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Biomedical subjects

M S Golub

Publications and source records attributed to M S Golub.

At least 19 recordsLinked to original sources
PubMed2007

Complex, multimodal behavioral profile of the Homer1 knockout mouse.

Proteins of the Homer1 immediate early gene family have been associated with synaptogenesis and synaptic plasticity suggesting broad behavioral consequences of loss of function. This study examined the behavior of male Homer1 knockout (KO) mice compared with wild-type (WT) and heterozygous mice using a battery of 10 behavioral tests probing sensory, motor, social, emotional and learning/memory functions. KO mice showed mild somatic growth retardation, poor motor coordination, enhanced sensory reactivity and learning deficits. Heterozygous mice showed increased aggression in social interactions with conspecifics. The distribution of mGluR5 and N-methyl-D-aspartate receptors (NMDA) receptors appeared to be unaltered in the hippocampus (HIP) of Homer1 KO mice. The results indicate an extensive range of disrupted behaviors that should contribute to the understanding of the Homer1 gene in brain development and behavior.

Analysis of Variance↗
PubMed2001

The adrenal and the metabolic syndrome.

This review discusses the possible interrelationships between adrenal steroid hormones and the metabolic syndrome. Abnormal regulation of the hypothalamic-pituitary-adrenal axis has been proposed. Studies in the United Kingdom associated the metabolic syndrome with low birth weight and hyperactivity of the entire axis. In Italy, increased pituitary responsiveness to stimulation with vasopressin and corticotrophin-releasing hormone was demonstrated in women with central obesity. Swedish researchers have reported that increased stress responses of the axis correlated with a less variable but decreased cortisol level. An allele of the glucocorticoid receptor was also associated with various components of the metabolic syndrome. Evidence also suggests that central obesity is associated with an increased peripheral conversion of cortisol to cortisone and subsequent feedback stimulation of the axis. On the other hand, central fat may have an increased local metabolism in the direction of cortisol. Roles for dehydroepiandrosterone and aldosterone in the syndrome have also been proposed.

Adrenal Cortex Hormones↗
PubMed2001

Inhibitors of arachidonic acid metabolism have variable effects on calcium signaling pathways.

The metabolic pathways of arachidonic acid (AA) have been shown to be important in the regulation of cellular function. Several studies have demonstrated both direct and indirect effects of products of these pathways in the regulation of vascular actions, and in particular on signaling pathways. Because intracellular calcium concentration is a significant mediator of stimulus-coupled signal transduction, we investigated the effects of AA pathway inhibitors on angiotensin II (Ang II)-induced calcium mobilization in cultured rat vascular smooth muscle cells (VSMC). Thus, specific calcium pools were examined for differential effects resulting from inhibitors of the three major pathways of AA metabolism. Inhibition of lipoxygenase (LO) with 2.5 micromol/L of 5,8,11 eicosatriynoic acid (ETI), cyclooxygenase (CO) with 2 micromol/L of ibuprofen (IBU), and cytochrome P-450 (P450) with 1 micromol/L of 7-ethoxyresorufin (7ER) all reduced total Ang II-induced intracellular calcium transients ([Ca2+]i) in fura 2-loaded cultured rat VSMC. However, the sites of action affected were unique for each inhibitor. Pretreatment of VSMC with either ETI or IBU inhibited thapsigargin (TG) (1 micromol/L)-sensitive calcium increments (control; 118.0 +/- 33.1 nmol/L, n = 9, ETI; 34.7 +/- 4.8 nmol/L, n = 9, IBU; 40.3 +/- 8.8 nmol/L, n = 8, P < .05 v control). Both caffeine (CAF) and ryanodine (RY) treatment attenuated Ang II-induced [Ca2+]i; however, pretreatment with ETI, IBU, or 7ER did not alter this effect. In other studies, the LO inhibitor ETI attenuated Ang II-induced Ca2+ influx, whereas inhibitors of CO and P450 pathways had no effect. These data show that 1) E

8,11,14-Eicosatrienoic Acid↗
PubMed2001

Long-term fructose feeding impairs vascular relaxation in rat mesenteric arteries.

To investigate the long-term influence of insulin resistance and hyperinsulinemia on vascular reactivity, both muscarinic and alpha2-receptor-mediated relaxations and the contribution of nitric oxide to these mechanisms were studied in the fructose-fed rat. Male Sprague-Dawley rats were fed either fructose-rich chow (FFR, n = 6) or normal chow (CNT, n = 6) for 40 weeks. Systolic blood pressure was measured by tail-cuff method. A 3-mm segment of mesenteric artery was excised, cannulated and pressurized, pretreated with prazosin (10(-6) mol/L) and propranolol (3 x 10(-6) mol/L), then precontracted with serotonin (10(-6) mol/L). Endothelium dependent relaxation was induced by addition of acetylcholine (10(-9) to 10(-4) mol/L), or a selective alpha2-agonist B-HT 920 (10(-9) to 10(-5) mol/L), with or without the nitric oxide synthase inhibitor L-NAME (10(-4) mol/L). Systolic blood pressure was significantly higher in FFR at the early period; however, there was no difference at the end of 40 weeks compared to CNT. Fasting plasma insulin was much higher in FFR than in CNT (110+/-62 v 41+/-11 microU/mL, P < .05), whereas plasma glucose was not different. Maximum relaxation to acetylcholine was attained at 10(-6) mol/L in FFR but at 3 x 10(-7) mol/L in CNT. The degree of maximum relaxation attained with acetylcholine was similar in FFR and CNT (89+/-9 and 94+/-4% of precontraction), although attenuated (P < .01) by the addition of L-NAME only in FFR (to 34+/-22%, P < .05) but not in CNT (to 82+/-25%). The half-maximal relaxation dose of acetylcholine was greater in FFR (P < .01) compared with CNT and was significantly increased (P < .05) by L-NAME in both groups. B-HT 920 at 10(-5) mol/L induced a greater relaxation in CNT (36+/-10% of serotonin constriction) than in FFR (19+/-14%, P < .05). These responses were significantly blunted by L-NAME. Thus, muscarinic receptor-mediated vascular relaxation is less sensitive and more nitric oxide dependent in FFR versus CNT. Alpha2-adrenergic-mediated relaxation, predominantly mediated by nitric oxide, is also impaired in FFR. It is possible that prolonged insulin resistance and hyperinsulinemia in FFR could alter endothelial-dependent vasodilatory mechanisms, thereby contributing to the increase in blood pressure seen in this model.

Acetylcholine↗
PubMed2001

Synergistic antidiabetic activities of zinc, cyclo (his-pro), and arachidonic acid.

Previous studies have already shown that prostate extract (PE) has antidiabetic activity when given to animals and humans. In this study, we explore whether this antidiabetic activity is related to the high concentrations of zinc, cyclo (his-pro) (CHP), and the prostaglandin precursor, arachidonic acid (AA), in prostate tissue. When streptozotocin-induced diabetic rats were given drinking water containing 10 mg/L zinc and 100 mg/L PE for 3 weeks, fasting blood glucose levels and glucose clearance rates, but not plasma insulin levels, were significantly lower than at pretreatment. In subsequent experiments, blood glucose levels in rats given PE for 3 weeks were significantly lower than in rats given distilled water or 10 mg/L zinc alone. However, in rats given 100 mg/L CHP with zinc, blood glucose levels were also lower than in rats given PE alone. Time-course studies in diabetic rats given drinking water containing 20 mg/L Zn, 20 mg/L L-histidine, and 10 mg/L CHP showed that blood glucose levels dropped 209 +/- 53 mg/dL in 1 day and stayed low for 2 weeks. When CHP was replaced with 100 mg AA/L, blood glucose levels dropped 230 +/- 64 mg/dL in 5 days, but returned to the original values 11 days later. Growth rate improved and water consumption decreased significantly in CHP- and AA-treated diabetic rats. High intake of L-histidine and testosterone increased blood glucose concentrations in diabetic rats. To determine optimal dosages of CHP and AA, we gave rats drinking water containing 10 mg/L Zn and 0.5 mg/L L-histidine with various concentrations of CHP or AA. The most effective doses for reducing blood glucose levels were 0.32 mg CHP/kg/day and 11 mg AA/kg/day. These data suggest that the active antidiabetic ingredients in the PE are CHP, zinc, and AA or its precursors.

Animals↗
PubMed2000

Lifelong feeding of a high aluminum diet to mice.

In three experiments, high aluminum diets (1000 microg Al/g diet) were fed to mice throughout their life span to determine whether neurodegenerative changes were seen with aging. Brain Al concentrations were slightly lower in Al-treated mice than controls. Generally, no increased mortality or gross evidence of neurodegeneration was seen in Al-treated mice. Eighteen and 24 month old Swiss Webster mice fed the high aluminum diet differed from controls on some neurobehavioral tests, but differences were no greater than previously seen with shorter term exposure in younger mice. Both brain Al concentration and susceptibility to oxidative damage, as measured with TBARS, were lower in the Al-treated aged mice than in controls. In addition, Al-treated aged Swiss Webster and C57BL/6J mice showed somewhat enhanced performance in the Morris water maze. Finally, Al treatment did not exacerbate the effect of MPTP treatment on a grip strength measure in either 66 or 235 day old male mice. Swiss Webster and C57BL/6J mice do not appear to provide useful models for studying Al-induced neurodegenerative changes in aging.

Aluminum↗
PubMed2000

Chronic marginal iron intakes during early development in mice result in persistent changes in dopamine metabolism and myelin composition.

Marginal iron (Fe) deficiency is prevalent in children worldwide, yet the behavioral and biochemical effects of chronic marginal Fe intakes during early development are not well characterized. Using a murine model, previous work in our laboratory demonstrated persistent behavioral disturbances as a consequence of marginal Fe intakes during early development. In the present study, Swiss-Webster mice fed a control Fe diet (75 microgram Fe/g diet, n = 13 litters) or marginal Fe diet (14 microgram Fe/g diet, n = 16 litters) during gestation and through postnatal day (PND) 75 were killed on PND 75 for assessment of tissue mineral concentrations, dopamine metabolism, myelin fatty acid composition, and c- and m-aconitase activities. In addition, these outcomes were assessed in a group of offspring (n = 13 litters) fed a marginal Fe diet during gestation and lactation and then fed a control diet from PND 21-75. Marginal Fe mice demonstrated significant differences in brain iron concentrations, dopamine metabolism and myelin fatty acid composition relative to control mice; however, no difference in c- or m-aconitase activity was demonstrated in the brain. The postnatal consumption of Fe-adequate diets among marginal Fe offspring did not fully reverse all of the observed biochemical disturbances. This study demonstrates that chronic marginal Fe intakes during early development can result in significant changes in brain biochemistry. The persistence of some of these biochemical changes after postnatal Fe supplementation suggests that they are an irreversible consequence of developmental Fe restriction.

Aconitate Hydratase↗
PubMed2000

Moderate zinc-iron deprivation influences behavior but not growth in adolescent rhesus monkeys.

Primate species demonstrate a prolonged period of development before reproductive maturity that includes distinctive periods of rapid growth in the late fetal, late infancy and early adolescent stages. Rhesus monkeys resemble humans in this discontinuous pattern of growth and also in its relationship to brain development. Studies of zinc deprivation in rhesus monkeys have suggested an important relationship among growth rate, nutrient status and behavioral performance in infancy as well as adolescence. Recently, moderate combined zinc and iron deprivation (intake 0.2 mg Zn and 0.8 mg Fe/d, compared with control intake of 2.9 mg Zn and 1.7 mg Fe/d) during the adolescent growth spurt (29-32 mo. of age) of female rhesus monkeys (n = 8/group) was shown to influence behavior without affecting growth. Behavioral assessments included the Continuous Performance Test, the Delayed Nonmatch to Sample Test and activity (measured with an actimeter). The behavioral syndrome was characterized by reduced activity, reduced participation in behavioral testing and slower response. These changes could be reversed or prevented to some extent by altering the diet to include tablets of powdered beef (adding approximately 1.7 mg Zn and 0.7 mg Fe to daily intake). The study suggests that behavior may be sensitive to the quality of the diet available during the period of rapid adolescent growth and development.

Animals↗
PubMed2000

Chronic marginal iron intakes during early development in mice alter brain iron concentrations and behavior despite postnatal iron supplementation.

The objective of this study was to investigate the behavioral and cognitive outcomes associated with chronic marginal iron (Fe) intakes during early development. Offspring (3 males and 3 females/litter) of Swiss-Webster female mice who had been fed a control Fe diet (75 microg Fe/g diet) or marginal Fe diet (14 microg Fe/g diet) for 9 wk before mating were weaned on postnatal (PND) 21. Offspring of marginal Fe dams were fed either the marginal Fe diet (marginal group) or a control diet (replete group) from PND 21 throughout the duration of the study, whereas offspring of control dams consumed the control diet ad libitum (control group). On PND 30, 45 and 60, one male and female per litter underwent grip strength and auditory startle testing. A Morris maze was used to assess cognitive function in males starting at PND 50. Marginal Fe mice consistently demonstrated significantly lower grip strength, which was independent of differences in body weight. In addition, marginal Fe males demonstrated attenuated startle responsiveness, as well as altered performance in the Morris water maze. These differences in performance were found in association with lower brain Fe concentrations. Postnatal Fe supplementation did not reverse all of these disturbances because differences in brain Fe concentrations and maze learning persisted. This study demonstrates that chronic marginal Fe intakes during early development can result in persistent biochemical and behavioral changes in mice.

Animals↗
PubMed2000

Adolescent health and the environment.

The effects of toxicants depend on the dose and the time in the life span when exposure occurs. The biology of adolescence is distinctive and provides opportunities for unique actions of toxicants both in terms of disruption of function and disruption of maturation. Maturation of a number of organ systems occurs during this period, including not only the reproductive system but also the respiratory, skeletal, immune, and central nervous systems. Adolescence is a time of increased risk for infectious disease and accidental injury, making the effects of toxicants on the immune and central nervous systems particularly harmful. Differences in blood volume, respiratory parameters, metabolic needs, and capacity all contribute to altered pharmacokinetics. Exposures can also change. Increased food intake associated with rapid adolescent growth alters exposure to food contaminants. Voluntary drug consumption increases, including drinking; smoking; substance abuse; and the use of over-the-counter, prescription, and performance-enhancing drugs. At the same time, adolescents are introduced to toxicants in the workplace. Basic research in the toxicology of adolescence needs to take into account the appropriateness of animal models for this distinctive human developmental stage; risk assessment must take into account pharmacokinetic and lifestyle factors. Screening methodologies that would identify toxic effects unique to adolescence would also be valuable.

Adolescent↗
PubMed1999

Behavioral and hematologic consequences of marginal iron-zinc nutrition in adolescent monkeys and the effect of a powdered beef supplement.

BACKGROUND: The adolescent growth spurt and menarche increase iron and zinc needs and could precipitate functional deficiencies if dietary sources are inadequate. OBJECTIVE: The effects of mild, combined zinc and iron deprivation during the growth spurt and the ability of meat as a common dietary source of zinc and iron to reverse these effects was studied. DESIGN: Pubertal female rhesus monkeys were fed control diets (n = 8) or diets marginally deficient in zinc (2 microg/g diet; n = 8) and iron (10 microg/g diet; n = 8) for 3 mo. A powdered beef supplement (104 microg Zn/g and 43 microg Fe/g, 11 +/- 2 g/d) was then fed daily to half of the deprived group for 3 additional months. RESULTS: Growth and hematology were not affected significantly by iron-zinc deprivation, but plasma zinc and iron were somewhat lower in the deprived group than in the control group after 3 mo. The deprived monkeys reduced their participation in behavioral testing, responded more slowly and less frequently to test stimuli, and were less active. The beef supplement increased participation in testing and stabilized activity levels, but response times remained depressed. Plasma ferritin was lower in the nonsupplemented deprived monkeys than in the controls by the end of the experiment. Four of 8 of the deprived monkeys had iron deficiency anemia compared with none of the controls and 1 of 8 who received the beef supplement. CONCLUSIONS: Marginal zinc and iron deprivation in early adolescence can lead to behavioral and hematologic dysfunction in nonhuman primates and dietary beef supplements can prevent and reverse some of these effects.

Animal Nutritional Physiological Phenomena↗
PubMed1999

Morphometric studies of myelination in the spinal cord of mice exposed developmentally to aluminum.

Swiss-Webster mice were exposed to diets containing 7 or 1000 microg aluminum (Al)/g as Al lactate from conception through maturity (45 days of age). This exposure has previously been shown to cause changes in CNS myelin composition and peroxidizability; in this study myelin sheath widths were measured. Initially, samples of epon embedded, toluidine blue stained cervical spinal cord sectioned at 0.5 mm were examined light microscopically. Qualitatively, Al-treated mice appeared to have a diffuse paleness in nerve tracts. No indication of myelin structural damage (splitting, degeneration) was noted. Quantitative microscopy was performed using images captured with Scion Image Dage 1.59 at 1000x with oil. Axon perimeters and sheaths were measured with NIH image using a standardized sampling pattern in the right medial dorsal and ventral regions of the cervical spinal cord in 6 mice (3 male, 3 female) per group. Mean myelin sheath widths were 16% smaller in the Al-treated group compared to controls (p=.03). There was no effect of sex or region (dorsal/ventral). Axon perimeters were also smaller on the average in the Al treated group but this difference was not significant (p=.16). The relationship between sheath width and axon diameter was similar in the two groups. The density of myelinated axons was greater in some areas for the Al-treated group. The data indicate that dietary aluminum exposure can interfere with myelination in the spinal cord.

Aluminum↗
PubMed1999

Aluminum uptake and effects on transferrin mediated iron uptake in primary cultures of rat neurons, astrocytes and oligodendrocytes.

Transferrin (Tf) is known primarily for its role in the transport and cellular uptake of iron (Fe). Tf is also the major serum binding protein for Al. In this study, primary rat oligodendrocyte, neuron and astrocyte cultures were found to differ in Tf mediated Fe and Al uptake and in the effect of Al-Tf on Fe-Tf uptake during 4 h incubation periods. When incubated with Al-Tf (1.25 microM), oligodendrocytes displayed a 3- to 4-fold increase (p=.0002) in Al, neurons demonstrated a much smaller (p=.06) increase, and no increase was seen for astrocytes. When incubated with equimolar Al citrate or Al chloride, no increase in cellular Al was seen in any of the three cell types. Oligodendrocytes, astrocytes and neurons all demonstrated greater 59Fe uptake from Fe-Tf than Fe chloride. This uptake could be inhibited by excess Fe-Tf in oligodendrocytes and neurons, but not astrocytes. A small but significant inhibition of 59Fe uptake from Fe-Tf was seen after addition of Al-Tf to the incubation medium of oligodendrocytes, but not neurons or astrocytes. Oligodendrocytes may be particularly vulnerable to the accumulation of excess intracellular Al, and to interference of Al with Fe uptake. Such effects could contribute to Al-induced neurotoxicity if they result in altered myelin formation or maintenance.

Aluminum↗
PubMed1998

Membrane composition can influence the rate of Al3+-mediated lipid oxidation: effect of galactolipids.

In the first part of the present study we investigated the effects of pre-natal and early postnatal exposure of mice to high levels of dietary Al3+ on myelin lipid composition and lipid oxidation. We found: (1) a significantly higher (104%; P<0.01) content of brain myelin galactolipids in the high-Al3+ group than in controls, and, (2) a significant correlation (r2=0.70; P<0.01) between the concentration of myelin galactolipids and TBARS (2-thiobarbituric acid-reactive substances) content, a parameter of lipid oxidation. Based on these results, we evaluated in an in vitro model (liposomes) whether galactolipids could affect the capacity of Al3+ to stimulate Fe2+-initiated lipid oxidation, and whether this effect could be due to the promotion of changes in membrane physical properties (membrane phase separation and rigidification). The presence of galactolipids (10-40 mol%) in the liposomes caused a concentration-dependent increase in the stimulatory effect of Al3+ on Fe2+-induced TBARS production, and on the ability of Al3+ to induce phase separation and membrane rigidification. The capacity of Al3+ (10-100 microM) to induce lateral phase separation in liposomes composed of phosphatidylcholine/phosphatidylserine/galactolipid (36:24:40, molar ratio) was correlated significantly (r2=0.99; P<0. 001) with the stimulatory action of Al3+ on Fe2+-induced TBARS production. We propose that the high content of galactolipids found in myelin from Al3+-intoxicated mice could favour Al3+-induced changes in membrane physical properties, with the subsequent acceleration of lipid oxidation rates.

Aluminum↗
PubMed1998

Newborn tissue concentrations of bupivacaine following maternal epidural administration during labor in guinea pigs.

Newborn plasma concentrations of maternally administered bupivacaine are often measured, but it is unclear how well they reflect tissue concentrations. Bupivacaine (0.25%) was administered epidurally (0. 12 ml/kg) 10 min prior to labor induction in 6 term-pregnant guinea pigs. Plasma, brain, heart and liver samples were obtained for bupivacaine analysis from newborns (n = 22) after spontaneous delivery. Liver bupivacaine concentrations were 2-3 times greater than those in the plasma, brain, and heart. A similar pattern of tissue concentrations was seen in a smaller number of newborns delivered by cesarean section. Liver bupivacaine concentration decreased with drug-delivery interval in littermates, while heart and brain concentrations showed no relationship with drug-delivery interval. Blood gases of newborns reflected acidosis, which may have influenced tissue drug concentrations. Under conditions of the study, bupivacaine concentrations in heart and brain, potential sites of bupivacaine action, were lower than those observed in a peripheral blood sample.

Anesthetics, Local↗
PubMed1998

Evidence for increased functional vascular Na+/K+ pump activity in the obese Zucker rat.

Insulin is known to stimulate Na+/K+ ATPase and to relax vascular smooth muscle. We hypothesized that vascular tone in the obese Zucker (fa/fa) rat, a hyperinsulinemic model in which hypertension can develop, may be influenced by insulin's ability to stimulate Na+/K+ ATPase at the vascular level. We studied isometric preparations of tail and femoral arteries from 10-wk-old, male obese Zucker rats, which were hyperinsulinemic but still normotensive vs. lean controls. Sensitivity to potassium-induced relaxations, an index of vascular Na+/K+ ATPase activity was significantly greater in the obese Zucker rat than control. Sensitivity to transmural-nerve-stimulation-induced contractions was decreased in the femoral and tail arteries from obese rats as compared with lean controls. Insulin (50 to 200 mU/ml) mimicked potassium-induced relaxations in the femoral artery, an effect that was significantly greater in the obese group. These data suggest that in the young hyperinsulinemic Zucker rat, insulin has a stimulatory effect on the vascular Na+/K+ pump, which may be associated with a decreased presynaptic adrenergic influence on vascular tone. Development of resistance to these vascular relaxant effects of insulin with advancing age might contribute to the onset of hypertension in this model.

Animals↗
PubMed1998

Increased functional Na(+)-K+ pump activity in the vasculature of fructose-fed hyperinsulinemic and hypertensive rats.

We hypothesized that hyperinsulinemia may alter insulin's ability to stimulate vascular Na+/K(+)-ATPase pump activity and modulate changes in vascular responsiveness associated with hypertension. We measured potassium-induced relaxation as an indicator of Na+/K(+)-ATPase pump activity in isolated femoral arteries from fructose-fed (FF) hyperinsulinemic, Sprague-Dawley rats. FF rats had higher mean arterial blood pressures than did normal diet-fed (NF) rats (FF, 125 +/- 2.2, n = 20, vs. NF, 113.5 +/- 2.5 mmHg, n = 20, p < 0.05) and were hyperinsulinemic (FF, 64 +/- 4 vs. NF, 37 +/- 2, microU/ml insulin, p < 0.01). FF rats were more sensitive to KCl in the Na+/K+ pump bioassay (FF, 0.86 +/- 0.07, n = 21 vs. NF, 1.18 +/- 0.08, n = 17, p < 0.05, expressed as ED50 in mmol/l KCl). Exogenous insulin (100 mU/ml) increased Na+/K+ pump sensitivity in FF rats as compared with a boiled insulin control (insulin 45 +/- 6%, n = 11, vs. control, 11 +/- 7%, n = 13, p < 0.01, expressed as percent increase in sensitivity, i.e., ED50). There were no significant differences in Na+/K+ pump sensitivity between insulin and control responses in the NF animals (insulin 29 +/- 6%, n = 11, vs. control 46 +/- 5%, n = 10, NS). Dose-response curves were obtained in tail and femoral arteries from the same animals to norepinephrine and acetylcholine, basally and after exogenous insulin. FF vessels had reduced sensitivity to norepinephrine as compared with the NF group. Insulin increased sensitivity to acetylcholine-induced relaxations and increased AII-induced contractions in FF-rat vessels. These data suggest that in the FF rat insulin's influence on the vascular Na+/K+ pump is enhanced and may modulate the changes in vascular responsiveness seen in this model.

Acetylcholine↗