ABSTRACT
In the adult mammal the circadian system, which allows predictive adaptation to daily environmental changes, comprises peripheral oscillators in most tissues, commanded by the suprachiasmatic nucleus (SCN) of the hypothalamus. The external environment of the fetus is provided by its mother. In primates, maternal melatonin is a candidate to entrain fetal circadian rhythms, including the SCN rhythms of metabolic activity. We found in the 90% of gestation capuchin monkey fetus expression of the clock genes Bmal-1, Per-2, Cry-2, and Clock in the SCN, adrenal, pituitary, brown fat, and pineal. Bmal-1, Per-2, and the melatonin 1 receptor (MT1) showed a robust oscillatory expression in SCN and adrenal gland, whereas a circadian rhythm of dehydroepiandrosterone sulphate was found in plasma. Maternal melatonin suppression changed the expression of Bmal-1, Per-2, and MT1 in the fetal SCN. These effects were reversed by maternal melatonin replacement. In contrast, neither maternal melatonin suppression nor its replacement had effects on the expression of Per-2 and Bmal-1 or MT1 in the fetal adrenal gland or the circadian rhythm of fetal plasma dehydroepiandrosterone sulphate. Our data suggest that maternal melatonin is a Zeitgeber for the fetal SCN but probably not for the adrenal gland.
Subject(s)
Fetus/metabolism , Gene Expression Regulation, Developmental/physiology , Melatonin/physiology , Trans-Activators/genetics , ARNTL Transcription Factors , Adrenal Glands/physiology , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , CLOCK Proteins , Cebus , Circadian Rhythm/genetics , Circadian Rhythm/physiology , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Dehydroepiandrosterone Sulfate/blood , Female , Hydrocortisone/blood , Nuclear Proteins/genetics , Pregnancy , Receptor, Melatonin, MT1/biosynthesis , Receptor, Melatonin, MT1/genetics , Reverse Transcriptase Polymerase Chain Reaction , Suprachiasmatic Nucleus/physiology , Temperature , Transcription Factors/geneticsABSTRACT
Progesterone in hormone replacement therapy (HRT) preparations increases, while hysterectomy greatly reduces, the incidence of breast cancer. Cross-talk between the progesterone and growth factor signaling pathways occurs at multiple levels and this maybe a key factor in breast cancer survival and progression. To test this hypothesis, we characterized the effect of progesterone pre-treatment on the sensitization of the epidermal growth factor (EGF) signaling pathway to EGF in the breast cancer cell line ZR-75. For the first time in ZR-75 cells and in agreement with previous work using synthetic progestins, we demonstrate that pre-treatment with the natural ligand progesterone increases EGF receptor (EGFR) levels and subsequent ligand-dependent phosphorylation. Downstream we demonstrate that progesterone alone increases erk-1 + 2 phosphorylation, potentiates EGF-phosphorylated erk-1 + 2 and maintains these levels elevated for 24 h; over 20 h longer than in vehicle treated cells. Additionally, progesterone increased the levels of STAT5, another component of the EGF signaling cascade. Progesterone increased EGF mediated transcription of a c-fos promoter reporter and the nuclear localization of the native c-fos protein. Furthermore, progesterone and EGF both alone and in combination, significantly increase cell proliferation. Several results presented herein demonstrate the conformity between the action of the natural ligand progesterone with that of synthetic progestins such as MPA and R5020 and allows the postulation that the progestin/progesterone-dependent increase of EGF signaling provides a survival advantage to burgeoning cancer cells and may contribute to the breast cancer risk associated with endogenous progesterone and with progestin-containing HRT.
Subject(s)
Breast Neoplasms/metabolism , Epidermal Growth Factor/drug effects , ErbB Receptors/metabolism , Progesterone/pharmacology , Breast Neoplasms/pathology , Cell Line, Tumor/drug effects , Cell Proliferation/drug effects , Female , Gene Expression Regulation, Neoplastic , Humans , Phosphorylation/drug effects , Progesterone/administration & dosage , Signal Transduction/drug effectsSubject(s)
Myocardial Infarction/epidemiology , Age Factors , Aged , Cohort Studies , Emergency Service, Hospital , Female , Humans , Male , Middle Aged , Risk Factors , Seasons , Sex Factors , Smoking/adverse effects , Time FactorsABSTRACT
No disponible
Subject(s)
Middle Aged , Aged , Male , Female , Humans , Risk Factors , Seasons , Tobacco Use Disorder , Sex Factors , Time Factors , Cohort Studies , Myocardial Infarction , Age Factors , Emergency Service, HospitalABSTRACT
In this study, we examined the effects of interleukin-10 (IL-10) on the outcome of experimental cerebral malaria (CM), a lethal neurological syndrome that occurs in susceptible strains of mice after infection with Plasmodium berghei ANKA (PbA). Constitutive IL-10 mRNA levels were significantly higher in the spleen and brain of resistant animals. In vivo neutralization of endogenous IL-10 in CM-resistant mice induced the neurological syndrome in 35.7% of these mice, as opposed to 7.7% in controls. IL-10 inhibited PbA antigen-specific interferon-gamma (IFN-gamma) production in vitro but not tumour necrosis factor (TNF) serum levels in vivo. Susceptible mice, on the other hand, were significantly protected against CM when injected with recombinant IL-10. Overall, our findings suggest that IL-10 plays a protective role against experimental cerebral malaria.
