Biomedical subjects

Susan N Perkins

Publications and source records attributed to Susan N Perkins.

25 records · Page 2Linked to original sources

PubMed2003

Exercise and intestinal polyp development in APCMin mice.

PURPOSE: Epidemiological evidence suggests that physical activity protects against colon cancer. We previously used a mouse predisposed to intestinal polyps (APCMin) to evaluate this association and found the suggestion of fewer polyps in exercised males but not females. The present study was designed to further explore the potential exercise x sex interaction on polyp development and to begin to look at potential mechanisms. METHODS: Six-week-old APCMin mice (N = 60 males; 60 females) were randomly assigned to one of two groups by sex: treadmill running at 20 m.min-1, 5% grade, 45 min.d-1, 5 d.wk-1 (EX) or nonrunning controls (CON) (N = 30 per group). EX mice ran in running wheels while in quarantine (weeks 0-3), followed by treadmill running weeks 3-8. Body weights were measured weekly. Urine was collected at 5 wk and fasting blood at 7.5 wk. Body composition was measured, serum was frozen, and polyp number and size were measured at sacrifice. RESULTS: EX resulted in lower body weights (P < 0.01) and reduced fat mass (P < 0.01). Fasting glucose was lower in EX (P < 0.01), and leptin was lower in EX (P = 0.05) compared with CON. EX did not affect serum insulin-like growth factor-1 or urinary corticosterone. Total polyp number and size were not statistically different between groups; however, there were fewer jejunal polyps in EX (3.6 +/- 0.7, mean +/- SE) versus CON males (5.2 +/- 0.8; P = 0.04) and an even larger difference when only the consistent runners were kept in the analysis (2.7 +/- 0.5 in EX; P = 0.01). CONCLUSION: Despite favorable changes in body composition, blood glucose, and leptin, 8 wk of running resulted in only minor changes related to polyp development in male but not female APCMin mice.

Animals↗

PubMed2003

Effect of raloxifene on insulin-like growth factor-I, insulin-like growth factor binding protein-3, and leptin in premenopausal women at high risk for developing breast cancer.

Elevated insulin-like growth factor I (IGF-I) is associated with an increased risk for developing breast cancer in premenopausal women, whereas lower leptin levels have been documented in premenopausal breast cancer cases. We determined the effect of raloxifene on IGF-I, insulin-like growth factor binding protein 3 (IGFBP-3), and leptin in premenopausal women at high risk for developing invasive breast cancer. Twenty-eight premenopausal women (median age 43 years) participating in a pilot breast cancer prevention trial provided 56 matched serum samples. Specimens were collected at baseline and after treatment with 60 mg of raloxifene daily. Median treatment duration was 3 months (range: 6 weeks to 12 months). Samples were frozen at -70 degrees C until analysis. IGF-I, IGFBP-3, and leptin were measured by ELISA. Significance was evaluated by the Wilcoxon signed rank test. Raloxifene administration increased serum IGFBP-3 [mean change 245 ng/ml; P = 0.017; 95% confidence interval (CI), 76-415] and leptin (mean change 2.1 ng/ml; P = 0.005; 95% CI, 0.6-3.7). No significant change in serum IGF-I was detected (mean change 2.6 ng/ml; P = 0.84; 95% CI, -15.4 to 20.6). IGF-I:IGFBP-3 molar ratio was stable (mean change -0.014; P = 0.30; 95% CI, -0.041 to 0.012). Raloxifene administration is associated with an increase in IGFBP-3 and leptin in premenopausal high risk women. Increases in IGFBP-3 may potentially decrease the activity of circulating IGF-I. The effect of modulating the IGF pathway and leptin on breast cancer risk needs additional evaluation.

Administration, Oral↗

PubMed2002

Nickel(II)-induced apoptosis in murine T cell hybridoma cells is associated with increased fas ligand expression.

Nickel(II) exposure has multiple effects on the immune system, including thymic involution, decreased T cell number in the spleen, and decreased natural killer cell activity. Using a murine T cell hybridoma cell line (KMls 8.3.5.1) to model nickel-induced cell death in immune cells, we found that nickel(II) acetate treatment rapidly induced apoptosis in these cells, as signified by membrane blebbing, chromatin condensation, increased annexin V staining, and an increased proportion of cells with hypodiploid DNA. Preceding these morphological changes, nickel(II) treatment increased expression of Fas ligand (FasL) mRNA and protein levels and also increased caspase-3-like protease activity. Coincubation with caspase inhibitors markedly inhibited nickel(II)-induced apoptosis, with Z-IETD-FMK, an inhibitor of caspase-8 and granzyme B, nearly as effective as less selective caspase inhibitors. Agents that generate reactive oxygen species (ROS) cause apoptosis in a variety of cells by inducing expression of FasL. Given that nickel(II) can directly generate ROS, exposure to nickel(II) may lead to apoptosis through a similar mechanism.

Animals↗

PubMed2002

Modulation of cyclophilin gene expression by N-4-(hydroxyphenyl)retinamide: association with reactive oxygen species generation and apoptosis.

To explore the mechanisms underlying the pro-apoptotic effects of the synthetic retinoid N-4-(hydroxyphenyl)retinamide (4-HPR) on LNCaP human prostate cancer cells, we used the differential display-polymerase chain reaction (DD-PCR) technique to identify 4-HPR-responsive genes. RNA extracted from LNCaP cells that had been treated for 24 h with 4-HPR at a dose (2.5 microM) optimal for apoptosis induction was used for DD-PCR analysis using random primers. A differentially expressed 115 bp fragment was cloned and sequenced and then identified in GenBank as having a high degree of homology with several members of the cyclophilin gene family. Northern blot analyses using specific probes for cyclophilin A, cyclophilin D, and the cloned 115-bp fragment were performed on RNA extracted from LNCaP cells and MCF-7 human breast cancer cells treated with 4-HPR, N-acetylcysteine (NAC, an anti-oxidant), 4-HPR plus NAC, cyclosporin A, R-1881 (a synthetic androgen), dehydroepiandrosterone, all-trans retinoic acid, or prednisone. 4-HPR downregulated the transcript detected by the 115-bp fragment. Expression patterns detected by the 115-bp fragment and cyclophilin D probes were identical in response to each treatment; none of these treatments affected cyclophilin A expression. Furthermore, expression of mRNA transcripts detected by the 115-bp fragment and cyclophilin D probes correlated with the generation of reactive oxygen species (ROS), as detected by measurement of 2,7-dichlorofluorescein oxidation. Therefore, members of the cyclophilin gene family, such as cyclophilin D (a component of the mitochondrial permeability transition pore previously linked with oxidative stress and apoptosis), may play a role in the ROS-mediated apoptotic effects of 4-HPR.

Antineoplastic Agents↗

PubMed2002

Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice.

Heterozygous p53-deficient (p53(+/-)) mice, a potential model for human Li-Fraumeni Syndrome, have one functional allele of the p53 tumor suppressor gene. These mice are prone to spontaneous neoplasms, most commonly sarcoma and lymphoma; the median time to death of p53+/- mice is 18 months. We have shown previously that juvenile-onset calorie restriction (CR) to 60% of ad libitum (AL) intake delays tumor development in young p53-null (-/-) mice by a p53-independent and insulin-like growth factor 1 (IGF-1)-related mechanism. To determine whether CR is effective when started in adult p53-deficient mice, and to compare chronic CR with an intermittent fasting regimen, male p53+/- mice (7-10 months old, 31-32 mice/group) were randomly assigned to the following regimens: (i) AL (AIN-76A diet), (ii) CR to 60% of AL intake or (iii) 1 day/week fast. Food availability on non-fasting days was controlled to prevent compensatory over feeding. Relative to the AL group, CR significantly delayed (P = 0.001) the onset of tumors in adult mice, whereas the 1 day/week fast caused a moderate delay (P = 0.039). Substantial variation in longevity and maximum body weight within treatments was not correlated with variation in growth characteristics of individual mice. In a separate group of p53+/- mice treated for 4 weeks (n = five mice per treatment), plasma IGF-1 levels in CR versus AL mice were reduced by 20% (P < 0.01) and leptin levels were reduced by 71% (P < 0.01); fasted mice had intermediate levels of leptin and IGF-1. Our findings that CR or a 1 day/week fast suppressed carcinogenesis-even when started late in life in mice predestined to develop tumors due to decreased p53 gene dosage-support efforts to identify suitable interventions influencing energy balance in humans as a tool for cancer prevention.

Animals↗

PubMed2001

Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans.

Calorie restriction (CR) is the most effective and reproducible intervention for increasing lifespan in a variety of animal species, including mammals. CR is also the most potent, broadly acting cancer-prevention regimen in experimental carcinogenesis models. Translation of the knowledge gained from CR research to human chronic disease prevention and the promotion of healthy aging is critical, especially because obesity, which is an important risk factor for several chronic diseases, including many cancers, is alarmingly increasing in the Western world. This review synthesizes the key biological mechanisms underlying many of the beneficial effects of CR, with a particular focus on the insulin-like growth factor-1 pathway. We also describe some of the opportunities now available for investigations, including gene expression profiling studies, the development of pharmacological mimetics of CR, and the integration of CR regimens with targeted, mechanism-based interventions. These approaches will facilitate the translation of CR research into strategies for effective human chronic disease prevention.

Aging↗

PubMedDate not supplied

Phenotypic effects of calorie restriction and insulin-like growth factor-1 treatment on body composition and bone mineral density of C57BL/6 mice: implications for cancer prevention.

BACKGROUND: Calorie restriction (CR) inhibits carcinogenesis and delays aging. Some anti-carcinogenic effects of CR are mediated by decreased circulating insulin-like growth factor-1 (IGF-1); however, IGF-1 also plays an important role in regulating growth and bone density. MATERIALS AND METHODS: We quantified tradeoffs involving the CR/IGF-1 axis in C57BL/6 mice by examining body composition and bone characteristics in ad libitum fed, 20, 30 or 40% CR mice that received placebo or recombinant murine IGF-1 delivered with a time-release pellet. After 26 days, carcasses were scanned with a PIXImus II dual-energy X-ray absorptiometer. RESULTS: CR reduced body weight and percent body fat and had non-linear effects on bone density. IGF-1 restored bone density to control levels or greater in the CR mice. CONCLUSION: Cancer prevention efforts based on CR and down-regulation of the IGF-1 pathway will require consideration of deleterious effects on bone.

Absorptiometry, Photon↗