efficacy, some of these supplementations may be useful now, without randomized clinical trials.
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PMID:Nutrition and dietary supplements. 1051 85

Cell senescence limits cell divisions in normal somatic cells and may play a central role in age-related diseases. In this review, we examine the theory that cell senescence underlies and is a pivotal event in human aging and age-related diseases. The model remains completely consistent with what we currently know of cell biology, cell senescence, and the pathology of all human age-related diseases including atherosclerosis, osteoarthritis, immune senescence, skin aging, Alzheimer's dementia, and cancer. Although there is in vitro and ex vivo data to support the model, there is currently no in vivo data supporting the theory. Such data is probably obtainable using available methods and, if confirmatory, would not only have stunning therapeutic consequences, but significant commercial consequences as well.
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PMID:Cell senescence in human aging: a review of the theory. 1075 58

Paracetamol (acetaminophen) is one of the most widely used of all drugs, with a wealth of experience clearly establishing it as the standard antipyretic and analgesic for mild to moderate pain states. First used clinically by von Mering in 1893, paracetamol did not appear commercially until 1950 in the United States and 1956 in Australia. During the 1960s and 1970s, increasing concern was raised about the toxicity of nonprescription analgesics, but in normal use paracetamol exhibited a consistent safety profile. Its exemplary safety record was marred by the discovery in 1966 that a major overdose could be complicated by severe and sometimes fatal liver damage. Fortunately, early treatment with N-acetylcysteine prevents liver toxicity. A turning point in the choice of pediatric analgesic came in the 1980s when aspirin was linked to Reye's syndrome. As a consequence, paracetamol became the mainstay analgesic and antipyretic for children with a subsequent reduction in the incidence of Reye's syndrome. Currently, paracetamol is a first-line choice for pain management and antipyresis in a variety of patients, including children, pregnant women, the elderly, those with osteoarthritis, simple headaches, and those with noninflammatory musculoskeletal conditions. With proper use, paracetamol seldom causes adverse events and reports of serious side effects are rare. It has a broad tolerability and is of particular value in the treatment of patients in whom nonsteroidal anti-inflammatory drugs are contraindicated such as aspirin-sensitive asthmatics and people at risk of gastrointestinal complications. In the future, a better insight into the mechanism of action of paracetamol may be gained from a fuller understanding of the cyclooxygenase enzymes. In the meantime, paracetamol may find applications in other therapeutic areas, such as the prevention of atherosclerosis via a potential antioxidant activity. In summary, although it is more than a century since the first clinical use of paracetamol, it continues to be a first-line therapy of choice in adults and children with fever and pain. In addition, current research suggests that paracetamol may have a much broader clinical utility in years to come.
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PMID:Paracetamol: past, present, and future. 1131 82

An indirect competition immunoassay for the quantification of YKL-40 (cartilage gp-39, Chondrex) in guinea pig serum has been developed using egg yolk antibodies (IgY). The immune response of hens to YKL-40 was verified by immunoblot analyses. Highly specific antibodies were obtained 30 days after the first injection. The ELISA was developed in 96-well microtiter plates with quadruplicate determinations for each point. The assay was based on the ability of YKL-40 present in serum to displace the binding of antibodies to the coated antigen. An inhibition mixture containing standard YKL-40 or guinea pig serum, diluted 1/5, and primary antibodies, diluted 1/5000, was allowed to equilibrate for 2 h at room temperature and dispensed for 16 h at 4 degrees C in wells coated with 1 microg/ml of YKL-40. Detection was achieved by the addition of rabbit anti-chicken antibodies conjugated to peroxidase followed by tetramethylbenzidine. Specificity was assessed by parallelism between a dilution curve of serum and standard YKL-40. The sensitivity of detection was 10 ng/ml. Intra- and interassay coefficients of variation were both 8.7%. The analytical recovery was 101.5+/-5.4% (mean+/-standard deviation (SD), n=9). The YKL-40 concentration in serum from 12 adult guinea pigs was 330+/-216 ng/ml (mean+/-SD) with a lower value of 164 ng/ml and an upper value of 982 ng/ml. In contrast to the rat, a dilution curve of rabbit serum gave parallelism with the guinea pig standard, suggesting recognition of a similar epitope. Possible applications of the assay in the guinea pig include disease models where YKL-40 is overexpressed and could be used as a marker, i.e. osteoarthritis, rheumatoid arthritis, cancer, liver fibrosis, atherosclerosis and more generally, pathologies with increased tissue remodeling.
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PMID:Development of an enzyme-linked immunoassay for the quantification of YKL-40 (cartilage gp-39) in guinea pig serum using hen egg yolk antibodies. 1133 75

Extravascular coagulation and diminished fibrinolysis are processes that contribute to the pathology of both inflammatory arthritis and atherosclerosis. We hypothesized that, given its homology with plasminogen, apolipoprotein (apo) (a), the distinctive glycoprotein of the atherogenic lipoprotein (Lp) (a), may be equally implicated in inflammatory arthritis. We detected the presence of apo(a) as part of Lp(a) in human arthritic synovial fluid. The abundance of apo(a) in synovial fluid rose in proportion to plasma apo(a) levels and was higher in inflammatory arthritides than in osteoarthritis. In addition, apo(a) immunoreactive material, but not apo(a) transcripts, was detected in inflammatory arthritic synovial tissues. These data indicated that synovial fluid apo(a) originates from circulating Lp(a) and that diffusion of Lp(a) through synovial tissue is facilitated in inflammatory types of arthritis. In synovial tissues, apo(a) co-localized with fibrin. These observations could be reproduced in a model of antigen-induced arthritis, using transgenic mice expressing human Lp(a). Although in this mouse model the presence of apo(a) did not change the severity of arthritis, the co-localization of apo(a) with fibrin in synovial tissue suggests that, in humans, apo(a) may modulate locally the fibrinolytic activity and may thus contribute to the persistence of intra-articular fibrin in inflammatory arthritis.
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PMID:Plasma apolipoprotein(a) co-deposits with fibrin in inflammatory arthritic joints. 1158 72

Interleukin-1 (IL-1) is involved in a broad range of biological activities that affect immunological, inflammatory, and nonimmunological responses. Although the role of the IL-1 proteins in normal physiological responses in vivo remains incompletely defined, there is substantial evidence that excessive production of IL-1 contributes to the pathogenesis of many illnesses with autoimmune or inflammatory components, including rheumatoid and osteoarthritis, type I diabetes mellitus and atherosclerosis. Despite numerous reports on IL-1 regulation, very little is known regarding the molecular details of IL-1 production, particularly at the transcription level. This review will focus on our studies of transcriptional regulation of the murine IL-1beta gene and, where appropriate, comparison to similar studies of the human IL-1beta gene. A basic understanding at this level should lead to effective pharmacological intervention and, ultimately, to control of inflammatory disease.
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PMID:Molecular Dissection of the Murine IL-1beta Promoter. 1185 46

Chondroitin sulfate (CS) used for treatment of osteoarthritis exerts distinct effects on human articular chondrocytes in vitro. We performed a binding analysis with 99mTc-labeled CS (Condrosulf, a commercial CS preparation containing calcium stearate) and cultured human chondrocytes in order to evaluate the presence of specific receptors. Saturation binding at 37 degrees C for 2 h revealed the presence of high-affinity binding sites for CS with a Kd of 2.3 x 10(-9) mol/L and a Bmax of 5.0 x 10(8). Extensive dialysis of Chondrosulf led to a decrease of the binding affinity by 52.5 +/- 19.5% and of the number of CS binding sites/cell by 62.0 +/- 14.0%, demonstrating that the additive present in the Condrosulf preparation enhances CS binding. The nature of the binding site is not yet known but evidence exists in the literature that the scavenger receptor CD36, thoroughly investigated on macrophages, is also found on chondrocytes and might be involved in CS binding. Therefore, we undertook a comparative binding study with human monocytes and labelled LDL and oxidized LDL, the latter being a postulated atherogenic agent in atherosclerosis. For [125I]-LDL binding we found a Kd of 0.45 x 10(-8) mol/L and a Bmax of 0.14 x 10(6) on quiescent monocytes and for [125I]-(ox)LDL binding a Kd of 1.8 x 10(-8) mol/L and a Bmax of 1.3 x 10(6) using LPS-activated monocytes. These data are comparable to the binding affinity found for lipoprotein-proteoglycan-complexes and hence are an indication but not a proof that CD36 is involved in CS binding to human chondrocytes.
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PMID:Binding of [99mTc]chondroitin sulfate to scavenger receptors on human chondrocytes as compared to binding of oxidized [125I]LDL on human macrophages. 1250 34

To understand the potential role of cyclooxygenase (COX) in normal and inflammatory human diseases, we characterized the expression of COX-1 and COX-2 in biopsies of osteoarthritis, atherosclerosis, and cancer. Tissues were prepared for immunohistochemistry by standard methods, and representative cases assayed via Western blot and quantitative RT-PCR. COX-2 was not detected in normal human tissues with few exceptions. Moderate to marked COX-2 was observed in the macula densa (MD) and thick ascending limb (TAL) in human fetal kidneys, but was not detected in neonatal and adult MD and TALs. Low level, constitutive COX-2 was detected in colonic epithelium, peribronchial glands, and pancreatic ductal epithelium. Low to moderate COX-2 was detected basally in the cortex, hippocampus, hypothalamus, and spinal cord, and in reproductive tissues during ovulation, implantation and labor. No COX-2 was detected in the existing vasculature in normal tissues, and was also not expressed throughout the ductus arteriosus. COX-2 was markedly induced in human tissues of osteoarthritis, atherosclerosis and cancer. COX-2 was prominently expressed in the synovium, fibrocartilage of osteophytes, and in the blood vessels in the osteoarthritic (OA) knee joint. COX-2 was also prominently detected in the macrophages/foam cells in atherosclerotic plaques, and in the endothelium overlying and immediately adjacent to the fibrofatty lesion. Moderate- to intense COX-2 expression was consistently observed in the inflammatory cells, neoplastic lesions, and blood vessels in all epithelial-derived human cancers studied. In contrast, COX-1 was relatively ubiquitously observed in both normal and pathophysiological conditions. These data collectively imply COX-2 plays an important role in mediating a variety of inflammatory diseases, and imply COX-2 inhibitors may be effective in the prevention and/or treatment of OA, heart disease, and epithelial cancers.
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PMID:Cyclooxygenase-2 in human pathological disease. 1266 83

The pathogenesis of arterial calcification and chondrocalcinosis has become concurrently illuminated in recent years. For example, both processes occur in chronic inflammation-mediated degenerative diseases associated with aging (including atherosclerosis and osteoarthritis). Both processes are also modulated by altered gene expression by resident cells and by the release of mineralization-competent cell fragments (matrix vesicles and apoptotic bodies). Among the variety of genetic diseases associated with artery calcification are disorders that also promote cartilage calcification and/or dysregulated bone formation. Our discussion highlights that pathologic arterial and articular cartilage calcification both can be owing to genetic deficiencies of calcification inhibitors such as the inorganic pyrophosphate-generating ectoenzyme PC-1/nucleotide pyrophosphatase phosphodiesterase 1. Conversely, pathologic arterial and articular cartilage calcification also can primarily arise as a consequence of active processes driven by inflammatory cytokines and by disordered calcium and inorganic phosphate homeostasis. As discussed in this review, recent developments in the pathogenesis of arterial calcification provide valuable information pertinent to potential future advances in controlling chondrocalcinosis.
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PMID:Parallels between arterial and cartilage calcification: what understanding artery calcification can teach us about chondrocalcinosis. 1270 85


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