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Biomedical subjects

D Steinberg

Publications and source records attributed to D Steinberg.

At least 145 records · Page 8Linked to original sources
PubMed1991

Fibroblast chemotaxis after tendon repair.

Healing canine flexor tendons were treated with early controlled passive mobilization. The repair site and proximal and distal tendon stumps were stained for fibronectin and examined by light microscopy at three, seven, eleven, and seventeen days. Fibronectin increased dramatically in the epitenon adjacent to the repair site seven days after repair, a time when epitenon cellular activity was at its peak. By seventeen days, fibronectin staining had decreased substantially, both at the repair site and in the tendon stumps. A delayed increase in fibronectin activity was noted in the endotenon adjacent to the repair site. Fibronectin production appears to be an important component of the early tendon repair process. Fibroblast chemotaxis and adherence to the substratum in the days after injury and repair appears to be related directly to fibronectin secretion. This study is the first to provide documentation of fibronectin localization in a clinically relevant tendon repair model.

Animals↗
PubMed1991

Feasibility of using an oleate-rich diet to reduce the susceptibility of low-density lipoprotein to oxidative modification in humans.

Oxidized low-density lipoprotein (LDL) is more atherogenic than native LDL. The initial step in the oxidation is the peroxidation of polyunsaturated fatty acids. Thus, decreasing the concentration of polyunsaturated fatty acids should reduce the susceptibility of LDL to oxidation. Therefore, we tested the possibility that diets enriched in oleate might result in LDL that is less susceptible to oxidative modification. LDL isolated from subjects consuming an oleate-enriched diet, compared with LDL from subjects on a linoleate-enriched diet, contained significantly more oleate (28.7% vs 11.5%) and less linoleate (31.9% vs 50.9%). Generation of conjugated dienes was significantly lower in the LDL from the oleate group. Most important, after incubation with endothelial cells, LDL from the oleate group underwent less degradation by macrophages. These studies demonstrate the feasibility of altering the diet in a way that will not raise LDL cholesterol concentrations and yet will decrease the susceptibility of LDL to oxidative modification.

Adult↗
PubMed1991

Gene expression in macrophage-rich human atherosclerotic lesions. 15-lipoxygenase and acetyl low density lipoprotein receptor messenger RNA colocalize with oxidation specific lipid-protein adducts.

Oxidatively modified low density lipoprotein (LDL) exhibits several potentially atherogenic properties, and inhibition of LDL oxidation in rabbits decreases the rate of the development of atherosclerotic lesions. In vitro studies have suggested that cellular lipoxygenases may be involved in LDL oxidation, and we have shown previously that 15-lipoxygenase and oxidized LDL are present in rabbit atherosclerotic lesions. We now report that epitopes of oxidized LDL are also found in macrophage-rich areas of human fatty streaks as well as in more advanced human atherosclerotic lesions. Using in situ hybridization and immunostaining techniques, we also report that 15-lipoxygenase mRNA and protein colocalize to the same macrophage-rich areas. Moreover, these same lesions express abundant mRNA for the acetyl LDL receptor but no detectable mRNA for the LDL receptor. We suggest that atherogenesis in human arteries may be linked to macrophage-induced oxidative modification of LDL mediated by 15-lipoxygenase, leading to subsequent enhanced macrophage uptake, partly by way of the acetyl LDL receptor.

Arachidonate 15-Lipoxygenase↗
PubMed1991

Role of oxidized low density lipoprotein in atherogenesis.

Evidence to support an important role of oxidative modification in mediating the atherogenicity of LDL continues to grow. New hypotheses suggest mechanisms by which Ox-LDL or products of Ox-LDL can affect many components of the atherogenic process, including vasomotor properties and thrombosis, as well as lesion initiation and progression itself. These ideas suggest new approaches, that in combination with lowering of plasma cholesterol, could lead to the prevention of atherosclerosis and its complications.

Animals↗
PubMed1991

Evidence for a dominant role of lipoxygenase(s) in the oxidation of LDL by mouse peritoneal macrophages.

It has been suggested that the oxidative modification of low density lipoprotein (LDL) is a key event in atherogenesis. Several mechanisms have been proposed to explain how different types of cells modify LDL. In this study we examine the relative contributions of superoxide anions and cellular lipoxygenase (LO) in the modification of LDL by macrophages. Superoxide dismutase (SOD) inhibited LDL oxidation by macrophages but only by 25%. Under the same conditions, several LO inhibitors (eicosatetraynoic acid (ETYA), piriprost, and A-64077) almost completely inhibited the modification of LDL by macrophages. SOD had a greater inhibitory effect on the modification of LDL by U937 cells and fibroblasts (32% and 64%, respectively) but again LO inhibitors had a much greater effect (79 to 100% inhibition). Incubation of [1-14C]linoleic acid with mouse peritoneal macrophages resulted in its conversion to a single more polar product coeluting with 13- and 9-HODE by reverse phase HPLC. When the cells were preincubated with LO inhibitors, formation of this product was significantly inhibited. It is concluded that the modification of LDL by macrophages is mediated in large part by lipoxygenase-type activity.

Animals↗
PubMed1991

Structural and microbiological evaluation of a degradable sustained-release device for use in periodontal therapy.

Degradable protein matrices containing chlorhexidine were tested as intra-pocket drug delivery systems in the treatment of periodontal diseases. The properties of the device were mainly dependent upon the degree of cross linking in the matrix, which could be varied according to the preparative conditions. The degree of cross linking was determined by amino acid analysis based on the amount of free lysine in the protein. The release of chlorhexidine and of the plasticizer used in the preparation of the matrix were determined. The release of chlorhexidine from the matrix was prolonged for a period of 300 hours, and the release of plasticizer ceased after four hours. Limited clinical trials suggest that one of the degradable devices--that containing the highest amount of cross-linking--causes a significant reduction in the amount of perio-pathogenic bacteria following its insertion into the periodontal pockets of patients with periodontal disease.

Adult↗
PubMed1990

Lipoproteins and atherogenesis. Current concepts.

The frontiers in atherosclerosis research are moving from lipoprotein metabolism and control of hyperlipidemia to the cellular events in the artery wall. Emerging hypotheses, including the oxidative modification hypothesis, are already suggesting new approaches that could complement and be additive to control of hypercholesterolemia in the prevention of atherosclerosis.

Arteriosclerosis↗
PubMed1990

Sustained-release delivery systems for treatment of dental diseases.

Sustained-release delivery systems allow the effective targeting of drugs for treating dental and periodontal diseases. Since dental diseases are chronic, the therapeutic agents used should persist in the oral cavity for as long as possible. Implanting fluoride, chlorhexidine, and other antiseptic agents embedded into sustained-release polymeric matrices into the oral cavity prevents cariogenic plaque accumulation. Both fibers and slab-like sustained-delivery devices bearing chemotherapeutic agents reduced periopathogenic bacteria levels associated with clinical improvement. This review provides useful background information for researchers seeking to develop controlled-release delivery systems for dental applications.

Animals↗
PubMed1990

Low density lipoprotein rich in oleic acid is protected against oxidative modification: implications for dietary prevention of atherosclerosis.

Oxidative modification of low density lipoprotein (LDL) enhances its potential atherogenicity in several ways, notably by enhancing its uptake into macrophages. In vivo studies in the rabbit show that inhibition of LDL oxidation slows the progression of atherosclerotic lesions. In the present studies, rabbits were fed either a newly developed variant sunflower oil (Trisun 80), containing more than 80% oleic acid and only 8% linoleic acid, or conventional sunflower oil, containing only 20% oleic acid and 67% linoleic acid. LDL isolated from the plasma of animals fed the variant sunflower oil was highly enriched in oleic acid and very low in linoleic acid. These oleate-rich LDL particles were remarkably resistant to oxidative modification. Even after 16-hr exposure to copper-induced oxidation or 24-hr incubation with cultured endothelial cells, macrophage uptake of the LDL was only marginally enhanced. The results suggest that diets sufficiently enriched in oleic acid, in addition to their LDL-lowering effect, may slow the progression of atherosclerosis by generating LDL that is highly resistant to oxidative modification.

Animals↗
PubMed1990

Colocalization of 15-lipoxygenase mRNA and protein with epitopes of oxidized low density lipoprotein in macrophage-rich areas of atherosclerotic lesions.

Oxidation of low density lipoprotein (LDL) enhances its atherogenicity, and inhibition of such oxidation decreases the rate of progression of atherosclerotic lesions. The mechanism of LDL oxidation in vivo remains uncertain, but in vitro studies have suggested that cellular lipoxygenases may play a role by initiating lipid peroxidation in LDL. In situ hybridization studies using a 15-lipoxygenase riboprobe and immunostaining using antibodies against 15-lipoxygenase showed strongly positive reactivity largely confined to macrophage-rich areas of atherosclerotic lesions. Polymerase chain reaction with 15-lipoxygenase-specific oligonucleotides and restriction enzyme digestions of the amplified fragment were used to confirm the presence of 15-lipoxygenase message in the reverse-transcribed lesion mRNA. Immunostaining with antibodies reactive with oxidized LDL (but not with native LDL) indicated that the lipoxygenase colocalizes with epitopes of oxidized LDL, compatible with a role for macrophage lipoxygenase in the oxidation of LDL in vivo. Since oxidized LDL is chemotactic for blood monocytes, early lesions might progress at a markedly accelerated rate because of further recruitment of more monocytes which, in turn, would increase further the rate of oxidation of LDL. These data suggest that therapy targeted to block macrophage lipoxygenase activity might decrease the rate of development of atherosclerotic lesions.

Animals↗
PubMed1990

Oxidative modification of LDL: comparison between cell-mediated and copper-mediated modification.

Macrophage-derived foam cells are hallmarks of early atherosclerotic lesions. Oxidatively modified LDL has been suggested to be a more atherogenic form than native LDL. Oxidized LDL--but not native LDL--is chemotactic to monocytes and is avidly degraded by macrophages, resulting in their conversion to foam cells. Incubation of LDL with any of several different types of cells, or with copper ion even in the absence of cells, results in the oxidative modification of LDL. While the cell and the copper systems generate oxidatively modified LDL with similar properties, the two systems differ in their sensitivity to inhibition by superoxide dismutase and by several lipoxygenase inhibitors. In cultured endothelial cells, inhibitors of lipoxygenase, some of them without non-specific antioxidant activity, inhibited cell-mediated modification by 50-80%. In contrast, superoxide dismutase inhibited the process by 20% or less. Moreover, we have shown that soybean lipoxygenase in a cell-free system can modify LDL directly to a form recognized and degraded specifically and rapidly by macrophages. Lipoxygenase-modified LDL is also chemotactic for human monocytes and is cleared rapidly from the circulation, properties shared by cell- or copper-modified LDL. Thus, it is suggested that cellular lipoxygenase(s) may play an important role in cell-mediated oxidative modification of LDL.

Animals↗
PubMed1990

Lipoproteins in normal and atherosclerotic aorta.

Each method used for the extraction and isolation of intimal lipoproteins has advantages and disadvantages. Gentle extraction methods are needed to characterize subtle modifications in the structure and biologic properties of the lipoproteins, whereas more aggressive methods are needed if the goal is to maximize the yield of lipoproteins from atherosclerotic arteries. The present paper evaluates different methods used for the isolation of intimal lipoproteins. Normal intima contains remnant-like and low density lipoprotein (LDL)-like particles that more strongly stimulate cholesterol esterification in macrophages than do control plasma LDL. Both fractions contain apolipoprotein (apo) E but neither shows clear signs of oxidative modification. LDL-like particles from atherosclerotic lesions, on the other hand, contain malondialdehyde- and 4-hydroxynonenal-lysine adducts in apo B, are chemotactic for monocytes and show increased degradation in macrophages, a process that oxidized LDL prepared in vitro can compete with. The findings support the conclusion that at least a portion of the LDL isolated from atherosclerotic lesions is similar, if not identical, to oxidatively modified LDL.

Animals↗
PubMed1990

The effect of sustained release application of chlorhexidine on salivary levels of Streptococcus mutans in partial denture wearers.

The effect of a slow-releasing dosage (SRD) coating of chlorhexidine on the salivary levels of Streptococcus mutans and on plaque index scores in patients with removable partial dentures (RPD) was tested. The SRD proved to be effective in maintaining a low level of S. mutans counts after mechanical cleaning, as compared to a baseline established during the control period. Plaque index scores were lower following the treatment and correlated with the microbiological results. Our findings indicate that a single application of sustained-release chlorhexidine to removable partial dentures effectively maintains S. mutans levels as well as reducing the plaque score for a minimum period of 1 week.

Chlorhexidine↗
PubMed1990

Arterial metabolism of lipoproteins in relation to atherogenesis.

In this short review we have concentrated on the ways in which modification of LDL structure may account for foam cell formation. We have presented in vivo evidence as well as in vitro evidence supporting the proposition that modification of native LDL is a prerequisite for foam cell formation and atherogenesis. Actually, oxidized LDL can contribute to atherogenesis in other ways as well. Oxidized LDL is chemotactic for circulating monocytes, yet inhibits the motility of the tissue macrophage as shown by Quinn et al. Also, oxidized LDL is cytotoxic as discussed above and this could play a crucial role in the transition from the fatty streak lesion to the clinically more consequential fibrous plaque and complicated lesion. If further research supports the importance of LDL modification in atherogenesis, a whole new array of possibilities opens itself to us for intervention. Anything that interferes with the relevant modifications of the LDL structure would presumably be additive to interventions lowering the plasma concentration of LDL. At the moment, the only such intervention that appears to be feasible is prevention of LDL oxidation. Possibly we may find ways to interfere with immune mechanisms that are involved in some patients; conceivably we might be able to interfere with the aggregation of LDL with itself or with other complexes in the artery wall that appear also to favor initiation of the atherogenic process.

Animals↗
PubMed1990

A new degradable controlled release device for treatment of periodontal disease: in vitro release study.

The substantivity of a drug in the periodontal pocket is an important factor determining its effect on the subgingival flora. Therefore, one of the predominant factors in the development of a sustained release delivery device is the ability to control the rate of release of the drug. Previous studies have demonstrated the advantages of the local sustained release of chlorhexidine from nondegradable devices in the treatment of periodontal diseases. The aim of this study was to develop a degradable sustained release device composed of a cross-linked protein containing chlorhexidine as the therapeutic agent. The in vitro release profile of chlorhexidine from the degradable films was altered by the amount of chlorhexidine incorporated into the film, by the cross-link density of the polymer, and by the chlorhexidine salt used. The chlorhexidine in the final pharmaceutical preparation did not lose its antibacterial activity as was shown in an in vitro antibacterial test. This work demonstrates that the release of chlorhexidine from a degradable delivery system and the degradation of the matrix can be controlled by variation in the formulation. This presents a new dental drug delivery system that can be used as an adjunct in the treatment of periodontal diseases in the future. These studies enable us to choose the pharmaceutical formulations for clinical trials to be conducted testing the efficacy of this treatment modality.

Biodegradation, Environmental↗
PubMed1990

Prevention of low density lipoprotein aggregation by high density lipoprotein or apolipoprotein A-I.

We have shown previously that low density lipoprotein (LDL) subjected to vortexing forms self-aggregates that are avidly phagocytosed by macrophages. That phagocytic uptake is mediated by the LDL receptor. We now show that LDL self-aggregation is strongly inhibited (80-95%) by the presence of high density lipoprotein (HDL) or apolipoprotein (apo) A-I. Another type of LDL aggregation, namely that induced by incubation of LDL with phospholipase C, was also markedly inhibited by HDL or apoA-I. The aggregation of LDL induced by vortexing was not inhibited by 2.5 M NaCl, and apoA-I was still able to block LDL aggregation at this high salt concentration, strongly suggesting hydrophobic interactions as the basis for the effect of apoA-I. The fact that apoA-I protected against LDL aggregation induced by two apparently quite different procedures suggests that the aggregation in these two cases has common features. We propose that these forms of LDL aggregation result from the exposure of hydrophobic domains normally masked in LDL and that the LDL-LDL association occurs when these domains interact. ApoA-I, because of its amphipathic character, is able to interact with the exposed hydrophobic domains of LDL and thus block the intermolecular interactions that cause aggregation.

Apolipoprotein A-I↗