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Biomedical subjects

A Chait

Publications and source records attributed to A Chait.

At least 73 records · Page 4Linked to original sources
PubMed1995

Extensive brain mapping of calcitonin-induced anorexia.

The purpose of this study was to compare the localization in the brain of calcitonin-induced anorexia to the distribution of calcitonin binding sites (as described by others). We, thus, performed an extensive mapping of brain structures to determine those involved in calcitonin-induced anorexia. A significant anorexia is found after injection of calcitonin (15 ng in 0.3 microliters) into several brain areas. Forebrain: lateral septum, lateral part of the anterior commissure, and bed nucleus of the stria terminalis; hypothalamus: floor of the anterior part of the hypothalamus, paraventricular nucleus and adjacent perifornical area; thalamus: nucleus reuniens, an area internal to the mamillo-thalamic tract, and medial geniculate body; other areas: amygdala, lateral hippocampus, and central gray. No significant effect is found in the following areas: forebrain: nucleus accumbens, striatum, and medial septum; hypothalamus: lateral, ventro-medial, dorso-medial, and posterior nuclei; thalamus: centro-medial nucleus, lateral part of the zona incerta, and lateral geniculate body; hippocampus: dorsal and ventral parts; midbrain: central tegmentum, ventral tegmental area, and substantia nigra. When these results are compared to the distribution of calcitonin binding sites in the brain, two types of discrepancies are found. The first is the absence of effect in areas containing receptors: these areas may be involved in calcitonin-induced behaviors other than food intake. The second is the occurrence of anorexia in areas where no receptors are found: this finding is not easy to explain and raises some speculative hypotheses. In conclusion, calcitonin is active to decrease food intake in several brain areas, the strongest effect occurring in the paraventricular/perifornical area.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol. II. Cellular composition and proliferation.

In nonhuman primates (Macaca nemestrina) treated with the antioxidant probucol during diet-induced hypercholesterolemia, intimal lesion area in the thoracic aorta was decreased, with increased resistance of plasma LDL to oxidation. The cellular and molecular changes associated with the decrease in lesion size in the probucol-treated hypercholesterolemic animals are quantitatively evaluated in this study. Lesions from the probucol-treated animals appear less mature and have altered lipid distribution. Abundant lipid-laden smooth muscle cells are found in the intima and media of the probucol-treated animals, with fewer medial lipid-laden macrophages, compared with lesions at similar sites in the control hypercholesterolemic animals. In both the control and probucol-treated animals, macrophages are the predominant cells in most lesions, but the ratio of macrophages to smooth muscle cells is decreased in the lower thoracic and upper abdominal aortic sites in the probucol-treated animals. Lesions at all aortic sites in the probucol-treated animals have a 35% to 80% reduction in the percentage of cells in cell cycle traverse, as indicated by immunostaining for proliferating cell nuclear antigen (% PCNA-positive). In both groups, macrophages and smooth muscle cells are PCNA-positive, but the majority (> 60%) are macrophages. No difference in % PCNA-positive cells is seen in the iliac arteries, where the most advanced lesions were present at the time probucol administration was initiated. Limited Northern analysis of growth-regulatory molecules possibly involved in the cellular changes associated with lesions shows a 30% to 50% decrease in mRNA levels of platelet-derived growth factor (PDGF) B-chain, PDGF beta-receptor, colony-stimulating factor type 1, and monocyte chemotactic protein 1. Thus, a potential role for an antioxidant such as probucol in the treatment of atherosclerosis may be to alter the early inflammatory fibroproliferative processes of the disease. Whether these effects are directly related to the antioxidant properties or some other activity of probucol is not yet known.

Animals↗
PubMed1994

Oxidative susceptibility of low density lipoprotein subfractions is related to their ubiquinol-10 and alpha-tocopherol content.

The conjugated polyene fatty acid parinaric acid (PnA) undergoes a stoichiometric loss in fluorescence upon oxidation and can be used to directly monitor peroxidative stress within lipid environments. We evaluated the course of potentially atherogenic oxidative changes in low density lipoproteins (LDL) by monitoring the oxidation of PnA following its incorporation into buoyant (p = 1.026-1.032 g/ml) and dense (p = 1.040-1.054 g/ml) LDL subfractions. Copper-induced oxidation of LDL-associated PnA exhibited an initial lag phase followed by an increased rate of loss until depletion. Increased PnA oxidation occurred immediately after the antioxidants ubiquinol-10 and alpha-tocopherol were consumed but before there were marked elevations in conjugated dienes. Despite differences in sensitivity to early oxidation events, PnA oxidation and conjugated diene lag times were correlated (r = 0.582; P = 0.03), and both indicated a greater susceptibility of dense than buoyant LDL in accordance with previous reports. The greater susceptibility of PnA in dense LDL was attributed to reduced levels of ubiquinol-10 and alpha-tocopherol, which were approximately 50% lower than in buoyant LDL (mol of antioxidant/mol of LDL) and together accounted for 80% of the variation in PnA oxidation lag times. These results suggest that PnA is a useful probe of LDL oxidative susceptibility and may be superior to conjugated dienes for monitoring the initial stages of LDL lipid peroxidation. Differences in oxidative susceptibility among LDL density subfractions are detected by the PnA assay and are due in large part to differences in their antioxidant content.

Adult↗
PubMed1994

The biology of the artery wall in atherogenesis.

A great deal of progress has been made in the past few years in our understanding of the processes involved in atherogenesis and in mechanisms by which commonly accepted risk factors may affect these processes. These insights have allowed us to understand how various interventions may retard atherogenesis and decrease clinical events by improving plaque stability. The identification of new risk factors, such as lipoprotein(a), and of particular molecules that can be identified in atherosclerotic tissue, such as adhesion molecules, growth factors, cytokines, and proteins that regulate cholesterol uptake and removal, have identified several potential new targets for therapeutic intervention. Advances in molecular biologic techniques, including transgenic techniques, have markedly increased the types of potential interventions available. A major challenge for the future will be to determine which among this plethora of therapeutic possibilities holds the most promise for decreasing the morbidity and mortality associated with this disease.

Animals↗
PubMed1994

Inhibition of low density lipoprotein oxidation in vitro by the 6- and 7-hydroxy-metabolites of doxazosin, an alpha 1-adrenergic antihypertensive agent.

Antioxidants may be of use in the prevention of coronary artery disease by inhibiting low density lipoprotein (LDL) oxidation, a process that is believed to play an important role in atherogenesis. Because the structures of the 6- and 7-hydroxy-metabolites of doxazosin, an alpha 1-adrenergic-blocking antihypertensive agent, suggest that they might have antioxidant properties, studies were performed to determine whether these metabolites inhibit LDL oxidation. Micromolar concentrations of 6- and 7-hydroxydoxazosin, but not doxazosin itself, inhibited Cu(2+)-mediated oxidative modification of LDL in a dose-dependent fashion, similar to that observed with the lipophilic antioxidant, probucol. LDL modified in the presence of these metabolites was not taken up and degraded by macrophages to the same extent as LDL oxidized in their absence. In contrast to probucol, the antioxidant effect was lost after reisolation of LDL incubated with the metabolites. Whereas probucol, like vitamin E, sequesters with LDL, 3H-labeled 6- and 7-hydroxydoxazosin did not comigrate with lipoproteins on FPLC, but were associated with albumin and occurred free in solution. Thus, these metabolites of doxazosin may exert their antioxidant effect in the aqueous milieu of the lipoprotein, similar to vitamin C, and may be useful for the prevention of atherosclerosis in hypertensive individuals.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1994

Lipoprotein modification: cellular mechanisms.

Oxidatively damaged LDL may be of pivotal importance in atherogenesis. This review focuses on the cellular pathways involved in LDL oxidation in vitro, the biological properties of oxidized LDL, and the implications of these findings for the role of LDL oxidation in the development of atherosclerosis.

Animals↗
PubMed1994

Lipoprotein lipase is produced by cardiac myocytes rather than interstitial cells in human myocardium.

Lipoprotein lipase (LPL) may play an important role in myocardial metabolism by releasing free fatty acids from triglycerides for oxidation by myocytes. However, studies in species other than humans have differed in their conclusions as to whether LPL is produced by cardiac myocytes or interstitial cells. The location and source of LPL in human myocardium were determined on formalin-fixed samples from 25 cardiomyopathy patients and seven control patients. LPL protein was detected immunohistochemically on cardiac myocytes, adipocytes, and endothelial cells, as well as on interstitial cells consisting of both vascular pericytes and smooth muscle cells. In all 32 patients, in situ hybridization localized LPL mRNA to cardiac myocytes and adipocytes, but LPL mRNA was not detected in interstitial cells. Quantitative in situ hybridization failed to reveal correlations between LPL mRNA levels and New York Heart Association functional class, left ventricular ejection fraction, or beta-adrenergic agonist therapy. Also, quantitative in situ hybridization demonstrated apparently linear loss of detectable myocardial mRNA after onset of ischemia, with a disappearance half-time of approximately 26 hours. In summary, LPL is produced primarily by cardiac myocytes rather than by interstitial cells in human myocardium. Furthermore, LPL protein is present on cells with and without detectable LPL mRNA, suggesting that LPL is translocated from sites of synthesis to sites of utilization.

Adipocytes↗
PubMed1994

Inhibition of hypercholesterolemia-induced atherosclerosis in the nonhuman primate by probucol. I. Is the extent of atherosclerosis related to resistance of LDL to oxidation?

Lipoprotein oxidation is believed to play an important role in atherogenesis. To investigate whether inhibition of oxidation of low density lipoprotein (LDL) would alter atherogenesis in the nonhuman primate, we administered probucol, a potent antioxidant, to Macaca nemestrina fed a high-fat, high-cholesterol diet. Probucol was administered to half of the 16 monkeys 14 wk after starting the hypercholesterolemic diet, and was given daily until they were sacrificed after 11 mos. To evaluate the antioxidant effect of probucol, the resistance of isolated plasma LDL to in vitro oxidation was evaluated. Probucol significantly increased the resistance of LDL to oxidative modification, as shown by an increase in the lag time required for conjugated diene formation. Lesions in the probucol-treated animals appeared less mature, and increased accumulation of lipid was observed in smooth muscle cells. Comparison of all control and probucol-treated monkeys demonstrated that intimal lesion areas in the thoracic aortas of the probucol-treated monkeys were reduced by 43% (P < 0.0001), but no significant difference in lesion area was found in the abdominal aortas or in the iliac arteries. However, the lag phase of conjugated diene formation was not prolonged in 2 of the 8 probucol-treated animals. A plot of intimal lesion size versus lag phase of all 16 animals showed a trend that lesion size was inversely related to oxidation resistance for all anatomic sites. The strong inverse relationship between intimal lesion size and resistance of LDL to oxidation supports a role for lipoprotein oxidation in the development and progression of lesions of atherosclerosis. The possibility that some of the effect is due to other biological properties of probucol cannot be ruled out.

Animals↗
PubMed1994

Pathophysiological concentrations of glucose promote oxidative modification of low density lipoprotein by a superoxide-dependent pathway.

Oxidized lipoproteins may be important in the pathogenesis of atherosclerosis. Because diabetic subjects are particularly prone to vascular disease, and glucose autoxidation and protein glycation generate reactive oxygen species, we explored the role of glucose in lipoprotein oxidation. Glucose enhanced low density lipoprotein (LDL) oxidation at concentrations seen in the diabetic state. Conjugated dienes, thiobarbituric acid reactive substances, electrophoretic mobility, and degradation by macrophages were increased when LDL was modified in the presence of glucose. In contrast, free lysine groups and fibroblast degradation were reduced. Although loss of reactive lysine groups could be due to either oxidative modification or nonenzymatic glycation of apolipoprotein B-100, inhibition of lipid peroxidation by the metal chelator, diethylenetriamine pentaacetic acid, blocked the changes in free lysines. Thus, glycation of lysine residues is unlikely to account for the alterations in macrophage and fibroblast uptake of LDL modified in the presence of glucose. Glucose-mediated enhancement of LDL oxidation was partially blocked by superoxide dismutase and nearly completely inhibited by butylated hydroxytoluene. These findings indicate that glucose enhances LDL lipid peroxidation by an oxidative pathway involving superoxide and raise the possibility that the chronic hyperglycemia of diabetes accelerates lipoprotein oxidation, thereby promoting diabetic vascular disease.

Arteriosclerosis↗
PubMed1994

Reduced plasma peroxyl radical trapping capacity and increased susceptibility of LDL to oxidation in poorly controlled IDDM.

Oxidation of low-density lipoproteins (LDLs) has been postulated to play an important role in atherogenesis. Because oxidant stress may be increased and antioxidant defenses reduced in diabetes, the susceptibility of LDL to oxidative modification and total peroxyl radical trapping potential (TRAP) of plasma were evaluated in subjects with poorly controlled insulin-dependent diabetes mellitus (IDDM). The lag phase of conjugated diene formation after initiation of LDL oxidation by the addition of copper was shorter in diabetic subjects than in normal control subjects (126 +/- 11 vs. 165 +/- 15 min [means +/- SE], P < 0.05). This could not be attributed to the presence of oxidation-susceptible, small, dense LDL particles in the diabetic subjects, whose lipoprotein particle distribution did not differ from the control subjects. However, the total TRAP of plasma, a measure of antioxidant defense, was reduced (626 +/- 34 vs. 877 +/- 41 microM, P < 0.0001) in diabetes. Of the plasma antioxidants measured, only uric acid and vitamin A were decreased in diabetes (P < 0.01), and both levels correlated with TRAP (r = 0.75, P < 0.001; r = 0.54, P < 0.001, respectively). The correlation between uric acid levels and TRAP persisted when the diabetes and control groups were analyzed separately. The reduced TRAP of plasma and the increased susceptibility of LDL to oxidative modification observed is consistent with a role for lipoprotein oxidation in the pathogenesis of atherosclerosis in IDDM.

Adult↗
PubMed1994

Protein crystal growth in microgravity-temperature induced large scale crystallization of insulin.

One of the major stumbling blocks that prevents rapid structure determination using x-ray crystallography is macromolecular crystal growth. There are many examples where crystallization takes longer than structure determination. In some cases, it is impossible to grow useful crystals on earth. Recent experiments conducted in conjunction with NASA on various Space Shuttle missions have demonstrated that protein crystals often grow larger and display better internal molecular order than their earth-grown counterparts. This paper reports results from three Shuttle flights using the Protein Crystallization Facility (PCF). The PCF hardware produced large, high-quality insulin crystals by using a temperature change as the sole means to affect protein solubility and thus, crystallization. The facility consists of cylinders/containers with volumes of 500, 200, 100, and 50 ml. Data from the three Shuttle flights demonstrated that larger, higher resolution crystals (as evidenced by x-ray diffraction data) were obtained from the microgravity experiments when compared to earth-grown crystals.

Animals↗
PubMed1994

Apolipoprotein E localization in human coronary atherosclerotic plaques by in situ hybridization and immunohistochemistry and comparison with lipoprotein lipase.

Apolipoprotein E (apo E) mediates both lipid accumulation by and removal from cells and may be secreted by both macrophages and smooth muscle cells in vitro, but its cellular source in atherosclerotic plaques is not known. Lipoprotein lipase (LPL) also enhances cell lipid accumulation and is synthesized by macrophage foam cells in atherosclerotic plaques. To determine the cellular source of apo E in human coronary atherosclerotic lesions and its relationship to LPL synthesis, in situ hybridization and immunohistochemistry were performed on 12 atherosclerotic plaques and six nondiseased coronary artery segments from 10 cardiac transplant recipients. Apo E messenger RNA was localized to both non-foam cell and foam cell macrophages in plaques, but not to other cell types, and was not detected in nonatherosclerotic arteries. Half of the regions with non-foam cell macrophages expressed neither apo E nor LPL messenger RNA, whereas 86% of macrophage foam cell-containing regions contained both messenger RNAs. Polyclonal antisera raised against human apo E localized apo E protein to the surface of macrophages and surrounding matrix in plaques but not in control coronary segments. An LPL-specific monoclonal antibody demonstrated that, similar to apo E, LPL protein on foam cell and non-foam cell macrophages was detected in atherosclerotic lesions, but LPL was also localized to intimal muscle smooth muscle cells and was not distributed as widely in association with matrix as was apo E. The expression of both apo E and LPL in atherosclerotic lesions but not in normal intima suggest that these molecules play a role in lipid metabolism in atherosclerosis.

Apolipoproteins E↗
PubMed1993

Susceptibility of small, dense, low-density lipoproteins to oxidative modification in subjects with the atherogenic lipoprotein phenotype, pattern B.

PURPOSE: To test whether low-density lipoprotein (LDL) from subjects with an atherogenic lipoprotein phenotype characterized by small, dense LDL (pattern B) demonstrates greater susceptibility to oxidative modification than LDL from subjects exhibiting primarily larger, more buoyant LDL particles (pattern A). PATIENTS AND METHODS: Measures of susceptibility to oxidative modification were compared in six density subfractions of LDL isolated from pattern A and pattern B subjects. Seven male and three female pattern A subjects and five male and two female pattern B subjects, classified on the basis of peak LDL particle size, were studied. Plasma lipid and lipoprotein levels, apolipoprotein B, mean LDL particle diameter, lag phase, and rate of oxidation after initiation of oxidation by copper sulfate were measured. RESULTS: The lag time, a measure of resistance to oxidative modification, was inversely related (p < 0.001) to LDL density in both groups of subjects, without an independent effect of phenotype. The fraction that had the major LDL peak had a shorter lag time (p < 0.05) in pattern B than in pattern A. Pattern B subjects also demonstrated an increased rate of oxidation (p < 0.005) in fraction 1, which includes remnants of triglyceride-rich lipoproteins. CONCLUSIONS: The increased atherogenic risk associated with the pattern B phenotype may result in part from increased concentrations of lipoprotein subpopulations that are relatively susceptible to oxidative modification.

Adult↗
PubMed1993

Analgesic effects of antibiotics in rats.

Studies in forelimb-deafferented rats suggest that treatment with certain antibiotics can decrease pain sensation. To test this hypothesis, the analgesic effects of nine randomly selected antibiotics were studied in rats by using a constant-temperature hotplate. The results show that several antibiotics have antinociceptive properties, and two of them, chloramphenicol and ampicillin, can produce analgesia in a dose range used in human therapy (100 mg/kg). This analgesia is comparable to salicylate and ketoprofen analgesia but lower than pethidine's one. The analgesia is long lasting with chloramphenicol (10 h or more). These antinociceptive properties cannot be attributed to sedation because amphetamine-induced hyperactivity, measured in an open field, is not sensitive to injection of the most sensitive antibiotics.

Analgesics↗
PubMed1993

Vascular cell adhesion molecule-1 is expressed in human coronary atherosclerotic plaques. Implications for the mode of progression of advanced coronary atherosclerosis.

Endothelial attachment is the initial step in leukocyte recruitment into developing atherosclerotic lesions. To determine whether vascular cell adhesion molecule-1 (VCAM-1) expression may play a role in inflammatory cell recruitment into human atherosclerotic lesions, immunohistochemistry was performed with a polyclonal rabbit antisera, raised against recombinant human VCAM-1, on 24 atherosclerotic coronary plaques and 11 control coronary segments with nonatherosclerotic diffuse intimal thickening from 10 patients. Immunophenotyping was performed on adjacent sections to identify smooth muscle cells, macrophages, and endothelial cells. To confirm VCAM-1-expressing cell types, double immunostaining with VCAM-1 antisera and each of the cell-specific markers and in situ hybridization were performed. All atherosclerotic plaques contained some VCAM-1, compared to 45% of control segments. VCAM-1 was found infrequently on endothelial cells at the arterial lumen din both plaques (21%) and in control segments (27%), but was prevalent in areas of neovascularization and inflammatory infiltrate in the base of plaques. Double immunostaining and in situ hybridization confirmed that most VCAM-1 was expressed by subsets of plaque smooth muscle cells and macrophages. The results document the presence of VCAM-1 in human atherosclerosis, demonstrate VCAM-1 expression by human smooth muscle cells in vivo, and suggest that intimal neovasculature may be an important site of inflammatory cell recruitment into advanced coronary lesions.

Animals↗
PubMed1993

Elevated plasma low-density lipoprotein and high-density lipoprotein cholesterol levels in amenorrheic athletes: effects of endogenous hormone status and nutrient intake.

To determine the interactive effects of hormones, exercise, and diet on plasma lipids and lipoproteins, serum estrogen and progesterone levels, nutrient intake, and plasma lipid, lipoprotein, and apolipoprotein concentrations were measured in 24 hypoestrogenic amenorrheic and 44 eumenorrheic female athletes. When compared to eumenorrheic athletes, amenorrheic athletes had higher levels of plasma cholesterol (5.47 +/- 0.17 vs. 4.84 +/- 0.12 mmol/L, P = 0.003), triglyceride (0.75 +/- 0.06 vs. 0.61 +/- 0.03 mmol/L, P = 0.046), low-density lipoprotein (LDL; 3.16 +/- 0.15 vs. 2.81 +/- 0.09 mmol/L, P = 0.037), high-density lipoprotein (HDL; 1.95 +/- 0.07 vs. 1.73 +/- 0.05 mmol/L, P = 0.007), and HDL2 (0.84 +/- 0.06 vs. 0.68 +/- 0.04 mmol/L, P = 0.02) cholesterol. Plasma LDL/HDL cholesterol ratios, very low-density lipoprotein and HDL3 cholesterol, and apolipoprotein A-I and A-II levels were similar in the two groups. Amenorrheic athletes consumed less fat than eumenorrheic subjects (52 +/- 5 vs. 75 +/- 3 g/day, P = 0.02), but similar amounts of calories, cholesterol, protein, carbohydrate, and ethanol. HDL cholesterol levels in amenorrheic subjects correlated positively with the percent of dietary calories from fat (r = 0.42, n = 23, P = 0.045) but negatively with the percent from protein (r = -0.49, n = 23, P = 0.017). Thus, exercise-induced amenorrhea may adversely affect cardiovascular risk by increasing plasma LDL and total cholesterol. However, cardioprotective elevations in plasma HDL and HDL2 cholesterol may neutralize the risk of cardiovascular disease in amenorrheic athletes.

Adult↗