Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Smoking is the leading preventable cause of illness and premature death in Germany, claiming over 110,000 lives a year because it directly increases the risk of dying from heart disease, stroke, emphysema and a variety of cancers. The overwhelming majority of smokers begin tobacco use before they reach adulthood. Among those young people who smoke, the average age is now 13-14. In Germany, about 39% of male and 31% of female adults (age 18-60 years) continue to smoke, despite information about the unequivocally negative health consequences of smoking. The exact mechanisms of smoking-related vascular disease are not yet known. Smoking causes acute hemodynamic alterations such as increase in heart rate, systematic and coronary vascular resistance, myocardial contractility, and myocardial oxygen demand. These short-term effects could lower the ischemic threshold in smokers with coronary artery disease and contribute to the increased risk for acute cardiovascular events. Endothelial damage is thought to be an initiating event in atherosclerosis and early studies have demonstrated that long-term smoking has direct toxic effects with structural changes of human endothelial cells. Recent research has shown the importance of the functional role of the endothelium in regulating vascular tone, platelet-endothelial interactions, leukocyte adhesion and smooth muscle cell proliferation via synthesis and release of a variety of substances such as nitric oxide. There is strong evidence that smoking leads to endothelial dysfunction mainly by increased inactivation of nitric oxide by oxygen-derived free radicals. Smoking also increases oxidative modification of LDL and is associated with lower HDL plasma levels. Smoking induces a systemic inflammatory response with increased leukocyte count and elevation of the C-reactive protein level. Importantly, the prothrombotic effects of smoking have been repeatedly demonstrated to cause alterations in platelet function, imbalance of antithrombotic vs prothrombotic factors, and decrease of fibrinolytic activity. Given the enormous health hazard of tobacco use, complete abstinence from smoking should be achieved. Smoking cessation counselling should be given to healthy subjects and even more vigorously to patients with manifested disease. Every effort should be undertaken to prevent children and adolescents from starting to smoke. Brief tobacco dependence treatment is effective, and every smoker should be offered at least brief treatment at every office visit. More intensive treatment is more effective in producing long-term abstinence from tobacco. Nicotine replacement therapy (nicotine patches or gum), clinician-delivered social support, and skills training are the three most effective components of smoking cessation treatment. A framework for tobacco control measures is necessary to reduce tobacco consumption and exposure to tobacco smoke. Recommendations on specific tobacco control interventions are: 1. increase in tobacco taxes; 2. comprehensive tobacco advertising bans; 3. legislation prohibiting smoking in work and public places; 4. prohibiting the sales of tobacco products to persons under 18; 5. comprehensive disclosure of the physical, chemical and design characteristics of all tobacco products; 6. training of health professionals to promote smoking prevention and cessation interventions; and 7. development of a national network of smoking cessation treatment services.
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PMID:[Prevention of coronary heart disease: smoking]. 1625 91

Fibroblast growth factor 23 null mice (Fgf-23-/-) have a short lifespan and show numerous biochemical and morphological features consistent with premature aging-like phenotypes, including kyphosis, severe muscle wasting, hypogonadism, osteopenia, emphysema, uncoordinated movement, T cell dysregulation, and atrophy of the intestinal villi, skin, thymus, and spleen. Furthermore, increased vitamin D activities in homozygous mutants are associated with severe atherosclerosis and widespread soft tissue calcifications; ablation of vitamin D activity from Fgf-23-/- mice, by genetically deleting the 1alpha(OH)ase gene, eliminates atherosclerosis and ectopic calcifications and significantly rescues premature aging-like features of Fgf-23-/- mice, resulting in prolonged survival of Fgf-23-/-/1alpha(OH)ase-/- double mutants. Our results indicate a novel role of Fgf-23 in developing premature aging-like features through regulating vitamin D homeostasis. Finally, our data support a new model of interactions among Fgf-23, vitamin D, and klotho, a gene described as being associated with premature aging process.
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PMID:Premature aging-like phenotype in fibroblast growth factor 23 null mice is a vitamin D-mediated process. 1643 65

Four phosphinic peptide libraries with compounds having the general formula p-Br-Ph-(PO2-CH2)-Xaa'-Yaa'-Zaa'-NH2 have been prepared and screened against 10 matrix metalloproteinases (MMPs). We identified two phosphinic peptides with Ki values of 0.19 and 4.4 nM toward MMP-12 (macrophage elastase) that are more than 2-3 orders of magnitude less potent toward the other MMPs tested. These highly selective MMP-12 inhibitors contain a Glu-Glu motif in their Yaa'-Zaa' positions. Incorporation of this Glu-Glu motif into the sequence of a nonspecific fluorogenic peptide cleaved by MMPs provides a highly selective substrate for MMP-12. A model of one of these inhibitors interacting with MMP-12 suggests that the selectivity observed might be due, in part, to the presence of two unique polar residues in MMP-12, Thr239 and Lys177. These MMP-12-selective inhibitors may have important therapeutic applications to diseases in which MMP-12 has been suggested to play a key role, such as in emphysema, atherosclerosis, and aortic abdominal aneurysm.
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PMID:Development of selective inhibitors and substrate of matrix metalloproteinase-12. 1648 29

Proteolytic degradation of elastic fibers is associated with a broad spectrum of pathological conditions such as atherosclerosis and pulmonary emphysema. We have studied the interaction between elastins and human cysteine cathepsins K, L, and S, which are known to participate in elastinolytic activity in vivo. The enzymes showed distinctive preferences in degrading elastins from bovine neck ligament, aorta, and lung. Different susceptibility of these elastins to proteolysis was attributed to morphological differences observed by scanning electron microscopy. Kinetics of cathepsin binding to the insoluble substrate showed that the process occurs in two steps. The enzyme is initially adsorbed on the elastin surface in a nonproductive manner and then rearranges to form a catalytically competent complex. In contrast, soluble elastin is bound directly in a catalytically productive manner. Studies of enzyme partitioning between the phases showed that cathepsin K favors adsorption on elastin; cathepsin L prefers the aqueous environment, and cathepsin S is equally distributed among both phases. Our results suggest that elastinolysis by cysteine cathepsins proceeds in cycles of enzyme adsorption, binding of a susceptible peptide moiety, hydrolysis, and desorption. Alternatively, the enzyme may also form a new catalytic complex without prior desorption and re-adsorption. In both cases the active center of the enzymes remains at least partly accessible to inhibitors. Elastinolytic activity was readily abolished by cystatins, indicating that, unlike enzymes such as leukocyte elastase, pathological elastinolytic cysteine cathepsins might represent less problematic drug targets. In contrast, thyropins were relatively inefficient in preventing elastinolysis by cysteine cathepsins.
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PMID:Interaction between human cathepsins K, L, and S and elastins: mechanism of elastinolysis and inhibition by macromolecular inhibitors. 1722 55

Suitable mammalian models for aging with a wide range of age-associated pathology are desirable to study molecular mechanisms of human aging. Recent studies have identified that fibroblast growth factor 23 (Fgf-23) null mice and klotho hypomorphs could generate multiple premature aging-like features, including shortened lifespan, infertility, kyphosis, atherosclerosis, extensive soft tissue calcifications, skin atrophy, muscle wasting, T cell dysregulation, pulmonary emphysema, osteoporosis/osteopenia, abnormal mineral ion metabolism, and impaired vitamin-D homeostasis. The strikingly similar in vivo phenotypes of two separate genetically altered mouse lines implicate that the premature aging-like features may be partly regulated through a common signaling pathway involving both Fgf-23 and klotho; such speculation is experimentally supported by the observation that Fgf-23 requires klotho as a cofactor to exert its functions. Despite about 2000-fold higher serum levels of Fgf-23 in klotho mutants (compared to wild-type animals), these mice show physical, biochemical and morphological features similar to Fgf-23 null mice, but not as Fgf-23 transgenic mice; these observations suggest that widely encountered premature aging-like features in klotho mutant mice are due to the inability of Fgf-23 to exert its bioactivities in absence of klotho. The results of recent studies showing klotho as a cofactor in Fgf-23 signaling consequently explains that the premature aging-like features in klotho-deficient mice is not a primary cause, rather a consequence of lacking Fgf-23 activity. These understandings will help us to redefine the role of klotho as an aging factor.
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PMID:Premature aging in klotho mutant mice: cause or consequence? 1735 53

Elastin, one of the extracellular matrix components, is present in tissues requiring extensibility and resilience such as the aorta, lungs, ligaments and skin. Degradation of elastin is observed in diseases such as atherosclerosis, emphysema and metastasis. It has been suggested that degraded elastin-derived peptides interact with a variety of cell types and are involved in development of diseases. Two nonapeptides, Ala-Gly-Val-Pro-Gly-Leu-Gly-Val-Gly (AGVPGFGVG) and Ala-Gly-Val-Pro-Gly-Phe-Gly-Val-Gly (AGVPGFGVG), exist in hydrophobic regions of elastin. In this paper, we characterized these elastin-derived nonapeptides by macrophage migration assay. Both nonapeptides induced a maximal migration at 10(-8) M and elicited the same degree of responsiveness. To investigate the role of the sixth residue of the nonapeptides, seven analog peptides in which Leu or Phe is substituted by Ile, Val, Ala, Gly, Pro, Lys or Glu were synthesized and their macrophage migration activity tested. Among the nonapeptide analogs, only Ala-Gly-Val-Pro-Gly-Ile-Gly-Val-Gly induced the migration of macrophages at the optimal concentration of 10(-9) M and its responsiveness was the same as that of parent nonapeptide AGVPGFGVG. Results of the deactivation tests and the effect of lactose on macrophage migration showed that a lactose-insensitive receptor which mainly recognizes Ala-Gly-Val-Pro-Gly-Ile-Gly-Val-Gly is presumably present on the membrane of macrophages in addition to the elastin-binding protein (EBP) sensitive to lactose. These results suggest that Leu, Phe and Ile residues at the sixth position of elastin-derived nonapeptides are crucial for inducing macrophage migration and in particular, Ile residue is important for the recognition by receptor insensitive to lactose.
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PMID:Induction of macrophage migration through lactose-insensitive receptor by elastin-derived nonapeptides and their analog. 1739 24

Aging is a complex biological process driven by a selective class of molecules and pathways that affect overall deterioration of physiological functions to increase the risk of age-related diseases. A role of vitamin D in mammalian aging is well documented. Since vitamin D has an essential role in bone formation and mineralization, its deficiency results in impaired bone mineralization, such as rickets in children, osteomalacia in adults and osteoporosis in the aged population. Vitamin D replacement therapy therefore is one of the most commonly prescribed treatments for the elderly. Recent studies using genetically altered mouse models, such as in Fgf-23(-/-) and klotho mutant mice, that exhibit altered mineral ion metabolism due to high vitamin D activities showed features of premature aging that include atherosclerosis, emphysema, osteopenia/osteoporosis, hypogonadism, soft tissue calcifications and generalized atrophy of organs; the pathologic effects of vitamin D in these mouse models are obvious, as diminution or genetic ablation of the vitamin D pathway ameliorated most of the above-mentioned phenotypes, by reversing mineral ion metabolism, and the resultant effect being prolonged survival of the mutant mice. These in vivo mouse studies, although subject to further molecular characterization, add new insights into the role of vitamin D in aging.
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PMID:Vitamin D and aging: old concepts and new insights. 1753 60

Macrophage metalloelastase or matrix metalloproteinase-12 (MMP-12) appears to exacerbate atherosclerosis, emphysema, aortic aneurysm, rheumatoid arthritis, and inflammatory bowel disease. An inactivating E219A mutation, validated by crystallography and NMR spectra, prevents autolysis of MMP-12 and allows us to determine its NMR structure without an inhibitor. The structural ensemble of the catalytic domain without an inhibitor is based on 2813 nuclear Overhauser effects (NOEs) and has an average RMSD to the mean structure of 0.25 A for the backbone and 0.61 A for all heavy atoms for residues Trp109-Gly263. Compared to crystal structures of MMP-12, helix B (hB) at the active site is unexpectedly more deeply recessed under the beta-sheet. This opens a pocket between hB and beta-strand IV in the active-site cleft. Both hB and an internal cavity are shifted toward beta-strand I, beta-strand III, and helix A on the back side of the protease. About 25 internal NOE contacts distinguish the inhibitor-free solution structure and indicate hB's greater depth and proximity to the sheet and helix A. Line broadening and multiplicity of amide proton NMR peaks from hB are consistent with hB undergoing a slow conformational exchange among subtly different environments. Inhibitor-binding-induced perturbations of the NMR spectra of MMP-1 and MMP-3 map to similar locations across MMP-12 and encompass the internal conformational adjustments. Evolutionary trace analysis suggests a functionally important network of residues that encompasses most of the locations adjusting in conformation, including 18 residues with NOE contacts unique to inhibitor-free MMP-12. The conformational change, sequence analysis, and inhibitor perturbations of NMR spectra agree on the network they identify between structural scaffold and the active site of MMPs.
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PMID:Solution structure of inhibitor-free human metalloelastase (MMP-12) indicates an internal conformational adjustment. 1799 11

Oxidative stress results from an imbalance, an excess of oxidants, depletion of antioxidants or failure to repair oxidative damage induced by reactive oxygen species. A vast amount of evidence implicates oxygen-derived free radicals and high-energy oxidants as mediators in many pathological conditions of inflammation, shock, and organ responses to ischemia/reperfusion, which arise during a number of clinical surgical interventions, including transplant graft rejection and coronary bypass surgery, and in such diseases as, diabetes, atherosclerosis, hypertension, organ ischemia/reperfusion, cardiovascular inflammation, cardiac/brain infarction, cancer, pulmonary emphysema and autoimmune diseases. To eliminate or attenuate oxidative stress, antioxidant therapies have been developed and may be of great help to these patients. This review describes recent developments in the field of oxidative stress research and antioxidant function, summarizes new pharmacological strategies that are ongoing in antioxidant therapy with small molecules, free radical-scavenging enzymes, superoxide dismutases, catalase mimetics, flavonoids, vitamins and poly polymerase inhibitors, and presents experimental and clinical evidence of the role of antioxidants in diseases.
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PMID:Antioxidant therapy for prevention of inflammation, ischemic reperfusion injuries and allograft rejection. 1822 Jul 19

The discovery that two recently identified molecules, klotho and fibroblast growth factor 23 (FGF23), played an important role in calcium, phosphate, and vitamin D metabolism has transformed our traditional physiological view in which bone and mineral homeostasis was mainly regulated by parathyroid hormone, vitamin D, and calcitonin, according to mineral body needs. FGF23 is a 251-amino acid secreted protein produced by osteoblasts and osteocytes in bone following the stimulation by phosphate and vitamin D or the inhibition by dentin matrix protein 1. Originally isolated from tumoral cells of patients with tumor-induced osteomalacia and hypophosphatemia, FGF23 inhibits phosphate reabsorption in renal proximal tubular cells and 1alpha-hydroxylase activity, resulting in decreased synthesis of calcitriol. To exert these actions, FGF23 requires the conversion, by klotho, of the canonical FGF receptor 1 (IIIc) in a specific high affinity FGF23 receptor. On the other hand, klotho is a putative antiaging gene identified in 1997 when a particular mouse strain, created by random insertion mutagenesis, was found to be short-lived and displayed premature atherosclerosis, osteopenia, skin atrophy, pulmonary emphysema, hyperphosphatemia, hypercalcemia, and high serum calcitriol levels. The gene of klotho encodes a 1012-amino acid cell-surface protein with a short cytoplasmic tail and an extracellular domain that consists in tandem duplicated copies of a beta-glucuronidase-like sequence, which can be released into the circulation as soluble forms after being cleaved by metalloproteinases such as ADAM10 and ADAM17. By modulating FGF23 action, klotho regulates urinary phosphate excretion and calcitriol synthesis. By virtue of its beta-glucuronidase activity, klotho deglycosylates the calcium channel TRPV5 (transient receptor potential vallinoid-5) and regulates urinary calcium excretion. klotho also binds to Na(+),K(+)-ATPase in parathyroid cells and regulates calcium-stimulated PTH secretion. Finally, klotho extends life span via several mechanisms, including the reduction of calcitriol synthesis, serum calcium, and phosphorus levels; the induction of insulin resistance; and by increasing the resistance to oxidative stress.
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PMID:Klotho gene, phosphocalcic metabolism, and survival in dialysis. 1912 71


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