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Biomedical subjects

Holly M Brown-Borg

Publications and source records attributed to Holly M Brown-Borg.

At least 19 recordsLinked to original sources
PubMed2006

Ebselen effects on MPTP-induced neurotoxicity.

We evaluated the effect of ebselen on human SH-SY5Y dopaminergic neuronal cells and determined whether ebselen, a glutathione peroxidase-mimetic, protected against MPTP-induced dopamine depletion in mice. Ebselen (10-100 microM) inhibited the proliferation of SH-SY5Y cells dose-dependently. Ebselen did not induce any behavioral changes and did not block MPTP-induced tremor and akinesia. Ebselen had no effect on the monoamine oxidase activity and did not protect against MPTP-induced dopamine depletion in striatum.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Methionine flux to transsulfuration is enhanced in the long living Ames dwarf mouse.

Long-lived Ames dwarf mice lack growth hormone, prolactin, and thyroid stimulating hormone. Additionally the dwarf mice have enzyme activities and levels that combat oxidative stress more efficiently than those of normal mice. We have shown that methionine metabolism in Ames mice is markedly different than in their wild type littermates. In our previous work we hypothesized that the flux of methionine to the transsulfuration pathway is enhanced in the dwarf mice. The current study was designed to determine whether the flux of methionine to the transsulfuration pathway is increased. We did this by injecting either l-[methyl-(3)H]-methionine or l-[(35)S]-methionine into dwarf or normal mice and then determined retained label (in form of S-adenosylmethionine) 45 min later. The amount of retained hepatic (3)H and (35)S label was significantly reduced in the dwarf mice; at 45 min the specific radioactivity of SAM (pCi/nmol SAM) was 56% lower (p < 0.05) for (3)H-label and 64% lower (p < 0.005) for (35)S-label in dwarf than wild type mice. Retention of (35)S was significantly lower in the brain (37%, p < .04) and kidney (47%, p < 0.02) of the dwarf compared to wild type mice; there was no statistical difference in retained (3)H-label in either brain or kidney. This suggests that both the methyl-moiety and the carbon chain of methionine are lost much faster in the dwarf compared to the wild type mouse, implying that both transmethylation in the liver and transsulfuration in the liver, brain, and kidney are increased in the dwarf mice. As further support, we determined by real-time RT PCR the expression of methionine metabolism genes in livers of mice. Compared to wild type, the Ames dwarf had increased expression of methionine adenosyltransferase 1a (2.3-fold, p = 0.013), glycine N-methyltransferase (3.8-fold, p = 0.023), betaine homocysteine methyltransferase (5.5-fold, p = 0.0006), S-adenosylhomocysteine hydrolase (3.8-fold, p = 0.0005), and cystathionase (2.6-fold; tended to be increased, p = 0.055). Methionine synthase expression was significantly decreased in dwarf compared to wild type (0.48-fold, p = 0.023). These results confirm that the flux of methionine to transsulfuration is enhanced in the Ames dwarf. This, along with data from previous studies support the hypothesis that altered methionine metabolism plays a significant role in the oxidative defense of the dwarf mouse and that the mechanism for the enhanced oxidative defense may be through altered GSH metabolism as a result of the distinctive methionine metabolism.

Animals↗
PubMed2006

Trichopus zeylanicus combats fatigue without amphetamine-mimetic activity.

Chronic fatigue is a complex and little understood symptom for which there is no safe and effective pharmacotherapy. The present study was conducted to investigate the effectiveness of Trichopus zeylanicus whole plant powder on fatigue in young Sprague Dawley rats, and aged normal and long-living mutant Ames dwarf mice. Fatigue was evaluated by subjecting the animals to a forced swim test. Trichopus zeylanicus (250 and 500 mg/kg) treated young Sprague-Dawley rats resisted fatigue at a significant level (p < 0.005) compared with controls by an extended swim time in the forced swim test. Oral Trichopus zeylanicus (500 mg/kg) treatment for 2 weeks significantly increased the mobility time in the aged mutant (p < 0.05) and normal mice (p < 0.01) and significantly increased the swim time in the forced swim test in the aged normal mice (p < 0.05). Amphetamine-mimetic activity in Trichopus zeylanicus was excluded by suitable tests. These results show that Trichopus zeylanicus whole plant powder has anti-fatigue effects in young Sprague-Dawley rats and aged normal and mutant Ames dwarf mice providing scientific evidence for the Kani tribal practice in India.

Amphetamine↗
PubMed2006

Cardiac cytochrome-c oxidase deficiency occurs during late postnatal development in progeny of copper-deficient rats.

Although cytochrome-c oxidase (CCO) is a copper-dependent enzyme, the effect of maternal copper deficiency on the expression of CCO activity during postnatal development of the neonatal rat heart has not been investigated extensively. Here, we show that CCO activity in heart mitochondria isolated from neonates of copper-deficient dams did not exhibit significant reductions until postnatal days (PND) 15 and 21. In addition, immunoblot analysis indicated that the CCO subunit (Cox-1) was reduced on postnatal Days 10 and 21, and that Cox-4 was reduced on PND 21 in heart mitochondria of the neonates from copper-deficient dams. These findings indicate that the impairment of CCO activity in neonatal heart by maternal copper deficiency occurs late in the postnatal heart development. Furthermore, the concurrent reductions in Cox-1 and Cox-4 suggest that the impaired CCO activity reflects a CCO deficiency in heart mitochondria. CCO activity and Cox-1 in heart mitochondria were not fully restored by 6 weeks of postweaning copper repletion in the pups of copper-deficient dams. This indicates that prolonged maternal intake of moderately low dietary copper produces CCO deficiency in cardiac mitochondria of neonates during late postnatal heart development, after terminal differentiation of cardiomyocytes occurs. The resistance of CCO deficiency to repair by dietary copper supplementation may be related to the relatively slow turnover of the affected mitochondria in the terminally differentiated heart.

Animals↗
PubMed2005

Growth hormone alters methionine and glutathione metabolism in Ames dwarf mice.

Reduced signaling of the growth hormone (GH)/insulin-like growth factor-1(IGF-1)/insulin pathway is associated with extended life span in several species. Ames dwarf mice are GH and IGF-1 deficient and live 50-64% longer than wild type littermates (males and females, respectively). Previously, we have shown that Ames mice exhibit elevated levels of antioxidative enzymes and lower oxidative damage. To further explore the relationship between GH and antioxidant expression, we administered GH or saline to dwarf mice and evaluated components of the methionine and glutathione (GSH) metabolic pathways. Treatment of dwarf mice with GH significantly suppressed methionine adenosyltransferase (40 and 38%) and glycine-N-methyltransferase (44 and 43%) activities (in 3- and 12-month-old mice, respectively). Growth hormone treatment elevated kidney gamma-glutamyl-cysteine synthetase protein levels in 3- and 12-month-old dwarf mice. In contrast, the activity of the GSH degradation enzyme, gamma-glutamyl transpeptidase, was suppressed by GH administration in heart and liver. The activity of glutathione-S-transferase, an enzyme involved in detoxification, was also affected by GH treatment. Taken together, the current results along with data from previous studies support a role for growth hormone in the regulation of antioxidative defense and ultimately, life span in organisms with altered GH or IGF-1 signaling.

Animals↗
PubMed2005

Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity.

Dietary restriction of calories (caloric restriction [CR]) increases longevity in phylogenetically diverse species. CR retards or prevents age-dependent deterioration of tissues and an array of spontaneous and chemically induced diseases associated with obesity including cardiovascular disease, diabetes, and cancer. An understanding of the molecular mechanisms that underlie the beneficial effects of CR will help identify novel dietary, pharmacological, and lifestyle strategies for slowing the rate of aging and preventing these diseases as well as identify factors which modulate chemical toxicity. Here, we review the involvement of transcriptional coactivator proteins, peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 (PGC-1) alpha and beta, and regulated nuclear receptors (NR) in mediating the phenotypic changes found in models of longevity which include rodent CR models and mouse mutants in which insulin and/or insulin-like growth factor-I signaling is attenuated. PGC-1alpha is transcriptionally or posttranslationally regulated in mammals by: 1) forkhead box "other" (FoxO) transcription factors through an insulin/insulin-like growth factor-I -dependent pathway, 2) glucagon-stimulated cellular AMP (cAMP) response element binding protein, 3) stress-activated kinase signaling through p38 mitogen-activated protein kinase, and 4) the deacetylase and longevity factor sirtuin 1 (SIRT1). PGC-1alpha and PGC-1beta regulate the ligand-dependent and -independent activation of a large number of NR including PPARalpha and constitutive activated receptor (CAR). These NR regulate genes involved in nutrient and xenobiotic transport and metabolism as well as resistance to stress. CR reverses age-dependent decreases in PGC-1alpha, PPARalpha, and regulated genes. Strategies that target one or multiple PGC-1-regulated NR could be used to mimic the beneficial health effects found in models of longevity.

Animals↗
PubMed2004

Long-lived Ames dwarf mouse exhibits increased antioxidant defense in skeletal muscle.

Resting and exercised (both acute and chronic) hindlimb skeletal muscle from long-lived Ames dwarf and wild type mice at 3, 12, 18, and 24 months of age was tested for antioxidant enzyme activity and protein, non-enzymatic antioxidant ratios, mitochondrial hydrogen peroxide concentration, and plasma lactate levels. Differences were observed in GPX enzyme activity between mouse genotypes at all physical activity levels, with dwarf mice exhibiting depressed levels at younger ages (3 months: P = 0.09 [non-swim], P = 0.03 [acute swim], P = 0.04 [chronic swim]) and comparatively higher levels than wild type mice at older ages (18-24 months: P = 0.05 [acute swim], P = 0.07 [chronic swim]). Catalase enzyme activity and the GSH system rarely demonstrated significant differences between genotypes, regardless of age or activity. However, the chronic exercise group displayed a difference in GSH:GSSG ratios between mouse genotypes (P = 0.005). Plasma lactate concentrations were elevated in the wild type mice compared to the dwarf mice at all ages in all activity groups. These results suggest there are biological differences with regard to antioxidant defense that favor the Ames dwarf mouse in active and resting skeletal muscle when compared to wild type mice.

Animals↗
PubMed2004

Dopamine agonist 3-PPP fails to protect against MPTP-induced toxicity.

We investigated the neuroprotective effect of the dopamine agonist, 3-PPP [3-(3-hydroxyphenyl)-N-propylpiperidine] against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. MPTP (30 mg/kg, i.p., twice, 16 h apart) causes significant dopamine depletion in nucleus caudatus putamen (NCP) by 1 week. 3-PPP had no effect on the monoamine oxidase-B activity (MAO-B) activity in NCP. 3-PPP did not affect dopamine uptake, whereas mazindol significantly blocked the uptake of dopamine dose dependently. MPTP-induced behavioral changes in mice were not reduced by pretreatment with 3-PPP. This dopamine agonist did not prevent dopamine depletion caused by MPTP. MPP+ (20 microM) significantly inhibited the cell proliferation of SH-SY5Y dopaminergic neuronal cells. 3-PPP had no effect on the SH-SY5Y neuronal cell growth in culture and did not block the MPP(+)-induced cytotoxicity. This study shows that the dopamine agonist 3-PPP failed to protect against MPTP-induced dopaminergic neurotoxicity.

Animals↗
PubMed2004

Growth hormone alters components of the glutathione metabolic pathway in Ames dwarf mice.

Reduced signaling of the growth hormone (GH)/insulin-like growth factor-1(IGF-1)/insulin pathway is associated with extended life span in several species. Ames dwarf mice are GH and IGF-1 deficient and live 50-64% longer than wild-type littermates (males and females, respectively). Previously, we have shown that Ames mice exhibit elevated levels of antioxidative enzymes and lower oxidative damage. To further explore the relationship between GH and antioxidant expression, we administered GH or saline to dwarf mice and evaluated components of the glutathione (GSH) synthesis and degradation system. Growth hormone treatment significantly elevated kidney gamma-glutamyl-cysteine synthetase protein levels in 3- and 12-month-old dwarf mice. In contrast, the activity of the GSH degradation enzyme, gamma-glutamyl transpeptidase, was suppressed by GH administration in brain (P <.05), kidney (P <.01), heart (P <.005), and liver (P <.06). Activity levels of the detoxification enzyme, glutathione-S-transferase, were also suppressed in kidney tissues at 3 and 12 months of age and in 12-month-old dwarf liver tissues (P <.05). Taken together, the current results along with data from previous studies support a role for growth hormone in the regulation of antioxidative defense and, ultimately, life span in organisms with altered GH or IGF-1 signaling.

Animals↗
PubMed2003

Growth hormone administration to long-living dwarf mice alters multiple components of the antioxidative defense system.

Endocrine hormones are thought to be involved in processes that contribute to aging. Long-living dwarf mice are growth hormone (GH)-deficient and exhibit enhanced expression of antioxidative defense molecules when compared to normal, wild type littermates. In this study, 3- and 12-month-old Ames dwarf mice received with 50 microg GH or saline for 7 days. Tissues were collected and assayed for several antioxidant molecules. In addition to increased body and liver weights, GH treatment of dwarf mice decreased liver, kidney and heart catalase protein (P < 0.05). Catalase activity was significantly decreased in kidney and heart tissues of mice receiving GH compared to dwarf mice treated with saline. Glutathione peroxidase (GPX) protein was significantly reduced in liver, kidney and muscle of GH-treated mice (P < or = 0.03). Likewise, the activity of GPX was decreased in liver and kidney tissues following GH administration (P< or = 0.04). Exogenous GH increased glutathione levels in brain, muscle and liver (P< or = 0.03) compared to saline controls. This evidence, along with previous data, suggests that GH suppresses key components of systems that counter oxidative stress. Reductions in GH and IGF-1 signaling contribute to extended life spans in a variety of species, which may be partially explained by an increased ability to neutralize deleterious byproducts of metabolism.

Animals↗
PubMed2003

Altered methionine metabolism in long living Ames dwarf mice.

Ames dwarf mice (df/df) are deficient in growth hormone, prolactin, and thyroid-stimulating hormone and live significantly longer than their normal siblings. In the current study, we found that the hormone deficiencies affect methionine metabolism. We previously reported that the dwarf mice exhibit enzyme activities and levels that combat oxidative stress more efficiently than those of normal mice. Moreover, methionine or metabolites of methionine are involved in antioxidative processes. Thus, we performed an experiment that compared various parameters of methionine metabolism between 18-month old male dwarf (N=6) and wild type (N=5) mice. The specific activity of liver methionine adenosyltransferase (MAT) was significantly elevated (205%, p<0.0001) in the dwarf mice, as were cystathionine synthase (50%, p<0.01), cystathionase (83%, p<0.001), and glycine N-methyltransferase (GNMT, 91%, p<0.001) activities. Even though the activities of MAT and GNMT were elevated, the concentration of liver S-adenosylmethionine was decreased (24%, p<0.001) and S-adenosylhomocysteine increased (113%, p<0.001) in the dwarf mice. These data indicate that dwarf mice, compared to wild type mice, have a markedly different metabolism of methionine. Altered methionine metabolism may partially explain earlier reports indicating less oxidative damage to proteins in dwarf mice. Taken together, the data suggest that methionine metabolism may play a role in oxidative defense in the dwarf mouse and should be studied as a potential mechanism of extended lifespan.

Aging↗
PubMed2003

Long-living Ames dwarf mouse hepatocytes readily undergo apoptosis.

Ames dwarf mice live 50-64% longer and exhibit upregulated antioxidative defenses and lower cellular damage when compared to age-matched wild-type littermates. Due to the relationship between aging and apoptosis, the purpose of this study was to compare basal levels of apoptosis-related proteins in dwarf and wild-type tissues and to compare the response of dwarf and wild-type primary hepatocytes to oxidative stress. Hepatocytes from dwarf and wild-type mice (6 month-old) were isolated using collagenase perfusion and treated with hydrogen peroxide. Viability, activity, protein levels, and morphological changes were evaluated. Procaspase-3 protein levels were increased in dwarf kidney and liver (p<0.05) while Bcl-2 protein levels were significantly higher in dwarf liver at 24 months of age. Bax protein levels were markedly elevated in several tissues at different ages and Bcl-2/Bax ratios were lower in many dwarf tissues. In culture, peroxide-treated dwarf hepatocytes showed lower viability (p<0.03) and higher caspase-3 activity induction when compared to peroxide-treated wild-type cells. Peroxide-treated dwarf hepatocytes frequently showed morphological characteristics reminiscent of apoptosis, which were not observed in peroxide-treated wild-type hepatocytes. This suggests that when experiencing an oxidative challenge, Ames dwarf hepatocytes more readily undergo apoptosis than wild-type cells, providing an advantage to dwarf mice, whereby they more efficiently eliminate damaged cells, thus contributing to their longer lives.

Aging↗
PubMed2003

Increases in insulin-like growth factor-1 level and peroxidative damage after gestational ethanol exposure in rats.

Ethanol exposure during pregnancy elicits profound detrimental developmental and behavioral effects such as reduced levels of insulin-like growth factor-1 (IGF-1) in the fetus. However, few reports have addressed its impact on postpartum dams. This study was designed to examine the influence of gestational ethanol exposure on postpartum maternal organ oxidative damage and IGF-1 level. Pregnant female rats were pair-fed from Day 2 of gestation until labor with control or ethanol (6.36% (v/v)) liquid diets and were sacrificed 6 weeks after parturition (ethanol withdrawn after parturition). There was no difference in body weight during or after the gestational period between the control and ethanol groups. Litter size was significantly less for ethanol-fed dams. One-week postnatal pup survival was significantly lower in the ethanol-fed (57.1%) than the control (97.8%) group. Liver and kidney tissue IGF-1 levels and mRNA were elevated in the ethanol-fed mothers, accompanied by hepatic but not renal oxidative damage, indicated by profound lipid peroxidation (measured by malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)) and protein carbonyl formation. The levels of glutathione (GSH), glutathione disulfide (GSSG) and GSH/GSSG ratios in liver and kidney were not different between the ethanol-fed and control dams. Collectively, these data suggest that gestational ethanol exposure may lead to postpartum oxidative organ damage and a possible compensatory increase in organ IGF-1 levels.

Animals↗
PubMed2002

Effect of MPTP on Dopamine metabolism in Ames dwarf mice.

Hypopituitary dwarf mice exhibit a heightened antioxidative capacity and live extensively longer than age-matched controls. Importantly, dwarf mice resist peripheral oxidative stress induced by paraquat, and behaviorally, they maintain cognitive function and locomotor activity at levels above those observed in old wild-type animals. We assessed monoaminergic neurotransmitters in nigrostriatal tract and cerebellum after the administration of the dopaminergic neurotoxin, MPTP. There was no significant change in mitochondrial monoamine oxidase (MAO)-B and total MAO activity in the substantia nigra and nucleus caudatus putamen of wild-type and dwarf mice. Coenzymes Q-9 and Q-10 were present in similar quantities, as were dopamine, norepinephrine, and serotonin levels in the cerebellum and nigrostriatal tract. MPTP set off tremor, hind limb abduction, and straub tail behavior and induced significant dopamine depletion in the striatum of both dwarf and normal mice. This study shows that the MAO activity and the coenzyme content of dwarf mice are similar to those of their wild-type controls and hence susceptible to MPTP-induced toxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2002

Impaired cardiac excitation-contraction coupling in ventricular myocytes from Ames dwarf mice with IGF-I deficiency.

Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are involved in the regulation of cardiovascular function. GH/IGF-I deficiency is associated with impaired cardiac performance manifested as reduced left ventricular ejection fraction and diastolic filling. This study was to determine the impact of IGF-I deficiency on single cardiac myocyte excitation-contraction (E-C) coupling. Ventricular myocytes were isolated from adult Ames dwarf mice and age-matched wild-type siblings. Dwarf mice are characterized by severe IGF-I deficiency. Mechanical properties were evaluated using a video edge detection system. Myocytes were electrically stimulated at 0.5 Hz. The contractile properties analysed included peak shortening (PS), time to peak shortening (TPS) and time to 90% relengthening (TR(90)), and maximal velocities of shortening/relengthening (+/-d L/d t). Intracellular Ca(2+) transients were evaluated by fura-2 fluorescence microscopy. Dwarf mice exhibited significantly reduced body and heart weights and severely deficient plasma IGF-I. Myocytes from dwarf mice displayed significantly smaller cell lengths (CLs), prolonged TPS/TR(90) and reduced +/-d L/d t compared with the wild-type littermates. The absolute PS was similar although PS/CL was enhanced in the dwarf group. Myocytes from dwarf animals displayed reduced peak intracellular Ca(2+) levels and slowed intracellular Ca(2+) clearing associated with a comparable resting intracellular Ca(2+). Furthermore, myocytes from the dwarf hearts were equally responsive to an elevation in extracellular Ca(2+) and exhibited an augmented stepwise decrease in response to minimal increase in stimulating frequencies compared with those from the wild-type group. These results suggest that deficiency in IGF-I may be directly associated with cardiac E-C coupling dysfunction at the ventricular myocyte level.

Animals↗
PubMed2002

Effects of growth hormone and insulin-like growth factor-1 on hepatocyte antioxidative enzymes.

The physiological decline that occurs in aging is thought to result, in part, from accumulation of oxidative damage generated by reactive oxygen species during normal metabolic processes. Elevated levels of antioxidative enzymes in liver tissues are present in the Ames dwarf, a growth hormone (GH)-deficient mouse that lives more than 1 year longer than wild-type mice from the same line. In contrast, transgenic mice that overexpress GH exhibit depressed hepatic levels of catalase and have significantly shortened life spans. In this study, we evaluated the in vitro effects of GH and insulin-like growth factor 1 (IGF-1) on antioxidative enzymes in mouse hepatocytes. Hepatocytes were isolated from wild-type mice following perfusion of livers with a collagenase-based buffer. Dispersed cells were plated on Matrigel and treated with rat GH (0.1, 1.0, or 10 microg/ml) or IGF-1 (0.5, 5.0, or 50 nM) for 24 hr. Hepatocytes were recovered and protein was extracted for immunoblotting and enzyme activity assays of catalase (CAT), glutathione peroxidase (GPX), and manganese superoxide dismutase (MnSOD). A 41% and 27% decrease in catalase activity was detected in cells treated with GH, whereas IGF-1 reduced CAT activity levels to a greater extent than GH (P < 0.0001). The activity and protein levels of GPX were also significantly depressed in cells treated with GH, whereas activity alone was decreased in cells treated with IGF-1 (P < 0.04). GH significantly suppressed MnSOD levels by 40% and 66% in 1.0 and 0.1 microg/ml concentrations, respectively. Similarly, IGF-1 decreased MnSOD protein levels (5 nM; P < 0.05). These results suggest that GH and IGF-1 may decrease the ability of hepatocytes to counter oxidative stress. In addition, these experiments provide an explanation for the differing antioxidative defense capacity of GH-deficient versus GH-overexpressing mice, and they suggest that GH is directly involved in antioxidant regulation and the aging process.

Aging↗