Interleukin-4 is a neutrophil activator

We investigated the ability of the lymphokine, interleukin-4 (IL-4), to function as a neutrophil (PMN) activator. IL-4 enhanced PMN-mediated killing of opsonized bacteria (by up to 91.6% at 3 units of IL-4; p less than 0.05). IL-4 was a weak secondary granule secretagogue and did not by itself generate a respiratory burst. However, IL-4 did increase in a dose-dependent fashion the respiratory burst mediated by the peptide formyl-methionyl-leucyl-phenylalanine (10(-7) mol/L). Maximal potentiation of PMN activity occurred at 100 units of IL-4 (6.3 nmol superoxide produced without IL-4 to 9.8 nmol at 100 units; p less than 0.01). Enhancement of the respiratory burst was not a generalized phenomenon, since IL-4 did not potentiate the respiratory burst mediated by either phorbol myristate acetate, calcium ionophore A23187, or zymosan-treated serum. Similarly, IL-4 potentiated the formyl-methionyl-leucyl-phenylalanine-stimulated secretion of both lysozyme (40.2%) and beta-glucuronidase (108.2%). Finally, IL-4 was demonstrated to enhance the ability of PMN to phagocytose sheep erythrocytes opsonized with rabbit IgG (by up to 94.2% at 30 units of IL-4). This increased phagocytosis correlated with the recruitment of a population of PMNs that did not phagocytose targets in the absence of IL-4. In conclusion, IL-4 enhanced neutrophil-mediated bactericidal activity. This increase may have occurred secondary to the stimulation of phagocytosis by IL-4 or by potentiation of degranulation and the respiratory burst.     

Effects of high-intensity exercise on leptin and testosterone concentrations in well-trained males

Objective: A number of investigations have examined the effect of exercise on leptin concentrations, because leptin is associated with obesity, satiety, and reproductive function. High-intensity exercise is known to increase testosterone, an inhibitor of leptin. The objective of the study was to determine whether the leptin responses to a progressive, intermittent exercise protocol were related to serum testosterone concentrations. Most previous studies have examined leptin responses to low or moderately high exercise intensities. A second objective was to determine whether leptin responses were different than previous experiments using intermittent moderate and high-intensity exercise. Methods: Well-trained runners completed strenuous intermittent exercise consisting of treadmill running at 60, 75, 90, and 100% VO _2max and a subsequent resting control trial was also conducted. Results: There were significant increases in mean serum levels of leptin and testosterone with both quickly returning to baseline during recovery, but no relationship between the two hormones was found. After examining individual data for both hormones, it was discovered that subjects could be classified as leptin responders or nonresponders, whereas testosterone increased in all subjects. Responders had elevated serum leptin levels at baseline and exhibited increases after high-intensity exercise, whereas nonresponders did not show changes in leptin during exercise. Conclusions: Data suggest testosterone levels do not acutely affect leptin responses to exercise or 1-h of recovery. Moreover, varied leptin responses to intense exercise in comparable well-trained runners was observed and was associated with baseline leptin concentrations.     

MRI compatible MS2 nanoparticles designed to cross the blood–brain-barrier: providing a path towards tinnitus treatment

Fundamental challenges of targeting specific brain regions for treatment using pharmacotherapeutic nanoparticle (NP) carriers include circumventing the blood–brain-barrier (BBB) and tracking delivery. Angiopep-2 (AP2) has been shown to facilitate the transport of large macromolecules and synthetic nanoparticles across the BBB. Thus, conjugation of AP2 to an MS2 bacteriophage based NP should also permit transport across the BBB. We have fabricated and tested a novel MS2 capsid-based NP conjugated to the ligand AP2. The reaction efficiency was determined to be over 70%, with up to two angiopep-2 conjugated per MS2 capsid protein. When linked with a porphyrin ring, manganese (Mn²⁺) remained stable within MS2 and was MRI detectable. Nanoparticles were introduced intracerebroventricularly or systemically. Systemic delivery yielded dose dependent, non-toxic accumulation of NPs in the midbrain. Design of a multifunctional MRI compatible NP platform provides a significant step forward for the diagnosis and treatment of intractable brain conditions, such as tinnitus.     

Effect of estrogen on serum DHEA in younger and older women and the relationship of DHEA to adiposity and gender

This case-controlled study consisted of 2 parts. The objective of part 1 was to determine the relationship between DHEA, body mass index (BMI), and age in young males, young females, and postmenopausal (PM) females. Part 2 examined the effects of estrogen on DHEA by analyzing the relationship between DHEA and age in young females on and off oral contraceptives (OCs) and PM females on and off estrogen or hormone replacement therapy (ERT/HRT). The study was performed at the Obstetrics and Gynecology Clinic, Texas Tech Health Sciences Center-Amarillo, Exercise Physiology Laboratory at Southeastern Louisiana University, and Woman's Health Research Institute, Woman's Hospital, Baton Rouge, LA. Part 1 groups consisted of: (1) young males between the ages of 18 to 40 years; (2) normally cycling females off OCs, ages 18 to 40 years; and (3) PM females older than 40 years not receiving ERT/HRT. Part 2 groups consisted of: (1) normally cycling females on OCs, ages 18 to 40 years;, (2) normally cycling females off OCs, ages 18 to 40 years; (3) PM females 50 years or older not receiving ERT/HRT; and (4) PM females 50 years or older receiving ERT/HRT. The main outcome measure was serum DHEA concentrations. For part 1, there were significant (P <.05) inverse relationships between DHEA and age for young males; young females, off OCs; PM females, no ERT/HRT r = -.44, -.26, and -.25, respectively. There were no significant relationships between DHEA and BMI for any of the groups. DHEA concentrations were significantly higher in young males than young females even after accounting for age. For part 2, DHEA concentrations were significantly higher in young females off OCs compared with young females on OCs, and significantly higher in PM women off ERT/HRT than those on ERT\HRT. There were significant inverse relationships between DHEA and age for young females and PM females on and off ERT/HRT. From these findings, we conclude that there is an inverse relationship between DHEA and age for young males, young females off OCs, and PM females, no ERT/HRT. No relationship between BMI and DHEA was observed in these same 3 groups. These results agree with previous findings in young men, but differ from previous findings in obese young females. The data also suggest that estrogen treatment (OCs and ERT/HRT) suppresses DHEA concentrations in premenopausal and PM females, and that DHEA declines with age in PM females regardless of estrogen treatment.     

Impact of the selective serotonin reuptake inhibitor citalopram on insulin sensitivity, leptin and basal cortisol secretion in depressed and non-depressed euglycemic women of reproductive age.

INTRODUCTION: Major depression in women of reproductive age may be accompanied by multiple endocrine and metabolic disturbances, which, in turn, may affect reproductive functioning. Enhanced cortisol synthesis, impaired leptin production and diminished insulin sensitivity have been reported in some depressed populations. We sought to determine whether an 8-week administration of citalopram would have an effect on these endocrine factors in a group of euglycemic depressed and non-depressed women of reproductive age. MATERIALS AND METHODS: Fourteen depressed and 18 non-depressed women (diagnosed by structured clinical interview) aged between 18 and 45 years completed an 8-week study. All depressed women were treated with citalopram and non-depressed subjects randomized to citalopram or no treatment in an open label cohort study. An oral glucose tolerance test with insulin levels was performed at baseline and at the end of the 8-week trial. Weight, blood pressure, fasting serum cortisol, fasting serum leptin and Beck Depression Inventory were assessed at baseline, 2, 4 and 8 weeks. RESULTS: Citalopram significantly improved depressive symptoms and Beck Depression Inventory scores in the depressed cohort. Cortisol production was higher in depressed women but did not diminish with citalopram therapy over 8 weeks. Indices of insulin sensitivity and leptin production were similar between depressed and non-depressed women and did not change despite citalopram therapy. CONCLUSION:. Insulin sensitivity in moderately depressed women of reproductive age does not differ from that in a similar group of non-depressed women. Insulin sensitivity, cortisol secretion and leptin production do not change significantly in depressed women following an 8-week course of citalopram despite substantial improvement in depression scores.     

Bioengineering embryonic stem cell microenvironments for exploring inhibitory effects on metastatic breast cancer cells

The recreation of an in vitro microenvironment to understand and manipulate the proliferation and migration of invasive breast cancer cells may allow one to put a halt to their metastasis capacity. Invasive cancer cells have been linked to embryonic stem (ES) cells as they possess certain similar characteristics and gene signatures. Embryonic microenvironments have the potential to reprogram cancer cells into a less invasive phenotype and help elucidate tumorigenesis and metastasis. In this study, we explored the feasibility of reconstructing embryonic microenvironments using mouse ES cells cultured in alginate hydrogel and investigated the interactions of ES cells and highly invasive breast cancer cells in 2D, 2&1/2D, and 3D cultures. Results showed that mouse ES cells inhibited the growth and tumor spheroid formation of breast cancer cells. The mouse ES cell microenvironment was further constructed and optimized in 3D alginate hydrogel microbeads, and co-cultured with breast cancer cells. Migration analysis displayed a significant reduction in the average velocity and trajectory of breast cancer cell locomotion compared to control, suggesting that bioengineered mouse ES cell microenvironments inhibited the proliferation and migration of breast cancer cells. This study may act as a platform to open up new options to understand and harness tumor cell plasticity and develop therapeutics for metastatic breast cancer.     

Leptin and thyroxine during sexual development in male monkeys: effect of neonatal gonadotropin-releasing hormone antagonist treatment and delayed puberty on the developmental pattern of leptin and thyroxine secretion

OBJECTIVE: Neonatal treatment of male monkeys with a gonadotropin-releasing hormone antagonist (Ant) increased the incidence of delayed puberty. Using blood samples that had been collected from monkeys with normal or delayed puberty, we assessed the potential involvement of leptin and thyroxine (T4) in sexual development. DESIGN AND METHODS: Monkeys were treated from birth until 4 months of age with vehicle, Ant or Ant/androgen and blood samples were drawn from 10 to 62 months of age. RESULTS: Serum leptin and total T4 concentrations declined in parallel throughout adolescence in all treatment groups. There was no transient rise in leptin before or in association with the onset of puberty. Also, leptin did not differ during the peripubertal period between animals experiencing puberty at that time versus those in which puberty was being delayed. Neonates treated with Ant either alone or with androgen replacement had higher leptin levels than controls throughout development. While leptin exhibited no significant changes during the peripubertal period, T4 values increased and declined in parallel with the peripubertal changes in hypothalamic-pituitary-testicular activity. CONCLUSIONS: These data do not support the concept that a transient rise in leptin triggers the onset of puberty in male monkeys. However, the disruption of neonatal activity of the pituitary-testicular axis alters the developmental pattern of leptin. The changes in T4 levels during the peripubertal period suggest that thyroid status may be a significant contributor to the process of sexual development in the male monkey and that peripubertal changes in secretion of this hormone may serve as an effective physiological response during a critical period of elevated energy expenditure.     

Pubertal endocrinology of the baboon: elevated somatomedin-C/insulin-like growth factor I at puberty

Previous data suggested an increase in the rate of weight gain and linear growth in the baboon between 3 and 4 yr of age, similar to the pubertal growth spurt in man. In this cross-sectional study, radioimmunoassayable concentrations of somatomedin-C/insulin-like growth factor I(SM-C/IGF-I) were compared in prepubertal (less than 3 yr), pubertal (3-4 yr), and adult (greater than 10 yr) animals. SM-C/IGF-I concentrations in prepubertal males (0.97 +/- 0.10 U/ml) were low and were not different from those in prepubertal females (0.98 +/- 0.15 U/ml). Between 3 and 4 yr, SM-C/IGF-I increased significantly in both sexes (8.87 +/- 0.74 and 5.27 +/- 0.52 U/ml, male and female, respectively) and decreased (5.92 +/- 1.2 and 2.75 +/- 0.13 U/ml, respectively) in animals greater than 10 yr of age. Sex differences were significant in the 3- to 4-yr-old animals (male greater than female, P less than 0.001). The pubertal elevation in SM-C/IGF-I concentrations is coincident with increases in indices of somatic growth and sexual maturation in the baboon. These and other data suggest that this animal may be an appropriate model for studies to define hormonal mechanisms of pubertal growth.